Fatal Adverse Events Research Articles

Disseminated intravascular coagulation is an underestimated but fatal adverse event associated with blinatumomab therapy: A pharmacovigilance analysis of FAERS.

Hematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR025) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab-related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR025 = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR025 = 15.14), and bone marrow failure (n = 14 [3.35%], ROR025 = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11-3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

Safety of Crovalimab Versus Eculizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria (PNH): Pooled Results From the Phase 3 COMMODORE Studies.

To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)-naive and -experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584). Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i-naive versus C5i-switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow-up from the COMMODORE 2 and 1 primary analyses. COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i-switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1-2 arthralgia and rash, and 16 (8%) had Grade 3 events. Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i-naive and C5i-switched patients.

Abstract 4119426: Enhancing early detection of ICI myocarditis cases during hospitalization: A role for large language models

Background: Immune-checkpoint inhibitor (ICI)-induced myocarditis is the most fatal immune-related adverse event (irAE). Early recognition and treatment of ICI myocarditis is associated with improved outcomes. However, current approaches to the diagnosis of ICI myocarditis have limitations. Open-source large language models (LLMs) are an accessible and scalable method of answering queries from human-generated text, and therefore may assist in the real-time early detection of ICI myocarditis among at-risk patients. Research Question: Can a free, open-source LLM detect cases of ICI myocarditis early in admission? Aims: We investigated the ability of a LLM pipeline to screen for ICI myocarditis within one day of admission using hospital medical records. Methods: Hospital admissions of patients on ICI therapy from November 4th, 2021, to September 5th, 2023 were retrospectively reviewed by a multidisciplinary immunotoxicity team using established, published definitions for the presence of ICI myocarditis. Progress notes written the day before, day of, and day after admission were fed into an open-source LLM pipeline built using Mistral 7B OpenOrca with retrieval augmentation generation (RAG). Performance of the LLM was measured via sensitivity and specificity in comparison to the gold standard of manual adjudication. Results: Of the 1874 hospital admissions of patients on ICI therapy, there were 22 (1.2%) cases of myocarditis. The average time to initiation of treatment was 2.45 days. Using notes written within one day after admission, the LLM detected ICI myocarditis with 95.5±8.7% sensitivity and 95.4±1.0% specificity, spending 2.13 seconds per chart. Conclusion: LLMs serve as a useful tool to screen for ICI myocarditis, detecting 95.5% of cases within one day of admission with 95.4% specificity. Future studies will investigate if integrating this tool into the real-time management of irAEs could lead to earlier diagnosis, faster initiation of treatment, and improved patient outcomes.

NCOG-40. RARE ADVERSE EFFECT OF TEMOZOLOMIDE IN A 65-YEAR-OLD FEMALE WITH GLIOBLASTOMA MULTIFORME: A CASE REPORT

Abstract BACKGROUND Temozolomide, an antineoplastic agent is primarily used to treat certain brain tumors, including glioblastoma multiforme (GBM). Common side effects include nausea, vomiting, constipation, loss of appetite, alopecia (hair loss), headache, fatigue, convulsions and rash. A rare (less than 1%) adverse effect includes aplastic anemia refractory to treatment. Herein we present a case of Temozolomide induced severe bone marrow suppression in a 65-year-old woman with GBM refractory to any treatment CASE PRESENTATION A 65-year-old female presented with dizziness and left-hand numbness. Imaging revealed a right hemisphere mass and she underwent partial resection with pathology showing GBM, IDH wildtype, with CDKN2A/B deletion. She was started on radiation therapy with concurrent temozolomide. After nearly 5 weeks of temozolomide/RT, she developed severe thrombocytopenia/neutropenia with onset of neutropenic fever and severe CMV infection, leading to her demise within a week. DISCUSSION Life threatening refractory cytopenias is a very rare side effect of Temozolomide with a high rate of morbidity/mortality. In the case of our patient, she initially had weekly CBC’s which were stable and hence was switched to a monthly schedule. The patient’s ANC and platelets showed a precipitous drop within a month and ended up with aplastic anemia. The development of this rare complication underscores the importance of increased awareness about this often-fatal adverse event and possibly more frequent monitoring to recognize it early, especially in these patients with an already limited life expectancy. A more tailored approach to monitoring blood work may be needed depending on patient factors. CONCLUSIONS Aplastic anemia refractory to treatment is a rare and life threating adverse effect of temozolomide. The frequency of checking blood work for patients on Temodar has not been definitively established with protocols ranging from once weekly to monthly. Given the potential for this fatal adverse event, it is important to develop better tools to help identify patients in whom more frequent monitoring may be necessary.

4E-BP3 deficiency impairs dendritic cell activation and CD4+ T cell differentiation and attenuates α-myosin-specific T cell-mediated myocarditis in mice.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4+ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4+ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4+ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.

Immune responses in checkpoint myocarditis across heart, blood and tumour.

Immune checkpoint inhibitors are widely used anticancer therapies1 that can cause morbid and potentially fatal immune-related adverse events such as immune-related myocarditis (irMyocarditis)2-5. The pathogenesis of irMyocarditis and its relationship to antitumour immunity remain poorly understood. Here we sought to define immune responses in heart, tumour and blood in patients with irMyocarditis by leveraging single-cell RNA sequencing coupled with T cell receptor (TCR) sequencing, microscopy and proteomics analyses of samples from 28 patients with irMyocarditis and 41 unaffected individuals. Analyses of 84,576 cardiac cells by single-cell RNA sequencing combined with multiplexed microscopy demonstrated increased frequencies and co-localization of cytotoxic T cells, conventional dendritic cells and inflammatory fibroblasts in irMyocarditis heart tissue. Analyses of 366,066 blood cells revealed decreased frequencies of plasmacytoid dendritic cells, conventional dendritic cells and B lineage cells but an increased frequency of other mononuclear phagocytes in irMyocarditis. Fifty-two heart-expanded TCR clones from eight patients did not recognize the putative cardiac autoantigens α-myosin, troponin I or troponin T. Additionally, TCRs enriched in heart tissue were largely nonoverlapping with those enriched in paired tumour tissue. The presence of heart-expanded TCRs in a cycling blood CD8 T cell population was associated with fatal irMyocarditis case status. Collectively, these findings highlight crucial biology driving irMyocarditis and identify putative biomarkers.

Predicting Immune Checkpoint Inhibitor-Related Pneumonitis via Computed Tomography and Whole-Lung Analysis Deep Learning

Background: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a fatal adverse event of immunotherapy. However, there is a lack of methods to identify patients who have a high risk of developing ICI-P in immunotherapy. Purpose: We aim at predicting the individualized risk of developing ICI-P by computed tomography (CT) images and deep learning to assist in personalized immunotherapy planning. Methods: We first explored the prognostic value of the commonly used clinical factors. Moreover, we proposed a novel whole-lung analysis deep learning (DL) model, which is constructed using a combination of Densely Connected Convolutional Networks (DenseNet) and Feature Pyramid Networks (FPN). This DL model mines global lung information from CT images for predicting the risk of developing ICI-P, and it is fully automated and does not require manually annotating images. Finally, 157 patients were collected and randomly divided into training and testing sets for performance evaluation. Results: In the testing set, the clinical model achieved an Area Under the Curve (AUC) of 0.710 and accuracy of 0.625. By mining global lung information, the DL model achieved AUC=0.780 and accuracy=0.729 in the testing set, where the DL score revealed a significant difference between ICI-P and non-ICI-P patients. Through deep learning visualization technique, we found that many areas outside of tumor (e.g., pleural retraction, pleural effusion, and the abnormalities in vessels) are important for predicting the risk of developing ICI-P in immunotherapy. Conclusions: The whole-lung analysis DL model provides an easy-to-use method for identifying patients at high risk of developing ICI-P by CT images, which is important for individualized treatment planning in immunotherapy. The performance improvement over the clinical model indicates that mining whole-lung information in CT images is effective for prognostic prediction in immunotherapy.

Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study.

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed to investigate this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age, 63 years). The overall response rate was 90% in response-evaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, high-risk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2-3 months prior to start of KRd treatment significantly decreased PFS and OS in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e., delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AE) were observed in 56% of the patients, and non-fatal or fatal AE that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large, real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial

Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1·0 mg/kg loading dose on day 1 and subsequent daily doses of 0·20 mg/kg from day 2, with options to decrease to 0·15 mg/kg, stay on 0·20 mg/kg, or increase to 0·25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0·14 (95% CI 0·07-0·29; p<0·0001) for patients with haemophilia A and 0·21 (0·10-0·45; p<0·0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. Novo Nordisk.

Osteonecrosis of the jaw in patients with clear cell renal cell carcinoma treated with targeted agents: a case series and large-scale pharmacovigilance analysis.

To optimize the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for cancer patients, we characterized and evaluated ONJ related to TKIs and ICIs by analyzing a public database and reviewing the relevant literature. TKIs and ICIs are limited to drugs that treat renal cancer recommended by the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Kidney Cancer. We described a case series of patients experiencing ONJ while on TKIs or ICIs. We also analyzed spontaneous reports submitted to the FAERS in an observational and retrospective manner between January 2004 and December 2022. Selecting ONJ' adverse events to TKIs and ICIs. Associations between TKIs, ICIs and ONJ were assessed using reporting odds ratios (ROR), drug interaction signals based on the Ω shrinkage measure. 29 patients with ONJ events while on TKIs and ICIs were included in our case series. 240 were related to ONJ AEs. Specifically, 32.1% ICSRs were linked to sunitinib, 16.7% to lenvatinib, 12.9% to pazopanib, 12.5% to nivolumab, 10.0% to axitinib, 5.4% to sorafenib, 5.0% to pembrolizumab, 4.2% to cabozantinib, and 1.3% to ipilimumab. More ICSRs were generally seen in male and reported in Europe. The median age was 63years. Renal cancer and lung cancer was the most common indication for TKIs and ICIs, respectively. Excluding missing data, the prevalence of mortality was highest for sunitinib-related ONJ ICSRs (18.5%), followed by sorafenib-related ONJ ICSRs (15.4%). With the criteria of ROR, sunitinib and lenvatinib were significantly associated with ONJ AEs. With the criteria of Ω, nivolumab + cabozantinib was significantly associated with ONJ AEs. TKIs and ICIs have been reported to have significant ONJ side effects. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

6937 A Rare Case of Pembrolizumab-induced Multiple Endocrinopathies Presenting with Acute Adrenal Crisis Secondary to Isolated ACTH Deficiency - A Case Report

Abstract Disclosure: R. Abdelmasih: None. W. Pan: None. Introduction: Pembrolizumab is an immune checkpoint inhibitor (ICI) that blocks programmed cell death receptor 1 (PD-1) which took a massive leap in the oncology world. However, we are still understanding more about its immune-related adverse events (irAEs). Here we report a case of adrenal crisis due to pembrolizumab-induced hypophysitis and adrenalitis. Case Description: A 74-year-old male with a history of left renal cell carcinoma post left nephrectomy 5 years ago, complicated with lung metastasis for which Pembrolizumab was started. 5 months after, patient developed hypothyroidism and was started on Levothyroxine. 3 months later, Patient presented with lethargy and hypotension. Physical exam revealed hypotension (MAP of 55), fever, and acute encephalopathy. AM cortisol 4.2 ug/dL, Patient was started on IV pressors and a stress dose of Hydrocortisone. Hemodynamics improved, and Hydrocortisone was tapered down. ACTH stimulation test revealed a subnormal response of cortisol 0.2, 1.7, and 2.7 ug/dL at 0, 30, and 60 minutes respectively in the setting of very low ACTH of &amp;lt; 1.5 pg/ml, other pituitary hormones were checked, revealing normal insulin-like growth factor was 116 ng/mL, LH 15.29 mIU/mL, and FSH 27.45 mIU/mL. TSH was high 15 mIU/mL and free T4 was 1.4 ng/dl, levothyroxine dose was increased, and hydrocortisone was maintained at 10 in am and 5 in pm with excellent response. Discussion:ICIs inhibit the immunological pathways that control T-cell activation, leading to multiple immune-related endocrinopathies. Thyroiditis is the most reported one (30%), though anti-PD1-induced hypophysitis is exceptionally rare (&amp;lt; 1%). To date, the pathophysiology of pembrolizumab-induced central AI is not clearly understood, it’s presumed that it causes lymphocytic hypophysitis often presenting with isolated ACTH deficiency. Also, Pembrolizumab-induced primary adrenal insufficiency has seldom been reported and not yet understood, interestingly, anti-steroidogenic enzyme antibodies were absent in those few most reported cases which suggests a different mechanism compared to traditional primary AI. We suggest that our patient had combined primary and secondary adrenal insufficiency based on ACTH stim test result with very low cortisol responses in the setting of very low ACTH, which we believe is what led to such severe presentation of adrenal crisis. Diagnosis of PD1-induced AI can be challenging due to the overlapping of advanced malignancy and AI presentation. A higher level of suspicion is prompted especially in patients who experienced other endocrine irAEs (as our patient who had PDL-1-induced hypothyroidism). We present this case to shed light on this rare yet potentially fatal endocrine adverse event that can be reversed by prompt diagnosis and timely management due to the increasing use of pembrolizumab. More cases are needed for a better understanding of such a rare adverse event. Presentation: 6/2/2024

Adverse events after colonoscopy in a randomised colorectal cancer screening trial

ObjectiveColonoscopy-related adverse events increase the burden of colorectal cancer (CRC) screening. This cross-sectional study evaluates adverse events during and after colonoscopy in a large, randomised CRC screening trial in Norway...

Regional diversity in drug-induced lung diseases among the USA, European Union, and Japan.

Drug-induced lung disease (DILD) is a considerable and potentially fatal adverse event with poorly understood risk factors. Large-scale, data-driven analyses investigating regional discrepancies in DILD incidence are lacking. The aim of this study was to investigate the potential association among DILD prevalence, regional differences and other factors based on large-scale data base. This retrospective observational study analyzed spontaneous adverse event reports from the FDA Adverse Event Reporting System (FAERS) database between January 2010 and December 2020. Regional disparities in DILD incidence were assessed among reports from the United States of America (USA), the European Union (EU), and Japan (JP). Using multivariate logistic regression accounting for age, sex, and reporting years, we calculated the reporting odds ratios (RORs) with 95% confidence intervals. Subgroup analyses were performed for different types of anticancer agents, including tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), and cytotoxic agents. Regional differences in RORs were observed for anticancer drugs in reports from JP and the EU compared with those from the USA (JP, ROR 4.432; EU, ROR 1.291) and for non-anticancer drugs (JP, ROR 3.481; EU, ROR 1.086). Significantly higher RORs were observed for all anticancer drug regimens reported in JP than in the USA (TKIs, ROR 3.274; ICIs, ROR 2.170; ADCs, ROR 2.335; cytotoxic agents, ROR 3.989). The EU reports exhibited higher RORs for TKIs and cytotoxic agents than the USA reports, with no significant differences in ICIs or ADCs (TKIs, ROR 1.679; ICIs, ROR 1.041; ADCs, ROR 1.046; cytotoxic agents, ROR 1.418). The prevalence of DILD in JP, the EU, and the USA differed. These findings have important implications in evaluating the safety profiles of drugs and patient safety in drug development and clinical practice. This study is the first to identify regional differences in DILDs using a large global database.

Clinical efficacy and immune response of BCL-2 inhibitors combined with hypomethylating agents in the treatment of acute myeloid leukemia

ObjectiveAcute myeloid leukemia (AML) is a malignant clonal proliferative disease with a high mortality rate. The combination therapy of BCL-2 inhibitor Venetoclax (VEN) and hypomethylating agents (HMAs) has significant anti-leukemia activity.MethodsWe analyzed the efficacy, safety and immune response characteristics of AML patients who were unfit for high-dose chemotherapy and accepted the medication of VEN + HMAs.ResultsAfter VEN + HMAs treatment, 31 newly diagnosed AML patients had the morphologic leukemia-free state rate (MLFS%) of 80.6% (25/31), complete response rate (CR%) of 54.8% (17/31), the minimal residual disease negative rate (MRD-%) of 51.6% (16/31), and the median progression-free survival (PFS) of 14 months. After treatment, the proportion of bone marrow primitive cells, the MRD level, white blood cell (WBC) count, fibrinogen (FIB) level and the proportion of B cells were significantly decreased. The red blood cell (RBC) count, hemoglobin (HGB) level, platelet count (PLT) count, activated partial thromboplastin time (APTT), the proportion of total T cells, CD8 + T cells and the IFN-γ level were significantly increased. After VEN + HMAs treatment, 12 relapsed AML patients had a MLFS% of 50% (6/12), CR% of 33.3% (4/12), MRD-% of 25% (3/12), and a median PFS of 7 months. After treatment, the proportion of bone marrow primitive cells and MRD level were slightly decreased, the proportions of CD8 + T cells and NK cells were significantly increased, the proportion of B cells and IL-10 level were significantly decreased. 12 AML patients who receive microtransplantation (MST) treatment using VEN + HMAs as a pretreatment regimen had a PFS of 20.5 months, which was much greater than VEN + HMAs group alone. Hematological recovery was better in the MST group with significantly increased RBC count, HGB level and PLT count. The most common adverse events were myelosuppression, agranulocytosis, infection and cardiovascular toxicity. No fatal adverse events were reported.ConclusionThe combination of BCL-2 inhibitors and HMAs had good efficacy and safety in AML patients who were unfit for high-dose chemotherapy, which may improve the immune microenvironment and enhance anti-leukemia immune response.

The risk of intraoperative venous air embolism from neurosurgical procedures performed in the lounging position: an in-depth analysis of detection, management, and outcomes of 1000 consecutive cases

OBJECTIVE The overall benefit of employing a sitting/semisitting position for neurosurgical procedures remains under criticism due to concerns for additional risk, especially the risk of intraoperative venous air embolism (VAE). The aim of this single-center cohort study was to evaluate the frequency and severity of VAEs and associated complications in patients undergoing neurosurgery in the lounging position. METHODS From 2010 to 2020, 1000 patients, including 172 patients with a patent foramen ovale, underwent surgery in the lounging position for different neurosurgical pathologies. All patients were monitored intraoperatively using continuous transesophageal echocardiography (TEE). The anesthesia team documented any observed incidences of VAEs and scored their severity according to the Tuebingen classification system (TCS) for VAE (TCS-VAE). The patients’ clinical condition, radiological findings, and hospital course were subsequently analyzed to assess complications in a retrospective analysis of prospectively collected data. RESULTS In the cohort of 1000 patients, 5 underwent cervical spine surgery and 995 underwent suboccipital craniotomy. VAE was detected by TEE in 51.4% (95% CI 48.4%–54.5%) of patients, with synchronous changes in end-tidal CO2 (grade 2–5 TCS-VAE) noted in 10.2% (95% CI 8.3%–12.3%). None of the patients presented with hemodynamic instability (grade 5 TCS-VAE). Patients with high-grade VAEs were significantly older (p = 0.02) and had lower BMIs (p = 0.001) than the respective mean value of the cohort. VAE grade was not associated with any of the outcome measures such as Karnofsky Performance Scale score, duration of ventilation, length of intensive care unit stay, and length of hospital stay. Postoperative acute respiratory distress syndrome (ARDS) was diagnosed in 0.3% (95% CI 0.0%–0.7%, n = 3) of all cases, and ARDS was associated with perioperative VAE grade (p = 0.001). No patient suffered a new permanent neurological deficit due to a paradoxical VAE. CONCLUSIONS In this large cohort, the risk of an intraoperative VAE during neurosurgery in the lounging position was assessed, and contrary to the general perception in the field, no permanent sequelae or fatal adverse events attributable to VAEs were observed. Furthermore, the overall incidence of ARDS was very low. This study clearly establishes that experienced interdisciplinary teams can safely use the lounging position for neurosurgical procedures.

Proton pump inhibitors and cardiovascular adverse events: a meta-analysis of randomized controlled trials.

Some observational studies suggest a cardiovascular risk from proton pump inhibitor (PPI) treatment, but observational data may be subject to bias. We conducted a meta-analysis of randomized controlled trial data on cardiovascular events during PPI treatment. Manufacturers of PPIs provided data from their PPI clinical trial programs. We included randomized trials with at least 100 subjects, treatment duration >30 days, and a non-PPI comparator (active or placebo). We obtained person-time of exposure per trial, to calculate summary incidence rate ratios (primary analysis) and incident rate differences (secondary analysis). Our primary composite outcome was major adverse cardiovascular events-plus (MACE+), which included nonfatal myocardial infarction, nonfatal stroke, fatal cardiovascular adverse events, hospitalization for unstable angina, or coronary revascularization; events were adjudicated blindly. Cardiovascular outcomes were infrequent in randomized trials of PPIs and our primary analysis found no overall association (summary incident rate ratio, MACE+ events, PPI:placebo, 0.72 (95% confidence interval [CI] 0.42-1.26). There was some heterogeneity by indication category, and by the incidence rate difference metric, gastroesophageal reflux disorder (GERD) trials had 1.04 (95% CI 0.58, 1.50) excess MACE+ events per 100 person-years of treatment versus placebo. Comparisons to active controls generally showed positive incidence rate differences with PPI treatment. Overall, we found no association of cardiovascular events with PPI treatment. Cardiovascular events appeared more frequent with PPI treatment in GERD trials, but results from this subgroup should be interpreted with the limitations of the analysis in mind, including sparse outcome counts and lack of individual patient data.

Subjective symptoms are triggers for the detection of immune checkpoint inhibitor-induced interstitial lung disease and associate with disease severity: a single-center retrospective study

BackgroundInterstitial lung disease (ILD) is one of the most common fatal immune-related adverse events (irAEs). ILD development adversely affects the continuation of anticancer drug therapy, including immune checkpoint inhibitor (ICI) therapy and prognosis. There are no established useful clinical indicators for the early detection of ILD. Furthermore, the factors that lead the attending physician to suspect ICI-induced ILD (ICI-ILD) remain unclear. This study aimed to investigate the ICI-ILD detection based on subjective symptoms and their relationship with disease severity in patients receiving anti-PD-1/PD-L1 antibody.MethodsThis was a retrospective observational study. We enrolled the patients who received anti-PD-1/PD-L1 antibody at Kyoto University Hospital between September 2014 and April 2021. Patients who developed ICI-ILD were stratified into two distinct groups based on factors that triggered the suspicion of ILD development. The “Subjective symptoms” group was defined as patients in whom ILD was detected based on subjective symptoms. Conversely, the “Routine examinations” group was defined as patients in whom ILD was suspected based on scheduled routine examinations. The severity of ILD in each group was assessed and its association with changes in the respiratory symptoms was examined.ResultsOf 926 patients who received anti-PD-1/PD-L1 antibody, 51 patients (5.5%) developed ICI-ILD. The incidence of ICI-ILD in patients with lung cancer was significantly higher than that in patients with other cancers (P < 0.001). Among the patients with ICI-ILD, 27 patients (52.9%) were classified into the “Subjective symptoms” group. The “Subjective symptoms” group exhibited a significantly higher proportion of Grade 3–5 ICI-ILD cases than the “Routine examinations” group (76.2% vs. 23.8%, P = 0.010). At the last visit, before the suspected onset of ILD, 21 of the 27 patients (77.8%) had no symptoms or no change in the respiratory symptoms.ConclusionSubjective symptoms triggered the suspicion of Grade 3–5 ICI-ILD. Enhanced monitoring and patient education could be essential for the early detection of ICI-ILD because ILD may develop rapidly. Our findings might help to manage ICI-ILD in clinical practice.

Palliative use of self-expanding metal stents in initially anticancer treatment-intolerant patients with esophageal cancer

BackgroundThe post-insertion clinical course of esophageal self-expandable metal stents (SEMS) in initially frail patients with esophageal carcinoma (EC) with dysphagia remains unclear. This study aimed to assess dysphagia improvement and evaluate prognosis in initially frail patients with advanced EC following SEMS insertion.MethodsWe retrospectively reviewed EC patients with EC who underwent esophageal SEMS insertion at our institution between January 2014 and March 2023. Inclusion criteria comprised Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 3 or ECOG PS 2 for individuals aged ≥ 75 years and recommendation for best supportive care by a multidisciplinary team.ResultsForty-six patients met the inclusion criteria. Among them, 37 patients (80.4%) were ≥ 75 years old, and 21 patients (45.7%) exhibited ECOG PS 3 or 4. Dysphagia score (DS) ≥ 3 was observed in 27 patients (58.7%). All esophageal SEMS insertions were successfully completed. Post-procedure, there were two fatal cases of aspiration pneumonia and one perforation incident. DS improved to ≤ 1 in 25 patients (54.3%), with multivariate analysis indicating DS 3–4 and Glasgow Prognostic Score (GPS) 1–2 as negative predictive factors. The median overall survival was 4.1 months (95% confidence interval 1.8–6.5).ConclusionsEsophageal SEMS insertion effectively alleviated dysphagia in initially frail EC patients, yet prognosis remained poor, with occurrences of some fatal adverse events. Careful selection of candidates for esophageal SEMS insertions is crucial in this demographic, particularly considering the challenges in improving dysphagia for patients with DS 3–4 and GPS 1–2.

The potential role of lung microbiota and lauroylcarnitine in T-cell activation associated with checkpoint inhibitor pneumonitis

Checkpoint inhibitor pneumonitis (CIP) is a potentially fatal adverse event characterized by new pulmonary infiltrates in cancer patients receiving immune checkpoint inhibitor therapy. This study aims to explore the interplay between lung microbiota, dysregulated metabolites, and host immunity in CIP. We recruited thirteen hospitalized CIP patients, eleven idiopathic pulmonary fibrosis (IPF) patients, and ten new-onset non-small cell lung cancer patients. Bronchoalveolar lavage fluid samples were collected for 16S rRNA gene sequencing. The percentages of immune cells were determined using manual counting and flow cytometry. Interactions among microbiota, metabolites, and lymphocytes were analyzed using cultured mouse splenocytes and human T cells. Proteobacteria emerged as the dominant phylum, notably abundant in both the CIP and IPF groups. Vibrio, Halomonas, Mangrovibacter, and Salinivibrio were the predominant microbiota because of their discriminative abundance patterns. Vibrio (r=0.72, P-adj=0.007) and Halomonas (r=0.65, P-adj=0.023) demonstrated strong correlations with lymphocytes. Vibrio metschnikovii and Mangrovibacter plantisponsors were more abundant in the CIP group than in the IPF group. Lauroylcarnitine, a key intermediary metabolite co-occurring with the predominant microbiota, exhibited a potent effect on cytokine secretion by mouse and human T cells, notably enhancing IFN-γ and TNF-α production from CD4 and CD8 cells invitro. Lauroylcarnitine, co-occurring with the predominant lung microbiota in CIP, could activate T cells invitro. These findings suggest potential involvement of lung microbiota and acylcarnitine metabolism dysregulation in the pathogenesis of CIP. This work was supported by Peking University People's Hospital Scientific Research Development Funds (RDJ2022-15) and Provincial Key Clinical Specialty Capacity Building Project 2020 (Department of the Respiratory Medicine).

Safety, tolerability, and pharmacokinetics of antisense oligonucleotide BIIB078 in adults with C9orf72-associated amyotrophic lateral sclerosis: a phase 1, randomised, double blinded, placebo-controlled, multiple ascending dose study

Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. Biogen.