First-line Therapy Research Articles

One-year effectiveness and safety outcomes of edoxaban treatment in Chinese patients with atrial fibrillation: First snapshot of more than 4,800 patients from the ETNA-AF-China study

Abstract Background Direct oral anticoagulants (DOACs) have become the first-line therapy for ischaemic stroke prevention in atrial fibrillation (AF) patients. Data on the effectiveness and safety of single DOAC in large Chinese populations are scarce. Purpose We firstly present the one-year outcome data of edoxaban treatment in 5001 Chinese AF patients. Methods This is a multi-centre, prospective, observational study, ETNA-AF-China, conducted in 89 centres from four economic regions in Mainland of China with a follow-up of two years. Primary endpoint of safety [bleeding events including intracranial hemorrhage (ICH), all-cause and cardiovascular (CV) mortality] and efficacy endpoints [stroke, systemic embolic events (SEE), transient ischemic attack (TIA)] were adjudicated. Annualised event rates and Kaplan­Meier (KM) survival curves are given. Results A total of 4822 patients (57.1% male) using edoxaban (60 mg OD: n=2614, 30 mg OD: n=2208) who completed one-year follow-up were included in the full analysis set. The mean (SD) age of the overall patient population was 70.3 (9.5) years, CHA2DS2-VASc and HAS-BLED scores were 2.9 (1.4), 1.7 (1.0), with creatinine clearance (CrCl) of 71.2 (27.7) mL/min. Patients receiving 30 mg OD edoxaban at baseline were older (73.4 vs 67.7 years), with higher CHA2DS2-VASc score (3.3 vs 2.6), larger percentage of frail (9.9% vs 3.4%), and higher renal impairment (defined as CrCl ≤80 mL/min, 70.3% vs 42.9%). Annualised rates for all-cause and cardiovascular death in the overall population were very low with 2.22%/year and 0.41%/year, respectively. (Figure 1) The death rates were nearly three times lower in those receiving standard dose (60 mg) than reduction dose (30 mg) of edoxaban. Annualised event rates for all stroke/SEE (1.03%/year) and ischemic stroke (0.60%/year) were similar between two dose groups. Overall, annualised rates for major bleeding (1.03%/year), ICH (0.18%/year), major gastrointestinal (GI) bleeding (0.48%/year) events were relatively low, and those on 60 mg dose experienced less above bleeding events. Cumulative survival analysis demonstrated a slow increase in time-to-first event curve of all-cause death; and from baseline to 1-year follow-up, significant lower events of all-cause death (log-rank p<0.001), major bleeding (p=0.002) in 60 mg vs 30 mg edoxaban groups. (Figure 2). Conclusion Low incidences of major bleeding, notably ICH, major GI bleeding, and CV death were observed in unselected 4822 patients with AF during 1-year of edoxaban treatment. These findings confirm the effectiveness and safety of routine edoxaban use in China, consistent with other countries, and reinforce the results of the ENGAGE AF-TIMI 48 trial.Figure 1Figure 2

#2041 Analysis of current real-world management of IgAN in five European countries

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Due to the often progressive nature of IgAN, patients generally face a poor prognosis if the condition is not appropriately controlled. Current treatment recommendations focus on disease management through the use of optimised supportive care, including use of an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB). A physician questionnaire and patient chart review was conducted to investigate the real-world management of IgAN in five European countries. Method Between 21 December 2022 and 6 February 2023, physicians from France, Germany, Italy, Spain and the UK completed a questionnaire on IgAN management, and patient charts from their centres were analysed. Physicians included had to spend >40% of their time in a clinical setting, and have been in practice between 2 and 40 years. Physicians had to have ≥50 CKD stage 1–4 patients under their management, including ≥4 non-dialysis IgAN patients. Patient charts included in the analysis were required to be from patients ≥12 years of age, diagnosed with IgAN and not on dialysis, with an estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73 m2. Results A total of 261 physicians answered the questionnaire on IgAN management and completed chart audits on 473 of their most recently seen patients. Charts included in the audit were predominantly from male (71%), Caucasian (78%) patients. The mean age of patients was 47 years and 76% were in CKD stage 3 or later. At referral, 66% of patients were receiving an ACEi and/or ARB, 21% were receiving another antihypertensive agent and 6% were taking a sodium-glucose cotransporter 2 inhibitor (SGLT2i). Most patients (88%) had undergone ≥1 kidney biopsy. At the time of initial biopsy, average eGFR was 51.0 mL/min/1.73 m2 and proteinuria was 2.7 g/day. Of patients who had a biopsy, 73% had a mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C) (MEST-C) score available. Due to biopsy results, 29% of patients initiated systemic steroids and 10% started an SGLT2i. On average, IgAN patients are prescribed five medications, with the number of medications increasing with age. The large majority of patients (92%) were taking an ACEi and/or ARB at the time of the most current visit; prescriptions with an ACEi and/or ARB included combination with an SGLT2i only (36%), with a systemic steroid only (10%), and with both an SGLT2i and a systemic steroid (5%). Less than half (41%) of patients were prescribed an ACEi and/or ARB alone. An ACEi and/or ARB were considered first-line therapy by 81% of physicians. Systemic steroids and SGLT2is were largely thought of as later line treatment options. The majority of physicians (66%) believed that their patients were completely adherent to their treatment regimen. Notably, over one-third (35%) of patients were on second-line therapy or later, with drivers of treatment change including increased proteinuria (31%), decreased eGFR (26%) and side effect management (15%). Over half (54%) of physicians were not completely satisfied with their patients’ overall response to treatment. Physicians anticipated that 74% of their patients would eventually progress to dialysis. Conclusion Many treating physicians are not satisfied with current treatment options for IgAN, with increasing levels of proteinuria, eGFR decline and side effects driving treatment change. Overall, this study indicates that there is a need for more effective and safe treatments for IgAN to prevent disease progression and improve prognosis.

#1028 Experience with ravulizumab in atypical hemolytic uremic syndrome

Abstract Background and Aims The arrival of eculizumab revolutionized the treatment of Atypical Hemolytic Uremic Syndrome (aHUS). Ravulizumab also offers C5 inhibition, but with 3-4 times longer half- life. We describe the experience with ravulizumab in patients with aHUS in two scenarios: 1. Switching from another C5 inhibitor in stable patients; 2. Direct initiation of therapy with ravulizumab (naïve). Method We present 9 patients with an average age of 42 ± 13 years and weight of 81 ± 12.4 kg. The switch to ravulizumab was initiated 2 weeks after the last dose of eculizumab in switch patients, while in naïve patients it was initiated after excluding other causes of aHUS. The initial dose was 2700 mg, followed by a second dose of 3300 mg after 2 weeks, and subsequently every 2 months. Analytical variables of renal function, hematological parameters, and complement were collected. Results Switch : 6 patients (50% females), 4/6 were transplant recipients (3 on prophylactic treatment). Regarding renal function, 5/6 patients had a complete response with eculizumab (creatinine 1.33 ± 0.32 mg/dL, eGFR 59.5 ± 34.3 mL/min/1.73 m2, proteinuria 115 ± 91.5 mg/g), and all of them had a complete hematological response. After the switch, all patients maintained a complete hematological response, stability of renal function, and serum complement levels. Naïve : 3 cases (2 males); 2/3 required hemodialysis (HD) at presentation. The renal response was complete in two patients and partial in the third (who discontinued HD after 90 days and currently remains stable with stage G3b chronic kidney disease). All three patients had a complete hematological response. Only 3 adverse effects were documented (arthralgia, headache, and rhinitis), with no cases of infection. Conclusion The use of ravulizumab is effective both in maintaining a complete response after switching from eculizumab and as a first-line therapy. The safety profile is comparable, with the main difference being the dosing regimen, as ravulizumab requires fewer administrations and leads to a reduction in direct and indirect costs.

#1283 Rituximab in addition to plasma exchange, cyclophosphamide and steroids for treatment of anti-GBM disease

Abstract Background and Aims Anti-GBM disease is a rare antibody-mediated vasculitis, usually treated with plasma exchange (PEX), cyclophosphamide (CYC) and steroids. There are limited data regarding the use of B-cell depleting therapies such as rituximab (RTX). We investigate the use of the addition of rituximab for the treatment of Anti-GBM disease. Method Ten-year (2012-2023) single-centre retrospective cohort study of patients with anti-GBM disease treated with or without rituximab, in addition to standard care, as first-line therapy. A Cox-proportional hazards regression model incorporating age, sex, ANCA status, dialysis need at presentation, lung haemorrhage, CYC (oral or IV) and RTX treatment was used to identify disease/treatment factors associated with outcome (death, end-stage kidney disease [ESKD], infection). Results Forty-five patients are included; baseline demographics, disease characteristics, treatments and outcomes are summarised in Table 1. In the Cox regression model, only increasing age was associated with risk of death (HR 1.08 [95% CI 1.02-1.17]). Age (HR 1.04 [1.01-1.08]), female sex (HR 4.93 [1.80-4.87]), and dialysis need at presentation (HR 5.28 [1.54-17.53]) were associated with ESKD-risk. Increasing age (HR 1.04 [1.00-1.09] and ANCA positivity (HR 3.08 [1.14-8.71]) were associated with risk of infection. The addition of rituximab was not significantly associated with risk of death (HR 0.82 (0.24-2.87), ESKD (HR 1.54 [0.64-3.96]) or infection 2.06 [0.67-5.71]. Conclusion Addition of rituximab to standard treatment for anti-GBM disease was not associated with improved renal outcome or survival benefit. However, rituximab use permitted lower cumulative doses of CYC and reduction in the number of PEX, without an increased risk of infection. Rituximab may have a role as a CYC- and PEX-sparing treatment in patients with anti-GBM disease.

In vitro interaction of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen in the asexual blood stage of Plasmodium falciparum 3D7.

Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.

#988 Peritoneal dialysis related peritonitis: insights from a long-term analysis of an Italian center

Abstract Background and Aims Peritonitis is a common and severe complication of peritoneal dialysis (PD). For comparative analysis standardized definitions are crucial, but most studies have been used heterogenous methods to measure outcomes. The ISPD 2022 guidelines have revised and clarified numerous definitions and proposed new peritonitis categories. Thus, deeper comprehension concerning the incidence, prevalence, and outcome of cause- and time specific peritonitis in contemporary cohorts is required. Method Between 1st January 2009 and 31st May 2023, 267 patients who started PD at our institution were included in the study (Tab. 1). All PD-related peritonitis episodes that occurred in our unit during the study period were collected. The new definitions and outcomes of ISPD 2022 recommendations were employed. Results During the study period 113 patients (42.3%) experienced 219 peritonitis (Tab. 2). The overall peritonitis rate was 0.25 episode/patient year. During the study period, 230 patients (88.5%) discontinued the dialytic technique; among them 122 were transferred to HD. Peritonitis represented the main cause of hemodialysis (HD) transfer (35.2%). Patient cumulative probability of remaining peritonitis-free at one year was 84.2%. The initial antibiotic regimen (cefazolin in association with tobramycin ip) was effective in 131 episodes (141/219, 64.3%), while the medical cure and refractory peritonitis rates were equal to 70.3 and 22.4%, respectively. The rates of peritonitis associated death, HD transfer, catheter removal and hospitalization were 6.8%, 18.3%, 18.7% and 64.4%, respectively. Relapsing, repeat, recurrent and enteric peritonitis accounted for 7.8%, 6.8%, 4.1% and 2.7% of all episodes, respectively. Catheter insertion, catheter related and pre-PD peritonitis were 4.2, 2.1 and 0.5%. Gram-positive and Gram-negative bacteria accounted for 74.1% and 21.3% of peritonitis, respectively. Initial antibiotic regimen was more effective in Gram-positive (76.4%) than Gram-negative (35.1%) microorganisms (p < 0.0001). Culture-negative peritonitis accounted for 25.6% of all specimens. In comparison with positive-culture peritonitis, culture-negative episodes showed a higher medical cure rate (88.4%, 46/52 vs 68.9%, 104/151; p < 0.01) and were significantly less likely to be complicated by hospitalization (48.1%, 25/52 vs 72.2%, 109/151; p < 0.05), catheter removal (9.6%, 5/52 vs 22.5%, 34/151; p < 0.05), HD transfer (9.6%, 5/52 vs 21.9%, 33/152; p < 0.05) and death (0%, 0/52 vs 8.6%, 13/151, p < 0.05). However, initial antibiotic regimen response was similar between culture-negative and culture-positive episodes (71.2%, 37/52 vs 62.3%, 94/151, p = ns). Rates of relapsing, repeat and recurrent peritonitis were 0.023, 0.018 and 0.011 episode/patient-year, respectively accounting for 7.8, 6.8 and 4.1% of all episodes The composite outcome of either catheter removal or death due to peritonitis was higher in relapsing (42.1%, 8/19, p < 0.05) and recurrent (44.4%, 4/9, p < 0.05) episodes than generic peritonitis (19.1%, 34/178) but similar to repeat peritonitis (3/15, 20%, p = ns). Although peritonitis from enteric causes represented only 2.7% of all episodes, they needed catheter removal in one-third of events (33.3%) and caused patient death (66.6%) in the remaining cases. Conclusion Although representing the leading cause of HD transfer cause, more than 50% of incident PD patients never experienced peritonitis. Carrying a worse outcome than generic peritonitis, entities such as relapsing, recurrent and enteric peritonitis should be aggressively treated. Conversely, culture-negative peritonitis showed a better prognosis as compared to positive-culture episodes. However, aiming at the prevention of microbial resistances, the reduction of culture-negative cases is necessary to minimize patient exposure to empiric therapy with multiple antibiotics. In our experience first-line empirical antibiotic therapy was effective in almost 65% of the cases. Nevertheless, the efficacy of this regimen was unsatisfactory in Gram-negative microorganisms requiring further microbiological and pharmacokinetic evaluation.

#2920 Peritoneal dialysis for volume overload in heart failure: a single-center experience

Abstract Background and Aims While diuretics are considered the first-line therapy to control volume overload in heart failure (HF), diuretic resistance can develop, limiting the effectiveness of pharmacological therapy. Peritoneal dialysis (PD) is a kidney replacement therapy usually implemented in advanced or acute kidney failure. However, it can be used to allow ultrafiltration and volume control in refractory cases, either due to kidney or refractory congestive HF. The aim of this study was to describe a single-center experience and study the clinical outcomes of a population of patients with HF that initiated PD for volume control. Method Retrospective single-center study with patients who started PD for volume control between January 1st 2011 and December 31st 2023, with a follow-up of 12 months after start of dialysis or until technique dropout. Demographic and clinical information regarding comorbidities, characteristics of HF, therapeutic management and markers of volume overload (NT-proBNP and CA-125) was collected. The impact on both therapy management and overload markers after six months of PD was also studied. Results Nineteen patients were included in this study, 78.9% of male gender and with a mean age of 63.4 ± 17.2 years. Comorbidities included diabetes in 63.2%, hypertension in 73.7%, coronary arterial disease in 57.8% and peripheral arterial disease in 26.3%. The NYHA (New York Heart Association) class was III or IV in 12 patients (63.1%), with an average left ventricle ejection fraction of 40% ± 14.1, due to ischemic and/or valvular causes in 73.7%. PD vintage was 12 months (IQR 0), with a median glomerular filtration rate (GFR) at the start of peritoneal dialysis of 15 ml/min (IQR 11) while nine patients (47.3%) started with a GFR above 15 mL/min. There was an increase in the number of patients being treated with renin-angiotensin-aldosterone system inhibitors, sodium-glucose co-transporter-2 inhibitors and mineralocorticoids receptor antagonists at six months. Outcomes reported low numbers of major adverse cardiac events, episodes of peritonitis and infection of the peritoneal catheter outer orifice. The number of hospitalizations due to HF was also significantly lower after start of PD (p-value = 0.044). There was a decrease in serum NT-proBNP levels after six months of therapy (p-value = 0.571), with a statistically significant decrease in CA-125 (p-value < 0.001). There was only one reported death during follow-up. Conclusion While PD has classically been viewed only as a kidney replacement therapy, it can also be considered a viable option for refractory volume overload associated with HF. Results suggest an optimization of HF guideline-directed therapy and a decreased number of hospitalizations, with consequent better management of the disease and improved quality of life. There was no negative impact associated with the implementation of PD in this population, with the decrease in CA-125 serum levels also suggesting an overall decrease of volume overload with this technique.

Current Standards in the Treatment of Hodgkin Lymphoma

This review discusses current trends in the treatment of Hodgkin lymphoma, focusing on optimizing therapy outcomes while minimizing toxicity. We summarize advances made by the incorporation of Brentuximab Vedotin into first line therapy for advanced stage Hodgkin lymphoma. Similarly, the incorporation of checkpoint-inhibition into first-line therapy holds great promise and early results suggest superior efficacy with reduced toxicity. In relapsed or refractory Hodgkin lymphoma, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation remains the standard approach. However, the remarkable efficacy of checkpoint inhibition in this setting has the potential to redefine treatment paradigms and obviate the need for HD-ASCT in select patients. Finally, we discuss the evolving landscape of nodular lymphocyte predominant Hodgkin lymphoma and reclassification to nodular lymphocyte predominant B-cell lymphoma, with increasing recognition of its distinct characteristics and treatment strategies.

Nanoemulsion Carriers for Ocular Fungal Infection: Main Emphasis on Keratomycosis.

Keratomycosis, also termed fungal keratitis (FK), is an invasive eye condition for which there is a lack of available effective treatment due to pharmacological shortages and vital ocular obstacles. This severe corneal infection typically suppurates and eventually ulcerates, ultimately causing blindness or decreased vision. According to epidemiological studies, FK is more common in warm, humid places with an agricultural economy. The use of nanoemulsion carriers for ocular fungal infection has been promoting better treatment and patient compliance. The persistent fungal infection like FK, affecting particularly the stroma heralds complications thereby posing difficulty in diagnosis and treatment. To help treat refractory cases and improve outcomes, recently targeted drug delivery techniques and novel antifungal drugs shall be explored. A delay in diagnosis may cause corneal fungal infections to have irreversible consequences, which cannot be avoided. However, infections can develop into ocular perforation even after receiving intense care. The commonly used chemotherapy for FK is based on topical (natamycin 5% is typically first-line therapy) and systemic administration of azole drugs. To address the problems related to better treatment, various nanoemulsion carriers were discussed. Novel drug delivery systems based on nanoemulsions are a viable therapeutic option for treating keratomycosis and may be a candidate method for overcoming obstacles in the treatment of many other ocular illnesses when combined with different hydrophobic medicines. With a brief explanation of the pathogenesis, this article seeks to give readers a thorough analysis of current trends, various treatment choices, and care strategies for fungal keratitis.

#284 Risk of dose-dependent methotrexate therapy on renal functions in patients with rheumatoid arthritis

Abstract Background and Aims Methotrexate is often used as first-line therapy for RA because of its proven efficacy, good safety profile, and low cost. The importance of MTX also comes from the fact that in combinatory treatments, the efficacy of bDMARDs or tsDMARDs is always higher when these drugs are combined to MTX, suggesting making MTX at the base of any conventional treatment of RA. Although renal impairment is a major concern in patients taking high-dose MTX for the treatment of malignancy, it has not been fully examined in RA patients treated with low-dose MTX, so we aimed at studying the dose- dependent effects of MTX on renal function and creatinine clearance. Method Three hundred and sixty adult RA patients, regularly attending rheumatology OPC for regular follow up participated in this retrospective cohort study. Young children, patients with any degree of renal impairment and other rhematic diseases were excluded. Serum creatinine and creatinine clearance were followed up at 1 year and 3 years of different doses of MTX therapy, and results were compared to baseline levels. Results Patients’ ages had a mean of 44.60 years, with most being females (80.6%). Range of disease duration was 2-34 years with the mean of 9.93 years. Most of the patients had significant disease activity, where 36.4% had moderate activity and 26.1% of them had high disease activity according to DAS 28 score. We noticed a significant decline of the creatinine clearance at 1 & 3 years follow up regardless the MTX dose used (P-value: ≤0.001 for both). Conclusion We may conclude that MTX therapy has a potential nephrotoxic effect regardless the dose or the duration of therapy, mandating a close monitoring of renal functions for patients maintained on the drug.

Development and validation of high-performance liquid chromatography method for the simultaneous quantification of rivastigmine hydrogen tartrate and asiaticoside co-loaded in niosomes: A Box–Behnken design approach

Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, is considered as the first-line therapy for mild to moderate Alzheimer’s disease. Asiaticoside (AS), a pentacyclic triterpenoid saponin, is well known as cognitive enhancer due to its antioxidant effect. Based on the hypothesis of their synergistic therapeutic potential, RHT and AS were co-encapsulated in niosomal formulation. A simple, precise, and accurate high-performance liquid chromatography method was developed for simultaneous quantitative analysis. The chromatographic parameters were optimized by Box-Behnken experimental design. The separation was performed on a reversed-phase Phenomenex C18 (150 mm × 4.6 mm, 5 μm) column at 30 °C under the UV detection of 210 nm. The optimized mobile phase consisted of a mixture of 20 mM potassium dihydrogen phosphate buffer (pH 2.6) and acetonitrile (72:28 % v/v) under the isocratic mode at the flow rate of 0.9 mL/min. The developed method was fully validated under the ICH guidelines and could be successfully applied for simultaneous quantitative analysis of RHT and AS in niosomal formulation.

#1649 Obinutuzumab is effective for the treatment of rituximab-resistant membranous nephropathy

Abstract Background and Aims Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in nondiabetic adults. Rituximab has become the first-line therapy for patients with MN after the recognition of MN as an autoimmune disease. However, 40% of patients with MN do not respond to rituximab. Obinutuzumab is a humanized and glycoengineered type II anti-CD20 monoclonal antibody that has superior in vitro B-cell cytotoxicity compared with rituximab which might provide an attractive option for rituximab-resistant MN. We presented our single-center experience of treating MN with obinutuzumab. Method Fourteen patients with rituximab-resistant PLA2R-associated MN who received obinutuzumab at the First affiliated hospital of Xi'an Jiaotong university between January 2022 and June 2023 were included in this retrospective study. Resistance to rituximab was defined as the failure to achieve complete (urinary protein excretion <0.3 g/d along with normal serum albumin concentration and stable renal function) or partial (urinary protein excretion <3.5 g/d or with ≥50% reduction vs baseline, accompanied by improvement or normalization of serum albumin concentration and stable GFR) remission of NS in 3-6 months after 2 doses of rituximab administration. Clinical and laboratory parameters were evaluated at presentation, before and after obinutuzumab administration. Results Of all patients with an average age of 50.0 ± 13.6 years, 10 (71.4%) patients were men, 8 (57.1%) patients had hypertension and 4 (28.6%) patients had diabetes. The median disease duration was 1.3 (1.0, 4.8) years. At presentation, the proteinuria and albumin levels were 7.94 ± 4.23 g/d and 21.5 ± 3.6 g/L, respectively. The mean serum creatinine level was 70.5 ± 10.7 µmol/L and the patients had a median baseline anti-PLA2R level of 193.5 (104.5,299.2) RU/mL. Six patients had been previously exposed to steroids, alkylating agents, calcineurin inhibitors in different combinations in addition to rituximab. Both patients received 1 g of obinutuzumab on day 0 and day 15. At obinutuzumab administration, the proteinuria and albumin levels were 8.43 ± 3.36 g/d and 22.4 ± 4.0 g/L, respectively. The mean serum creatinine level was 85.1 ± 28.5 µmol/L and median anti-PLA2R level decreased to 32.7 (10.7,178.) RU/mL compared with that at presentation. After a median follow-up of 5.4 (4.0, 9.7) months after obinutuzumab therapy, complete remission was achieved in 4 (28.6%) and partial remission was achieved in 8 (57.1%) of patients. Of the remaining two patients who did not achieve complete or partial remission, 1 patient had a follow-up of 4 months and had a 33% decline in proteinuria accompanied by improvement in serum albumin. The other patient had an anti-PLA2R level higher than 1500 RU/mL (exceeding detection upper limit) at obinutuzumab administration and an inadequate follow-up of 3 months without proteinuria decline. Whereas, anti-PLA2R level decreased to 18.17 RU/ml accompanied by B-lymphocyte depletion (absolute CD19 count <5 cells/ml) at that time. Of the 12 patients who achieved complete or partial remission, the median time from treatment to remission was 4.7 ± 2.3 months. Two patients with longer follow-up maintained complete remission at 1 year. At first complete or partial remission, the proteinuria and albumin levels were 3.47 ± 1.99 g/d and 32.5 ± 3.3 g/L, respectively. The mean serum creatinine level was 74.8 ± 24.1 µmol/L and anti-PLA2R levels of 11 patients had a decline in the titer to <2 RU/ml (negative result for our immunology laboratory). B-lymphocyte depletion was achieved in all these patients. Conclusion Obinutuzumab may represent an attractive alternative therapy in patients with resistance to rituximab. Larger prospective studies are needed to validate these findings.

#2154 Rituximab in the treatment of PLA2R-associated membranous nephropathy: insights from a hospital centre experience

Abstract Background and Aims Rituximab (RTX) is recommended as the first-line therapy for PLA2R-associated Membranous Nephropathy in patients with a moderate to high risk of progressive loss of kidney function, according to the KDIGO 2021 guidelines. This recommendation is based on the superior long-term efficacy and improved safety profile of RTX. This study aims to assess the use of RTX for the treatment of for PLA2R-associated Membranous Nephropathy at a hospital centre. Method A retrospective study was conducted on patients diagnosed with PLA2R-associated Membranous Nephropathy who underwent their first RTX administration between 2017 and 2022 at a tertiary hospital centre. Exclusion criteria involved patients with less than 6 months of follow-up post-RTX. The study evaluated the occurrence of immune remission, clinical remission, as well as instances of immune and proteinuria relapse, and recorded any adverse events. Results A total of 11 patients were included, with 54.5% being male. The mean age was 60.4 ± 14.7 years, and the median disease duration 69.0 [8.0-87.0] months. The mean follow-up time post-RTX was 36.7 ± 23.3 months. Regarding the risk of progressive loss of kidney function, 8 patients were classified as high risk, 1 as moderate risk, and 2 as low risk. RTX served as the initial immunosuppressive therapy for only 3 patients. Additional immunosuppressive therapies post-RTX, including further RTX doses, were administrated in 63.6% (n = 7) of patients. No response was observed in 18.2% (n = 2). Immune remission was achieved in 81.8% (n = 9), mean time of 3.8 ± 1.4 months. Within this group 55.5% (n = 5) patients achieved complete remission, 22.2% (n = 2) experienced partial remission, and 22.2% (n = 2) maintained nephrotic proteinuria, with immune remission consistently preceding clinical remission. Relapses occurred in 45.5% (n = 5), at a mean time of 20.8 ± 13.5 months. Patients with lower serum albumin at time of RTX administration were more likely to experience non-response or relapse (T (9) = 2.51, p = 0.03), with a Youden Index cut-off of 3.2 g/dL, demonstrating a sensitivity of 100% and a specificity of 85.7%. Patients with anti-PLA2R exceeding 150 RU/mL exhibited no response or relapsed. Four patients (36.4%) remained free of relapses throughout the entire follow-up period, mean time of 22.8 ± 10.0 months, with 1 keeping RTX maintenance therapy. During the 6 months post-RTX, 36.4% (n = 4) of patients experienced adverse events. Conclusion Rituximab demonstrated both efficacy and safety in treating PLA2R-associated Membranous Nephropathy. However, lower serum albumin levels and anti-PLA2R > 150 RU/mL at time of RTX administration were associated with worse response. Given the substantial need for additional immunosuppression, and considering lower albumin values and higher anti-PLA2R titres as risk markers, it is recommended to closely monitor these patients. Anti-PLA2R titres showed a meaningful association with disease activity, preceding changes in proteinuria levels. Therefore, tracking disease progression through the measurement of anti-PLA2R titres not only guides clinical decisions but also enables a judicious approach to subsequent RTX administrations.

Advances in Anti-Cancer Drug Development: Metformin as Anti-Angiogenic Supplemental Treatment for Glioblastoma

According to the WHO 2016 classification, glioblastoma is the most prevalent primary tumor in the adult central nervous system (CNS) and is categorized as grade IV. With an average lifespan of about 15 months from diagnosis, glioblastoma has a poor prognosis and presents a significant treatment challenge. Aberrant angiogenesis, which promotes tumor neovascularization and is a prospective target for molecular target treatment, is one of its unique and aggressive characteristics. Recently, the existence of glioma stem cells (GSCs) within the tumor, which are tolerant to chemotherapy and radiation, has been linked to the highly aggressive form of glioblastoma. Anti-angiogenic medications have not significantly improved overall survival (OS), despite various preclinical investigations and clinical trials demonstrating encouraging results. This suggests the need to discover new treatment options. Glioblastoma is one of the numerous cancers for which metformin, an anti-hyperglycemic medication belonging to the Biguanides family, is used as first-line therapy for type 2 diabetes mellitus (T2DM), and it has shown both in vitro and in vivo anti-tumoral activity. Based on these findings, the medication has been repurposed, which has shown the inhibition of many oncopromoter mechanisms and, as a result, identified the molecular pathways involved. Metformin inhibits cancer cell growth by blocking the LKB1/AMPK/mTOR/S6K1 pathway, leading to selective cell death in GSCs and inhibiting the proliferation of CD133+ cells. It has minimal impact on differentiated glioblastoma cells and normal human stem cells. The systematic retrieval of information was performed on PubMed. A total of 106 articles were found in a search on metformin for glioblastoma. Out of these six articles were Meta-analyses, Randomized Controlled Trials, clinical trials, and Systematic Reviews. The rest were Literature review articles. These articles were from the years 2011 to 2024. Appropriate studies were isolated, and important information from each of them was understood and entered into a database from which the information was used in this article. The clinical trials on metformin use in the treatment of glioblastoma were searched on clinicaltrials.gov. In this article, we examine and evaluate metformin’s possible anti-tumoral effects on glioblastoma, determining whether or not it may appropriately function as an anti-angiogenic substance and be safely added to the treatment and management of glioblastoma patients.

Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol.

Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.

Association of PD-L1 expression and clinical outcomes in ROS1 - rearranged advanced non-small cell lung cancer treated with crizotinib

BackgroundProgrammed cell death ligand 1 (PD-L1) is more readily expressed in ROS proto-oncogene 1 (ROS1) rearranged non-small cell lung cancer (NSCLC) compared to NSCLC cases lacking driver gene mutations. Prior research has established a link between PD-L1 expression and reduced effectiveness of EGFR or ALK inhibitors in EGFR or ALK-positive NSCLC. Nonetheless, the relationship between initial PD-L1 levels and the clinical impact of first-line crizotinib therapy in ROS1-rearranged NSCLC is still uncertain.MethodsFrom January 2016 to December 2021, a total of 246 patients with ROS1 positive tumors were collected. Out of these, 82 patients with advanced ROS1-rearranged NSCLC, who were treated with crizotinib as their initial therapy, were selected for the study. The study aimed primarily to evaluate the objective response rate (ORR) and progression-free survival (PFS), and secondarily to assess disease control rate (DCR) and overall survival (OS).ResultsOf the 82 advanced ROS1-rearranged NSCLC patients, 38 exhibited PD-L1 positivity, subdivided into 11 with high and 27 with low expression levels, while the remaining 44 showed no PD-L1 expression. The ORR for all included patients was 80.5%. No statistically significant variance in ORR was observed among ROS1-rearranged NSCLC patients across differing PD-L1 expression statuses. However, there was a statistically significant difference in DCR between PD-L1 negative group (100%) and high expression group (90.9%) (p=0.04). The median PFS spanned 26.4 months for the PD-L1 negative group, 16.6 for the low expression group, and 13.7 for the high expression group (p=0.001). Additionally, a notable statistical disparity was also observed in median PFS between the PD-L1 negative and positive groups (p=0.02). For the entire study population, the median OS was 53.0 months (95% CI 43.8 - 62.2). In the PD-L1-negative group, the median OS reached 57.2 months, compared to 53.0 months in the PD-L1-positive group, a difference lacking statistical significance (p=0.43).ConclusionsOur results suggest that for ROS1-positive NSCLC patients receiving crizotinib as first-line therapy, PD-L1 expression may serve as a negative prognostic marker for PFS rather than OS.

Assessment of Macrovascular Invasion in Advanced Hepatocellular Carcinoma: Clinical Implications and Treatment Outcomes with Systemic Therapy

Introduction: Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance. Methods: Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used macrovascular invasion progression disease (MVI-PD) to track MVI progression, and Response Evaluation Criteria in Solid Tumours version 1.1 progression disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD. Results: Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. 40 (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than three months was analyzed based on the assessment of imaging response during the first three months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p<0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498). Conclusion: Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.

Imatinib-induced ulcerative colitis.

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for patients with KIT mutation in gastrointestinal stromal tumor (GIST). Nausea, vomiting, diarrhea, dyspepsia and abdominal pain are common gastrointestinal adverse reactions of imatinib, but imatinib-induced ulcerative colitis (UC) is rarely reported. We presented a case of UC induced by imatinib in a 56-year-old male patient who experienced this adverse event after 5 years of imatinib 400 mg/d treatment following GIST resection. The patient's diarrhea and bloody stools showed significant improvement following the discontinuation of imatinib therapy and administration of antidiarrheal medications. Then, imatinib was restarted at a daily dosage of 400 mg. UC is a rare adverse event associated with imatinib. Physicians should consider the possibility of UC induced by imatinib when patients present with diarrhea and bloody stool after receiving imatinib treatment. This case offered objective evidence of UC induced by imatinib.

Comparative efficacy of six programmed cell death Protein-1 inhibitors as first-line treatment for advanced non-small cell lung cancer: a multicenter retrospective cohort study

The purpose of this study was to assess the comparative efficacy of six programmed cell death-1 inhibitors (nivolumab, pembrolizumab, sintilimab, tislelizumab, toripalimab, and camrelizumab) that have been used as first-line therapy for Chinese patients with advanced non-small cell lung cancer (NSCLC), which remains unclear. We determined the differences in efficacy by observing patient survival data, with the goal of informing future treatment options. Retrospective data analysis from June 2015 to April 2023 included 913 patients across six groups: nivolumab (123%, 13.5%), pembrolizumab (421%, 46.1%), sintilimab (239%, 26.1%), tislelizumab (64%, 7.0%), toripalimab (39%, 4.3%), and camrelizumab (27%, 3.0%). The median progression-free survival (PFS) for each group was 16.0, 16.1, 18.4, 16.9, 23.7, and 12.8 months, and the median overall survival (OS) was 33.7, 36.1, 32.5, not reached, 30.9 and 46.0 months for the nivolumab, sintilimab, pembrolizumab, tislelizumab, toripalimab, and camrelizumab groups, respectively. While differences existed in the objective response rates among groups (p < 0.05), there were no significant differences (all p > 0.05) in PFS or OS. The findings suggest comparable efficacy among these PD-1 inhibitors for NSCLC treatment, underscoring their collective suitability and aiding treatment decisions.

A hybrid protocol CLAG-M, a possible player for the first-line therapy of patients with mixed phenotype acute leukemia. A Polish Adult Leukemia Group experience

IntroductionMixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the “know-how” of MPAL is based only on retrospective analyses performed on small groups of patients.Materials and methodsIn this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed.ResultsSixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16–24) and 17 days (range, 12–24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes.ConclusionsCLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.