Low-dose Maintenance Research Articles

One-year clinical outcome of aspirin-free prasugrel monotherapy following stent implantation in patients with chronic coronary syndrome: insight from ASET-JAPAN study

Abstract Background Single antiplatelet therapy with a potent P2Y12 inhibitor without aspirin after coronary stent implantation may provide an adequate balance between ischemic and bleeding risks in selected patients. The 3-month follow-up of the Acetyl-Salicylic Elimination Trial (ASET)-Japan pilot study demonstrated the feasibility and safety of Prasugrel monotherapy without aspirin after successful percutaneous coronary intervention (PCI) in selected patients with chronic coronary syndrome (CCS). Purpose The current study aimed to evaluate the 1-year clinical outcome in the ASET-Japan. Methods The ASET-Japan pilot study was designed to demonstrate the feasibility and safety of the approved dose of prasugrel monotherapy in Japan without aspirin after optimal PCI with a platinum-chromium everolimus-eluting stent in CCS population. After successful procedure, all patients were treated with a locally approved maintenance dose of 3.75 mg/day of Prasugrel monotherapy up to 3-month. After 3-month, the choice of antiplatelet therapy was left to the discretion of the investigators. Patients were followed up to 1 year. The target lesion-related endpoint was a composite of cardiac death, spontaneous target-vessel myocardial infarction (MI) >48 h after the index PCI or clinical-driven target lesion revascularisation. Patient-Oriented Composite Endpoint (POCE) was defined as a composite of all cause mortality, any stroke, any MI and any revascularisation. Spontaneous MI was defined according to Forth universal definition. The event rate was estimated by the Kaplan-Meier method. The event was adjudicated by an independent clinical event committee. Results A total of 208 patients were enrolled in the study. The average anatomical SYNTAX score was 7.96 (±4.6). After procedure, prasugrel monotherapy was immediately initiated. After 3-month, Prasugrel monotherapy was continued in 88.6% up to 1-year. Aspirin monotherapy was prescribed to 10 patients (5.0%), while 6 patients (3.0%) were on DAPT at 1-year. All-cause mortality rate was 1.49%, with no occurrence of cardiovascular death. Revascularisation occurred in 4.0% (n=8) with no occurrence of TLR, while one patient (0.5%) underwent a clinical driven target vessel revascularisation. In summary, 7 out of 8 revascularisations were non-target vessel revascularisation (6 clinically-driven non-TVR). Spontaneous non TV-MI occured in 0.5% (n=1) of patients. There was no definite/probable stent thrombosis up to 1 year. The target lesion related endpoint rate at 1-year was 0%, whereas 1-year POCE rate was 7.0% (n=14). Conclusion Discontinuation of Aspirin and Prasugrel monotherapy at a low maintenance dose of 3.75 mg/day following an angiographically successful stent deployment was feasible and safe in selected patients with CCS and low SYNTAX score. This safety profile is confirmed at 1 year while the investigators, in their large majority and at their own discretion, had maintained the prasugrel treatment.

12224 Addressing Blood Glucose Fluctuations and Fasting Challenges in Sheehan Syndrome: A Case Study

Abstract Disclosure: H.A. Awadalla: None. A.N. Kiani: None. W. Taha: None. N.N. Solanki: None. A. Lattouf: None. A. Shermetaro: None. A. Taweel: None. Introduction: Sheehan's syndrome (SS) is a rare condition characterized by hypopituitarism resultingfrom ischemic necrosis of the pituitary gland due to severe postpartum hemorrhage.Patients may have hormonal insufficiencies, ranging from single pituitary hormoneinsufficiency to total hypopituitarism. The diagnosis of SS is often delayed due to itsnonspecific signs and symptoms, leading to many undiagnosed and untreated cases. Case Presentation:A 33-year-old African American female with a history of panhypopituitarism secondaryto Sheehan Syndrome presented with syncope, lightheadedness, and severehypoglycemia (blood glucose 12mg/dL). Despite regular food intake, she struggled withglycemic control, experiencing recurrent hypoglycemic episodes associated withnausea, vomiting, unintentional weight loss (25kg), and polydipsia/polyuria. Laboratoryfindings revealed low ACTH, sodium, cortisol, and elevated liver enzymes, consistentwith hypopituitarism. Cosyntropin stimulation test confirmed adrenal insufficiency. MRIshowed an empty sella. Initially treated with high-dose hydrocortisone, then transitionedto lower maintenance doses, she continued to experience glycemic fluctuations.Intravenous dextrose and insulin sliding scale were initiated. Upon discharge, she wasprescribed hydrocortisone and levothyroxine. Despite adjustments, hypoglycemiapersisted, managed with dietary modifications. This case underscores the challenges inmanaging Sheehan Syndrome-associated panhypopituitarism and the need for tailoredtreatment approaches to achieve metabolic stability. Conclusion: This case underscores the complexities of managing panhypopituitarism secondary toSheehan syndrome, emphasizing the importance of comprehensive hormonalreplacement therapy and thorough monitoring to achieve symptom control andmetabolic stability. Tailored treatment regimens and continuous assessments arecrucial to addressing individual hormone deficiencies and preventing associatedcomplications effectively in these patients. Presentation: 6/1/2024

Intravitreal steroid implants in the management of noninfectious intermediate and posterior uveitis

Abstract The management of intermediate and posterior uveitis poses a significant challenge of achieving adequate drug concentrations in the posterior segment over the chronic nature of the disease. Systemic agents seldom reach effective drug levels, and even with low maintenance or tapering doses, it is hard to avoid systemic toxicity. The use of intravitreal and periocular injections is often unable to prevent recurrences due to their short half-life. Since the emergence of intravitreal implants (Vitrasert, Retisert), it has become possible to circumvent these therapeutic challenges. A detailed review in the PubMed index yielded 155 articles, of which 22 were analyzed based on exclusion criteria. A recent shift from surgically sutured to minimally invasive injectable implants mainly indicated for noninfectious uveitis is evident from the literature. This review article also provides insights into dexamethasone (Ozurdex) and recent fluocinolone acetonide (Yutiq, Iluvien) implants with particular emphasis on their improved safety and efficacy. Dexamethasone implants favor the therapeutic goal of prevention of recurrences, whereas the use of fluocinolone implants helps to attain better visual outcomes due to their longer duration of action. Thus, the review provides recent literature supporting the role and indication of sustained release intravitreal implants in the management of noninfectious intermediate and posterior uveitis.

Effectiveness and safety of low dose Rituximab as remission-maintenance treatment for patients with refractory idiopathic inflammatory myopathies: results of a retrospective study from a monocentric cohort

ObjectiveOur aim was to assess efficacy and safety of Rituximab (RTX) in patients with refractory Idiopathic inflammatory myopathies (IIM) from a monocentric cohort. Thereafter, we evaluated the efficacy of a low-dose RTX regimen as a remission-maintenance therapy.MethodsWe retrospectively evaluated a cohort of patients affected with IIM treated with RTX. All patients were refractory to glucocorticoids (GC) and at least one immunosuppressant. Two infusions of 1 g two weeks apart were considered as standard cycle of RTX, a single dose of 1 g every six months was deemed as a low-dose RTX regimen. Complete and partial response were defined according to physician’s judgment, laboratory and radiological features.ResultsThirty-six patients affected with IIM were enrolled. Eighteen patients (50%) required the use of RTX for muscular involvement, 6 (16.7%) for interstitial lung disease (ILD), 12 (33.3%) for both myositis and ILD. We observed complete response to RTX in 25 patients (69.4%), partial response in 7 (19.4%) and no response in 4 (11.1%), with an overall response of 88.8% (partial and complete response). From the subgroup of twenty-five patients that achieved a complete response, six were treated with a low dose maintenance therapy maintaining a complete response to RTX. Twenty-six patients who achieved a complete or partial response were able to decrease the mean daily GC dose. Infections were the major adverse events detected in our study.ConclusionsRTX shows favorable outcomes in refractory patients with IIM. A low-dose regimen of RTX appears to be effective in maintaining remission after induction with standard dose.Key Points• The precise pathogenic mechanism of idiopathic inflammatory myopathies (IIM) remains elusive; however, a growing body of data support the autoimmune hypothesis. In this context, rituximab, a B cell-depleting agent, has emerged as a second-line therapeutic option in IIM.• Several studies have assessed It its effectiveness in refractory IIM patients.• Limited information exists on the use of Rituximab as maintenance therapy in patients who have achieved remission following induction therapy with Rituximab.

Decreased Kidney Function Explains Higher Vancomycin Exposure in Older Adults.

Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics. This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression). We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFRCKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09). The absence of age as a significant factor in the multivariable analysis suggests that eGFRCKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway

BackgroundDespite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as “statins” inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.MethodsProlonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.ResultsPC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.ConclusionOur study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.

Real-world use of inhaled corticosteroid/formoterol as needed in adults with mild asthma: the PRIME study.

Inhaled corticosteroid/formoterol fumarate (ICS/FF) as needed is recommended by the Global Initiative for Asthma (GINA) as sole therapy in adults with mild asthma, with low-dose maintenance ICS plus short-acting β2-agonist (SABA) as an alternative. SABA alone is no longer recommended. Given these changes in recommendations, the observational PRIME study aimed to describe real-world treatment patterns in mild asthma in Europe. Adults with asthma receiving low-dose maintenance ICS, or as needed ICS/FF or SABA were followed for 6 months. Data collected included Asthma Control Test (ACT), Asthma Control Questionnaire 5-item (ACQ-5), forced expiratory volume in 1 s (FEV1) and asthma exacerbations. The study was conducted in 883 patients in Germany, Italy, Poland and Spain; 833 (94.3%) completed follow-up. At enrolment, 32.2% received maintenance ICS, 56.3% ICS/FF as needed and 11.6% SABA as needed; 57.4%, 61.2% and 54.9%, respectively, had well-controlled asthma (ACQ-5/ACT definition). After 6 months, changes in mean FEV1 were small in the maintenance ICS and ICS/FF as needed groups, whereas there was a decline in FEV1 in the SABA as needed group. ACQ-5 total score improved from baseline in all three groups; 0.4%, 0.4% and 2.0% patients, respectively, had a severe exacerbation during the study. More patients received ICS/FF as needed than SABA as needed, suggesting that physicians are aware of the latest treatment recommendations. This real-world study provides additional support to the use of ICS/FF as needed as preferred treatment for patients with mild asthma, whereas SABA as needed was associated with a fall in lung function and more severe exacerbations.

Outcomes of patients with multiple myeloma refractory to standard dose vs low dose lenalidomide

Refractoriness to lenalidomide is an important factor determining the choice of therapy at first relapse in multiple myeloma (MM). It remains debatable if resistance to lenalidomide varies among MM refractory to standard doses vs low dose maintenance doses. In this study, we assessed the outcomes with subsequent therapies in patients with MM refractory to standard dose vs low dose lenalidomide. We retrospectively reviewed all patients with MM at our institution who received first line therapy with lenalidomide containing regimens, and assessed progression free survival (PFS) and overall survival for these patients for second line therapy, and with lenalidomide retreatment. For second line therapy, we found no difference in the PFS between standard dose refractory and low dose refractory groups (median PFS 14 months vs 14 months, p = 0.95), while the PFS for both these groups was inferior to the not refractory group (median PFS 30 months, p < 0.001 for both pairs). Similar trends were seen among these groups on lenalidomide retreatment, and on multivariable analysis. These data suggest that refractoriness to lenalidomide is not dose dependent, and definition of lenalidomide refractoriness should not depend on the dose of lenalidomide to which the disease was considered refractory.

Abstract 7274: Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model

Abstract Cysteine-binding targeted drugs AMG-510 and MRTX-849 provide a new therapeutic approach for advanced KRASG12C mutant cancers. However, clinical response has been limited. Responders eventually develop adaptive resistance by gaining additional MAPK pathway mutations, resulting in limited therapeutic benefit. High-dose pulsatile treatment with MAPK pathway inhibitors has been proposed as an alternative strategy to alleviate adaptive resistance while maintaining tumor control. The sensitivity of tumor cells to pan-inhibitors of the MAPK pathway, crucial for proliferation, creates a therapeutic opportunity window for immune cells to restore their function during an intermittent regimen. Congruently, we have previously shown that intermittent pan-MAPK pathway inhibitor treatment delays drug resistance, supports T cell activation, and enhances tumor delay when combined with immunotherapy. In this study, we investigated the effects of continuous and pulsatile KRASG12C inhibition on tumor and immune cells in order to design combinatorial strategies with immune-modulating agents that overcome drug resistance. Our data suggest that a weekly single high-dose regimen of AMG-510 is less effective at achieving tumor control in preclinical mouse models of KRAS mutant lung cancer compared to daily treatments. However, supplementing this pulsatile regimen with lower maintenance doses markedly slows the growth of LLC KRASG12C lung cancer. Flow cytometry analysis revealed that high-dose pulse regimen enhances T cell activation, evidenced by increased expression of TCF-1, Ki67, PD-1, and GITR, along with lower expression of co-inhibitory molecules Lag-3 and Tim-3, 3 days after treatment. In vitro, AMG-510 also improves the antigen presentation of OVA-expressing LLC-KML lung cancer cells via MHC class I and, to a lesser extent, MHC class II. Furthermore, we found that while combinatorial therapy with PD-1 blockade alone does not significantly impact tumor control, the combination with CTLA-4 blockade shows efficacy across pulsatile and continuous AMG-510 dosing cohorts. Overall, our findings suggest that the utilization of intermittent dosing regimens for selective KRASG12C inhibitors is a promising approach for improving clinical responses in lung cancers with KRAS mutations. Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors. Citation Format: Valeria Estrada Navarro, Vincent Panneton, Lauren Dong, Hyejin Choi, Divya Venkatesh, Rachana Maniyar, Isabell Schulze, Jedd D. Wolchok, Taha Merghoub. Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7274.

High Degree of Desensitization After 1 Year of Early-Life Peanut Oral Immunotherapy: Small Children Oral Immunotherapy (SmaChO) Randomized Controlled Trial

BackgroundThe prevalence of peanut allergy is about 2% and mostly lifelong. Studies of oral immunotherapy (OIT) with peanut – daily oral intake of an initially low and then increasing dose of peanut - often show problematic side effects but there are indications of better safety and effect in younger children compared with older children and adults. ObjectiveTo determine the safety and effectiveness of peanut OIT with a slow up-dosing strategy and low maintenance dose, in peanut allergic children 1-3 years of age, a 1-year interim analysis. MethodsIn a randomized controlled trial (2:1 ratio) 75 children with median age 31 months (IQR 23 – 40) were assigned to receive peanut oral immunotherapy (OIT) (n=50) or peanut avoidance (n=25). ResultsIn the OIT group and the avoidance group, 43/50 and 20/25 children, respectively, performed the 1-year open oral peanut challenge. A cumulative dose of 750 mg peanut protein after one year was tolerated by 72% (36/50) in the OIT-group compared to 4% (1/25) in the avoidance-group, p<0.001. Median tolerated cumulative dose was 2750 mg (IQR 275 – 5000) peanut protein in the OIT-group compared to 2.8 mg (IQR 0.3 – 27.8) in the avoidance-group, p<0.001. Of the doses administered at home during the first year of OIT, 1.4% resulted in adverse events, 79% were mild, and three doses of epinephrine were given at home to two individuals. ConclusionIn children 1-3 years of age, peanut OIT with the combination of slow up-dosing and low maintenance dose seems safe and effective after one year. ClinicalTrials.govNCT04511494

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): contemporary advances and current controversies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions ("salt-and-pepper" appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-D-aspartatereceptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.

P1011 Methotrexate polyglutamates in paediatric inflammatory bowel disease: Novel tool for therapeutic drug monitoring?

Abstract Background Methotrexate (MTX) is increasingly prescribed in paediatric inflammatory bowel disease (IBD), but therapeutic drug monitoring (TDM) is currently not feasible due to its characteristic pharmacokinetics and short half-life in plasma, which amounts to approximately 2.5-6.5 hours. Because of this, plasma MTX is no longer detectable shortly after administration. However, MTX-polyglutamates (PG1-5) are formed intracellularly and accumulate over time. Recently, we developed a technique for targeted erythrocyte MTX-PG analysis with the potential for TDM. Data in paediatric IBD with this technique are lacking so far. Here, we aimed to identify the potential of erythrocyte MTX-PG analysis to measure MTX levels in paediatric IBD. Methods In this observational cross-sectional study, we determined MTX-PG concentrations in erythrocytes retrieved from blood samples of paediatric IBD patients on low-dose MTX maintenance therapy, defined as exposure to a stable dose of MTX for at least twelve consecutive weeks. MTX-PG concentrations were determined by stable-isotope dilution liquid chromatography mass-spectrometry. Furthermore, we evaluated the effects of route of administration (oral versus subcutaneous), MTX dosage, and anthropometric data on MTX-PG concentrations. Results Fifty-two paediatric IBD patients on MTX maintenance therapy were included. The predominant subspecies was MTX-PG3 (mean 30.5 nmol/L, SD ± 20.0) and the mean MTX-PGtotal concentration was 88.6 nmol/L (SD ± 52.6). A higher dose was linearly associated with significantly higher MTX-PG3 (r = 0.56), MTX-PG4 (r = 0.52), MTX-PG5 (r = 0.48) and MTX-PGtotal (r = 0.49) levels. When adjusted for body surface area, MTX dose was also linearly associated with significantly higher MTX-PG3 (r = 0.51), MTX-PG4 (r= 0.39), and MTX-PGtotal (r= 0.40) concentrations. A reliable comparison regarding route of administration was not possible in this cohort, due to the small number of patients receiving subcutaneous MTX (n=3). Conclusion We observed high inter-individual variability in the reached erythrocyte MTX-PG concentrations. Body surface adjusted or unadjusted MTX dosage showed a positive linear correlation with erythrocyte MTX-PG concentrations in children with IBD. This is a prerequisite for TDM and provides a strong basis for further research into the relation between TDM of MTX, effectivity and toxicity.

The analysis of low-dose glucocorticoid maintenance therapy in patients with primary nephrotic syndrome suffering from COVID-19.

Objectives: This study aimed to describe the effects of low-dose (prednisolone acetate 2.5-7.5mg/day) glucocorticoids (GCs) maintenance therapy in patients with primary nephrotic syndrome (NS) suffering from coronavirus disease 2019 (COVID-19). Methods: A single-center retrospective study of NS patients with COVID-19 infection in Zhongda Hospital Affiliated to Southeast University from 1 February 2022 to 31 March 2023 was conducted. All enrolled patients underwent renal biopsy for the pathological diagnosis and reached complete remission (CR) or near-CR before COVID-19 infection. According to the maintained therapy regimen, patients were divided into low-dose GCs group and non-GCs group. Results: A total of 125 patients were enrolled in the study. Their median age was 46.0 ± 15.6years, and the median value of 24-h urine protein was 0.77g. The majority of these patients received treatment for more than 6months, with a significant portion achieving CR (29.6%) or near-CR (43.2%). The leading cause of NS was membranous nephropathy (52%). There were no significant differences in the baseline characteristics between low-dose GCs and non-GCs group. As compared to those in the non-GCs group, patients receiving low-dose GCs treatment showed less fatigue or muscle weakness, smell disorder, palpitations, decreased appetite, taste disorder, dizziness, sore throat or difficult to swallow and fever (p < 0.05). Moreover, patients in the low-dose GCs group were with higher median quality of life scores (85.0) than in the non-GCs group (p = 0.001). Further serum inflammatory factor analysis indicated that interleukin-6 (IL-6) levels in the non-GCs group were significantly higher than that in the low-dose GCs group (p < 0.05). Conclusion: Patients with NS in low-dose GCs maintenance therapy stage showed milder symptom, higher quality of life and decreased serum IL-6 levels compared to those, who were not on GCs maintenance therapy. These results suggest the beneficial effect of low-dose GCs therapy in NS patients with CR/near-CR suffering from COVID-19 infection.

IgG4-Related Disease with IgG1-Dominant Membranous Nephropathy: A Rare Case Report

ABSTRACT Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder affecting various organs and tissues. Kidney involvement in IgG4-RD commonly manifests as IgG4-related tubulointerstitial nephritis or IgG4-related membranous nephropathy, with the latter occurring less frequently. The identification of the phospholipase A2 receptor (PLA2R) antigen has improved our understanding of primary membranous nephropathy. Here, we present the case of a 60-year-old Chinese man initially diagnosed with IgG4-related pancreatitis, who achieved clinical remission with glucocorticoid therapy followed by low-dose glucocorticoid maintenance therapy. Two years later, the patient developed nephrotic syndrome. A kidney biopsy revealed membranous nephropathy characterized by glomerular subepithelial deposition of IgG1 and positive PLA2R staining. Rituximab (RTX) treatment resulted in complete clinical remission of nephrotic syndrome, and no recurrence was observed during the 24-month follow-up period. IgG4-RD complicated by membranous nephropathy is a rare pathological feature characterized by glomerular subepithelial IgG1 deposition and positive PLA2R antigen staining. In the present case, RTX treatment was effective in achieving clinical remission. These findings contribute to the evolving understanding of the relationship between IgG4-RD and membranous nephropathy.

Diagnostic Challenges in the Leukemia Phase of Blastic Plasmacytoid Dendritic Cell Neoplasm without Skin Involvement: A Clinical and Pathological Study

Objective: To improve the accurate diagnosis and treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) without skin involvement. Methods: One case of BPDCN with skin involvement progressing to the leukemia phase was used as a positive reference for bone marrow specimens, and a comparative study was conducted on one case of leukemia phase of BPDCN without skin involvement. Results: The male control was 70 years old and presented with a mass on the right forearm skin. Pathological examination indicated BPDCN. Only one cycle of decitabine + CAG was given and 5 months later, the disease progressed to the leukemia phase. Tumor cells expressed HLA-DR, CD123, CD4, CD56, CD7, CD36, TCL1 and CD304. NGS analysis of bone marrow tumor indicated ASXL1, IDH2, and TP53 mutations. The patient survived only 6 months during follow-up. Another female patient was 73 years old and was initially diagnosed with “T lymphoblastic leukemia” based on partial immunophenotyping results for 81.5% blast cells and the morphology of blast cells showing tailing phenomena. Further immunophenotyping showed that blast cells expressed CD56, HLA-DR, and CD304, partially expressed CD4, CD33, and CD117, and did not express CD34, CD13, CD3, CD5, CD7, CD8, CD10, CD11b, CD14, CD15, CD16, CD19, CD20, CD64, CD303 or MPO. Additional immunohistochemistry of bone marrow biopsy showed that CD43 was negative, TdT was mostly positive, CD4 was slightly positive, CD56 was mostly positive, CD123 was positive, CD117 was slightly positive, and lysozyme was partially weakly positive. The above results implied that after excluding BPDCN, acute myeloid leukemia subtype M5 should be considered. According to the diagnostic criteria of BPDCN in WHO 5th edition hematologic lymphoma, two scenarios can be established for diagnosing BPDCN: (1) CD4 and/or CD56 are positive and CD123 and one of pDC markers (TCL1, CD303, CD304) are expressed. (2) If any three pDC markers are expressed (CD123, TCL1, CD303, CD304), and all expected negative markers (CD3, CD14, CD19, CD34, Lysozyme, Myeloperoxidase) are negative, So the final diagnosis of BPDCN can be established according the former creteria. The latter case had ASXL1 and TET2 mutations detected by NGS analysis, achieved complete remission after receiving venetoclax + azacitidine for one cycle, followed by intermittent venoclax +demethylation agent or low-dose chemotherapy maintenance treatment and live for more than two years now. Conclusion:BPDCN without skin lesions is clinically rare, and its diagnosis is challenging. Comprehensive immunophenotyping and cautious interpretation of immunohistochemistry results such as dim lysozyme expression are crucial. Venetoclax-containing regimens have shown promising therapeutic effects.

Health-Related Quality of Life in Multiple Myeloma Patients Treated with High- or Low-Dose Lenalidomide Maintenance Therapy after Autologous Stem Cell Transplantation-Results from the LenaMain Trial (NCT00891384).

The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: -1.905 (range: -5.78-1.97); end of year 2: 16.071 (range: 5.72-26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL.

Anti-Glomerular Basement Membrane Disease in a Six-year-old Child: A Rare Presentation

Antiglomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis caused by auto-antibodies targeting auto-antigen expressed in basement membranes of capillary beds in lungs and kidneys. A six-year-old male presented with fever, cough, and generalized weakness for three days with respiratory distress for one day. The child had three prior admissions with similar complaints and was treated as a case of lower respiratory tract infection with severe iron deficiency anemia in the past. Multiple packed red cell transfusions were required in these past admissions. In this current admission, he had tachycardia, tachypnea, severe pallor, right-sided lung crepitations &amp; bronchial breath sounds. The hemogram showed severe anemia and leukocytosis. Urine examination showed mild proteinuria and microscopic hematuria. Chest X-ray (current admission) showed right middle and lower zone consolidation. HRCT of the chest revealed an interstitial pattern. A lung biopsy showed pulmonary hemorrhage and positive Prussian blue staining. Raised anti-GBM titers confirmed diagnosis of anti-GBM disease. Renal biopsy revealed normal glomerular morphology on histopathology; with immune fluorescence showing linear positivity for IgG (3+), Kappa (3+), and Lambda (3+). Electron microscopy reported mild effacement of visceral epithelial foot processes and subepithelial/intramembranous electron-dense deposits. He was treated with intravenous methylprednisone for 5 days followed by oral prednisolone for one month, which was thereafter tapered to a lower maintenance dose for 18 months. The child received six cycles of intravenous cyclophosphamide along with a daily low dose of steroids. Currently, the child is asymptomatic after one year of follow-up with seroconversion (antiGBM titers decreased) and normalization of the chest radiograph.

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients.

The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.

Low-Dose Maintenance Intravenous Iron Therapy Can Prevent Anemia in Children with End-Stage Renal Disease Undergoing Chronic Hemodialysis

Low-Dose Maintenance Intravenous Iron Therapy Can Prevent Anemia in Children with End-Stage Renal Disease Undergoing Chronic Hemodialysis

Efficacy analysis of oral dexamethasone in the treatment of infantile spasms and infantile spasms related Lennox–Gastaut syndrome

ObjectiveTreatment with adrenocorticotropic hormone (ACTH) or a corticosteroid is the first choice for infantile spasms (IS), and vigabatrin is the first choice for children with tuberous sclerosis. Although corticosteroids may be also effective against IS and IS-related Lennox–Gastaut syndrome (LGS), the use of dexamethasone (DEX), a kind of corticosteroid, for these diseases has been rarely reported. This retrospective study aimed to evaluate the efficacy and tolerability of DEX for the treatment of IS and IS-related LGS.MethodsPatients diagnosed as having IS (including patients whose condition evolved to LGS after the failure of early treatment) in our hospital between May 2009 and June 2019 were treated with dexamethasone after failure of prednisone treatment. The oral dose of DEX was 0.15–0.3 mg/kg/d. Thereafter, the clinical efficacy, electroencephalogram (EEG) findings, and adverse effects were observed every 4–12 weeks depending on the individual patient’s response. Then, the efficacy and safety of DEX in the treatment of IS and IS-related LGS were retrospectively evaluated.ResultsAmong 51 patients (35 cases of IS; 16 cases of IS-related LGS), 35 cases (68.63%) were identified as responders to DEX treatment, comprising 20 cases (39.22%) and 15 cases (29.41%) with complete control and obvious control, respectively. To discuss the syndromes individually, complete control and obvious control were achieved in 14/35 and 9/35 IS cases and in 6/16 and 6/16 IS-related LGS cases, respectively. During DEX withdrawal, 11 of the 20 patients with complete control relapsed (9/14 IS; 2/6 LGS). The duration of dexamethasone treatment (including weaning) in most of the 35 responders was less than 1 year. However, 5 patients were treated with prolonged, low-dose maintenance therapy, which continued for more than 1.5 years. These 5 patients showed complete control, and 3 patients had no recurrence. Except for one child who died of recurrent asthma and epileptic status 3 months after stopping DEX, there were no serious or life-threatening adverse effects during DEX treatment.ConclusionOral DEX is effective and tolerable for IS and IS-related LGS. all LGS patients were evolved from IS in this study. The conclusion may not apply to patients with other etiology and courses of LGS. Even when prednisone or ACTH is failed, DEX may still be considered as a treatment option. For children who respond to DEX but do not show complete control after 6 months of treatment, prolonged treatment with low-dose DEX administered in the morning might be considered.