Administration Of Immunosuppressive Drugs Research Articles

Clinical Characteristics and Treatment of Juvenile Myasthenia Gravis-A Single-Center Experience.

Juvenile myasthenia gravis (MG) is a rare autoimmune neuromuscular disease, often treated with anticholinesterases, corticosteroids, and immunosuppressants. However, optimal treatment durations remain unclear. This study investigated the clinical characteristics and treatment of juvenile MG, including medication duration. The administration period for all drugs, immunosuppressants, and prednisolone at doses greater than 0.35 mg/kg daily was extracted retrospectively from medical records. Nineteen participants (8 boys, 11 girls) aged 8 months to 14 years (median, 2.5 years) at onset were identified. Fourteen patients (73.7%) had ocular MG and five (26.3%) had generalized MG. Drug treatment was conducted in 18 cases; however, 7 patients did not complete the treatment. Among the patients who completed drug treatment, the duration of treatment ranged from 11 to 100 months (median, 47 months). In the six patients treated with continuous administration of prednisolone or immunosuppressants, the treatment duration ranged from 33 to 99 months (median, 56 months). No severe adverse effects requiring hospitalization were reported. The patients treated with prednisolone or immunosuppressants required at least 33 months of treatment. These results will help develop protocols for juvenile MG treatment.

Treatment Strategies for Anti-Synthetase Syndrome

Anti-aminoacyl tRNA synthetase (ARS) antibodies are the most frequent in idiopathic inflammatory myopathy, notably associated with anti-synthetase syndrome (ASyS), which is characterized by six clinical features: arthritis, myositis, interstitial lung disease (ILD), fever, Raynaud's phenomenon, and mechanical hands. Although patients with ASyS often respond well to initial glucocorticoid (GC) therapy, they tend to have a chronic, recurrent disease course. In anti-ARS-positive patients, the treatment goal involves suppressing disease recurrence and progression while achieving a minimal GC dose. In this regard, the administration and continuation of immunosuppressants, such as calcineurin inhibitors, have been suggested. B-cell depletion therapies are expected to be valuable in patients with refractory ASyS. Moreover, additional antifibrotic agents may be beneficial for patients with progressive fibrosing ILD.

Continuous immunosuppression is required for suppressing immune responses to xenografts in non-human primate brains.

Continuous immunosuppression has been widely used in xenografts into non-human primate brains. However, how immune responses change after transplantation in host brains under continuous immunosuppressive administration and whether immunosuppression can be withdrawn to mitigate side effects remain unclear. Human induced neural stem/progenitor cells (iNPCs) have shown long-term survival and efficient neuronal differentiation in primate brains. Here, we evaluate the immune responses in primate brains triggered by human grafts. The results show that the immune responses, including the evident activation of microglia and the strong infiltration of lymphocytes (both T- and B-cells), are caused by xenografts at 4months post transplantation (p.t.), but significantly reduced at 8months p.t. under continuous administration of immunosuppressant Cyclosporin A. However, early immunosuppressant withdrawal at 5months p.t. results in severe immune responses at 10months p.t. These results suggest that continuous long-term immunosuppression is required for suppressing immune responses to xenografts in primate brains.

Advances in the Use of Biologics and Biomaterials toward the Improvement of Pancreatic Islet Graft Survival in Type 1 Diabetes

Islet transplantation is a curative treatment for patients suffering from type 1 diabetes and has the potential to replace current treatment strategies involving the exogenous administration of insulin. Despite this potential, there are many hurdles in achieving successful long‐term graft survival due to autoimmune and foreign body reactions leading to graft rejection coupled with donor shortage and potential adverse effects from the need for long‐term administration of immunosuppressive drugs. As a result, various approaches have been proposed to increase the viability and function of islet grafts during isolation and ex vivo culture with the use of growth factors, hormones, and other therapeutic agents. In addition, other strategies have addressed how to enhance or maintain islet graft performance after implantation with improvements on immunosuppressive drug regimens and the use of biomaterials to encapsulate and protect the cells from graft rejection. This review focuses on the recent advances in strategies to improve islet viability and function with the addition of exogenous compounds and the implementation of conformal coating as a promising tool for immunoprotection of islet transplants.

A novel protocol for de-isolating moderately and severely immunocompromised COVID-19 patients.

Immunocompromised coronavirus disease 2019 patients are at a higher risk of prolonged viral shedding than immunocompetent patients. However, as of August 2023, there is no clear international standard for de-isolating vulnerable patients. A comprehensive assessment is advisable based on various information, such as the increase in immune escape of specific mutant strains as well as the patient's innate immunity and vaccination status; therefore, consultation with an infectious disease specialist is recommended. The patient population defined as moderately or severely immunocompromised by the Centers for Disease Control and Prevention and the European Centre for Disease Prevention and Control is significantly broad. A boundary between the two remains to be delineated, and the existing protocols allow the release of patients based on their symptoms alone. This may lead to an unnecessary extension or premature termination of isolation. In this study, we searched for studies, particularly those that used real-world data, discussed the results with experts in our hospital, and proposed new isolation criteria based on both testing and clinical symptoms. We classified patients into three groups namely severely, moderately, and mildly immunocompromised, defined by their background and the administration of immunosuppressive drugs. A separate flowchart for ending isolation is indicated for each group. This standard may be a useful support material, especially for non-specialists. Nevertheless, our criteria must be revised and added continuously; accumulating real-world data to support revision of and addition to the list is becoming increasingly important.

The Risk of Latent Tuberculosis Reactivation in COVID-19 Therapy

The high mortality rate among COVID-19 patients in the acute respiratory distress syndrome (ARDS) phase led to the administration of immunosuppressive drugs. Corticosteroids could block inflammation caused by cytokine storm, and prevent pneumonia, edema, fibrosis, and ARDS. Even though it was believed to have beneficial effects, corticosteroids can suppress T CD4+ and CD8+ cell-mediated immunity reaction through decreased IFNγ production thus leading to reactivation of latent Tuberculosis (LTBI). Therefore, the usage of corticosteroids in the ARDS phase of COVID-19 patients should be carefully given; pre-screening of LTBI may be done to avoid Tuberculosis reactivation.

Prognostic factors of virus-associated pneumonia other than COVID-19 in adults

ObjectiveTo determine prognostic factors of virus-associated pneumonia other than coronavirus disease 2019. MethodsWe retrospectively studied patients suffering from virus-associated community-acquired pneumonia, and who were admitted to Saitama Cardiovascular and Respiratory Center from 2002 to 2020. Prognostic factors were analyzed by univariable and multivariable regression analysis of patient demographics, laboratory data, chest imaging, severity on admission, and initial treatment. PatientsHIV-positive patients, those with non-resected lung cancer or receiving chemotherapy, and those with COVID-19 were excluded. Included were 363 patients diagnosed by nucleic acid amplification method, paired sera, and rapid diagnostic tests. ResultsA CURB-65 score of ≥3 was significant by univariable analysis for 60-day mortality but was nonsignificant by multivariable analysis. The poor prognostic factors that were significant by multivariable analysis (p < 0.05) included immunosuppressive state due to systemic corticosteroid or immunosuppressant administration, acute kidney injury on admission, and corticosteroid administration initiated within 5 days or 5 days to 2 weeks from onset. ConclusionA CURB-65 score of ≥3, which is considered to indicate severe pneumonia, was of limited value for predicting mortality of virus-associated pneumonia. We showed patients’ underlying diseases and complications to be independent factors of poor prognosis for 60-day mortality. Timing of the initiation of corticosteroid administration remains to be elucidated.

Immunosuppression in solid organ-transplant recipients and impact on nutrition support.

A key component to nutrition support is to consider immunosuppressive agents, the interaction with nutrients, and how the side effects of the medications influence nutrition support. The immunosuppression of the solid organ-transplant recipient involves the individualized titration of multiple therapeutic agents to prevent allorecognition and, thus, rejection of the transplanted organ. Induction immunosuppression includes the agents used at the time of transplant to prevent early rejection. Maintenance immunosuppression typically consists of oral medications taken for life. Regular therapeutic monitoring of immunosuppression is necessary to balance the risk of rejection with that of infections and malignancy. In the acute-care setting, multidisciplinary collaboration, including pharmacy and nutrition, is needed to optimize the route of administration, titration, and side effects of immunosuppression. Long-term nutrition management after transplant is also vital to prevent exacerbating adverse effects of immunosuppressive therapies, including diabetes mellitus, hypertension, dyslipidemia, obesity, and bone loss. This review summarizes common immunosuppressive agents currently utilized in solid organ-transplant recipients and factors that may influence decisions on nutrition support.

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of &amp;lt;0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

Exosomal miR-181d-5p Derived from Rapamycin-Conditioned MDSC Alleviated Allograft Rejection by Targeting KLF6.

Immune rejection and side effects of long-term administration of immunosuppressants are the two major obstacles to allograft acceptance and tolerance. The immunosuppressive extracellular vesicles (EVs)-based approach has been proven to be effective in treating autoimmune/inflammatory disorders. Herein, the anti-rejection advantage of exosomes (Rapa-Exo) from rapamycin-conditioned myeloid-derived suppressor cells (MDSCs) over exosomes (Exo-Nor) from the untreated MDSCs is shown. The exosomal small RNA sequencing and loss-of-function assays reveal that the anti-rejection effect of Rapa-Exo functionally relies on miR-181d-5p. Through target prediction and double-luciferase reporter assay, Kruppel-like factor (KLF) 6 is identified as a direct target of miR-181d-5p. Finally, KLF6 knockdown markedly resolves inflammation and prolongs the survival of corneal allografts. Taken together, these findings support that Rapa-Exo executes an anti-rejection effect, highlighting the immunosuppressive EVs-based treatment as a promising approach in organ transplantation.

The synergistic effect of full-spectrum light therapy and transient immunosuppressants prolonged allotransplant survival.

The lifelong administration of immunosuppressants remains its largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term anti-lymphocyte serum and cyclosporine-A. Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared to the control (group 1). However, group 4 with FBLT combined with short-term ALS/CsA significantly prolonged median composite tissue allograft survival time (266 days) compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) (p<0.01). Group 4 also showed a significant increase in Treg cells (p = 0.04) and TGF-β1 levels (p = 0.02), and a trend toward a decrease in IL-1β levels (p = 0.03) at 16 weeks after transplantation as compared to control Group 1. FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and anti-inflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival.

Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports.

With the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies. The inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response. In the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation. Our case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials.

Neonatal islets from human PD-L1 transgenic pigs reduce immune cell activation and cellular rejection in humanized nonobese diabetic-scid IL2rγnull mice

Strong xenorejection limits the clinical application of porcine islet transplantation in type 1 diabetes. Targeting T cell-mediated rejection is one of the main approaches to improve long-term graft survival. Here we study engraftment and survival of porcine islet cells expressing human programmed cell death ligand-1 (hPD-L1) in a humanized mouse model. Neonatal islet-like clusters (NPICCs) from transgenic hPD-L1 (hPD-L1-Tg) and wild-type (Wt) pigs were transplanted into nonobese diabetic-scid IL2rγnull mice stably reconstituted with human immune cells (hPD-L1 n = 10; Wt n = 6). Primary endpoint was development of normoglycemia during a 16-week observation period after transplantation. Secondary endpoints were porcine C-peptide levels and immune cell infiltration. Animals transplanted with hPD-L1-Tg neonatal islet-like clusters achieved a superior normoglycemic rate (50% versus 0%) and significantly higher plasma C-peptide levels as compared to the Wt group, indicating long-term beta cell function. Intracytoplasmic fluorescence-activated cell sorting analysis and immunohistochemistry revealed significantly decreased frequencies of interferonγ-expressing splenic hCD8-positive T cells and reduced intragraft-infiltrating immune cells. We here demonstrate that expression of hPD-L1 provides strong islet xenograft protection without administration of immunosuppressive drugs. These findings support the hypothesis that hPD-L1 has the capacity to control cellular rejection and therefore represents a very promising transgene candidate for clinical porcine islet xenotransplantation.

Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

A surgical case of abscess of the sternal region due to synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome

BackgroundSynovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a rare chronic inflammatory disorder characterized by cystic skin disease, aseptic osteomyelitis, and hyperostosis. It is rarely associated with subcutaneous abscesses in the anterior chest wall. Herein, we describe a case of a sternal abscess due to SAPHO syndrome that was successfully treated with debridement.Case presentationA 62-year-old female patient presented with a chief complaint of a mass in the right anterior chest region. Computed tomography showed the presence of an abscess around the sternum. Magnetic resonance imaging revealed inflammation of the spine. The patient also had a history of palmoplantar pustulosis, raising the suspicion of SAPHO syndrome; however, sternoclavicular joint infection could not be excluded. Abscess drainage and wall debridement were performed. However, reaccumulation of the abscess occurred early after surgery. Although culture tests of the abscess were negative, histopathological examination of the abscess wall revealed a tuberculoid granuloma. Owing to unsuccessful open wound management, debridement of the anterior thoracic skin and abscess wall and partial sternal resection were performed 2 months after the initial surgery. Negative-pressure wound therapy (NPWT) was applied for 4 weeks after surgery, followed by immunosuppressant administration. The patient underwent split-thickness skin grafting on postoperative day 65 and had no abscess recurrence at 18 months post-surgery.ConclusionsAbscesses in the sternal region caused by SAPHO syndrome can be difficult to differentiate from infectious arthritis. Therefore, drainage and debridement should be considered if infection cannot be excluded.

Analysis of death avoidance by concomitant use of prednisone in patients with renal transplant using the Food and Drug Administration Adverse Event Reporting System

BackgroundPatients with renal transplant are frequently administered immunosuppressants to prevent transplant-related adverse events. There are mainly nine immunosuppressants on the market, and multiple immunosuppressants are frequently administered for patients with renal transplant. Identifying which immunosuppressant was responsible when efficacy or safety was observed in patients taking multiple immunosuppressants is difficult. This study aimed to identify the immunosuppressant that was effective in reducing death in patients with renal transplant. A very large sample size was required to conduct prospective clinical trials of immunosuppressant combinations, which is impractical. We investigated cases wherein death occurred despite immunosuppressant administration in patients with renal transplant using Food and Drug Administration Adverse Event Reporting System (FAERS) data. Material and methodWe used FAERS data reported between January 2004 and December 2022 in patients with renal transplant who received one or more immunosuppressants. Groups were defined for each combination of immunosuppressants. Comparison between two identical groups except for the presence or absence of prednisone was performed using the reporting odds ratio (ROR) and the adjusted ROR (aROR) controlling for differences in patient background. ResultsWhen the group without prednisone was set as the reference, the aROR for death was significantly <1.000 in several cases in the group to which prednisone was added. ConclusionsThe inclusion of prednisone in the immunosuppressant combinations was suggested to be effective in reducing death. We provided the sample code of software R that can reproduce the results.

Establishment of a protocol to administer immunosuppressive drugs for iPS cell-derived cardiomyocyte patch transplantation in a rat myocardial infarction model

Transplantation of human allogeneic induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is a new, promising treatment for severe heart failure. However, immunorejection is a significant concern in allogeneic hiPSC-CM transplantation, requiring the administration of several immunosuppressive agents. An appropriate protocol for the administration of immunosuppressants may substantially affect the efficacy of hiPSC-CM transplantation in case of heart failure owing to allogeneic transplantation. In this study, we investigated the effect of immunosuppressant administration duration on the efficacy and safety of allogenic hiPSC-CM patch transplantation. We used a rat model of myocardial infarction to evaluate cardiac function using echocardiography six months after the transplantation of hiPSC-CM patches with immunosuppressant administration for either two or four months and compared them to control rats (sham operation, no immunosuppressant administration). Histological analysis performed at 6 months after hiPSC-CM patch transplantation revealed significant improvement in cardiac function in immunosuppressant-treated rats compared with those in the control group. Moreover, fibrosis and cardiomyocyte size was significantly reduced and the number of structurally mature blood vessels was significantly increased in the immunosuppressant-treated rats compared to control rats. However, there were no significant differences between the two immunosuppressant-treated groups. Our results show that prolonged administration of immunosuppressive agents did not enhance the effectiveness of hiPSC-CM patch transplantation, and therefore, highlight the importance of an appropriate immunological regimen for the clinical application of such transplantation.

Pharmacogenetic testing improves treatment responses in patients with PLA2R-related membranous nephropathy

To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients. A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment. Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05). Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.

Tracking the evolving ecosystem of recurrent hepatocellular carcinoma after liver transplantation.

4114 Background: Liver transplant (LT) contributes to the cure of hepatocellular carcinoma (HCC) by extending the conventional surgical margin, while removing the concurrent tumor-favoring conditions of the diseased liver. Over the past two decades, HCC has emerged as a preferable indication for LT, accounting for 22-45% of the cases globally. However, despite the stringent selection criteria, recurrence still occurs in a substantial proportion of patients, leaving 10-13 months of median survival after tumor relapse. To address this challenge, a thorough exploration of molecular mechanism behind HCC recurrence after LT is required. Here, for the first time, we performed a comprehensive analysis to depict the evolving and unique ecosystem of HCC in the context of LT and immunosuppressant (IS) administration. Methods: We retrospectively reviewed our biobank and collected 91 paired (primary tumors (PT) from the explant after LT and relapsed tumors (RT) from hepatectomy) FFPE tumor samples from 15 patients for whole exome sequencing (WES). Also, from Jan 2021, we prospectively collected surgical tumor specimens and their adjacent non-tumor tissues from 15 primary and 6 post-LT intrahepatic recurrence patients for single-cell RNA sequencing. Moreover, 6 paired samples from 3 patients were used for spatial transcriptomic analysis. Results: By analysing WES data, we confirmed that RT samples represent recurrent, instead of de novo tumors. Also, the phylogenetic analysis demonstrated strong clonal relationship between PT and RT based on shared SNVs. As to mutation landscape differences of PT and RT, we identified a significantly enriched mutation panel from RT, including MUC16, FAT3, APOB, COL6A3 and POTEC. And the accuracy of this panel for post-LT HCC recurrence surveillance using plasma derived cfDNA sequencing has been preliminarily validated in a prospective cohort of 17 patients. From the single-cell profiling, distinct immune microenvironment between PT and RT is identified. As predicted, proliferating T cells are decreased in RT due to IS. Pseudotime analysis of T cells revealed that T cells from PT mainly distribute at the terminal end of cytotoxic stage whereas T cells from RT mostly represent a naïve state, further confirming the T cell blocking effect of IS. In terms of myeloid cells, we surprisingly found that FOLR2+ tumor associated macrophages, which is conventionally considered as a favorable prognosis factor, is increased in RT. Spatial transcriptomics and IHC also confirmed their active interplay with tumor cells at invasive margin. We postulate that such increase might be a result of the healthy nature of liver graft. Conclusions: Our comprehensive dissection of the HCC ecosystem provides deeper insights into the tumor relapse after LT. Targeting novel mutations and strengthen the antigen presenting process between increased TAM and disabled T cells can be the future direction in this field. Clinical trial information: NCT04506398 .

Immune therapy related adverse events in metastatic non-small cell lung carcinoma patients at a rural academic center.

e21203 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for stage IV non-small cell lung cancer (NSCLC) patients. Immune related adverse events (irAEs) are the diverse immunologic side effects of patients receiving ICIs and may result in significant patient morbidity, subsequently impacting quality of life. If severe enough, irAEs may lead to hospitalization and may necessitate administration of immunosuppressants or IL-6 receptor antagonists. Our study sought to characterize irAEs in a patient population receiving ICIs at a rural tertiary care center. Methods: This was an IRB-approved retrospective cohort study using SPSS version 28. Patients with stage IV NSCLC receiving ICIs at ECU Health Medical Center were analyzed and 190 patients met inclusion criteria. Results: Of our cohort, 66.3% (n = 126) experienced at least one irAE of any grade, 46.3% (n = 88) were hospitalized due to grade 3 or 4 irAE, 55.7%(n = 106) were either started on steroids or had a dose increase to treat the irAE, 48.9% (n = 93) received immunosuppression to treat the irAE, and 41.5% (n = 79) had immunotherapy held either temporarily or permanently due to the irAE. 25.7% (n = 49) were rechallenged and 18.9% (n = 36) experienced an irAE after being rechallenged. 34.7% (n = 66) experienced pneumonitis, 22.1%(n = 42) constitutional symptoms, 17.8%(n = 34) gastrointestinal, 10.5%(n = 20) neurological, 10.5%(n = 20) dermatological, 6.8%(n = 13) endocrine, 3.6%(n = 7) hematological, 3.1%(n = 6) musculoskeletal, and 3.1%(n = 6) cardiovascular irAEs. When adjusting for race, sex, line of therapy, and histological type, logistic regression analysis yielded no significant difference in the probability of developing an irAE when comparing patients treated with nivolumab versus atezolizumab and pembrolizumab. Patients treated with atezolizumab (OR:0.17; p = 0.020; 95% CI:0.039-0.757) and pembrolizumab (OR:0.20; p = 0.021; 95% CI:0.055-0.785) were less likely to be hospitalized for an irAE when compared to patients treated with nivolumab. When rechallenged, no difference was noted in recurrent irAE development when comparing pembrolizumab and nivolumab. Cox regression analysis demonstrated that patients treated with atezolizumab (OR:0.36; p = 0.010; 95% CI:0.167-0.781) and pembrolizumab (OR:0.29; p &lt; 0.001; 95% CI:0.291-0.148) had better OS when compared to nivolumab. No difference was evident when comparing White and Black patients experiencing any grade irAE (n = 69, n = 53), grade 3 or 4 irAE (n = 44, n = 40), OS (n = 104, n = 80), and PFS (n = 104, n = 80). Conclusions: Our demonstrated irAE side effect profile is similar to those of published studies. No racial disparities were noted in our cohort when analyzing for any grade irAEs, grade 3 or 4 irAEs, OS, and PFS. Our study yields clinically pragmatic insight into better understanding how various factors, such as ICI selection and race, may impact patient outcomes.