Avoidable emergency department visits among palliative care cancer patients: novel insights from Saudi Arabia and the Middle East.

BACKGROUND: Several studies emerging from developed countries have highlighted a significant number of potentially avoidable emergency department (ED) visits by cancer patients during the end-of-life period. However, there is a paucity of information from developing nations regarding palliative care practices and the utilization of the ED by palliative care patients. Herein, we aim to characterize ED admissions among patients receiving palliative care at our tertiary center in Saudi Arabia. METHODS: This is a retrospective, cross-sectional study evaluating ED visits amongst adult patients with advanced cancer who were receiving treatment under the palliative care department. This study took place over a period of 12 months from July 2021 through to July 2022. Three palliative care specialist physicians independently and blindly reviewed each patient's ED visits and determined whether the visit was avoidable or unavoidable. RESULTS: A total of 243 patients were included in the final analysis, of which 189 (78.1%) patients had unavoidable visits and 53 (21.9%) patient visits were classified as avoidable. A significantly higher proportion of breast cancer patients presented with unavoidable admissions (14.3% vs. 3.8%, P = 0.037) compared to other cancer types. The incidence of dyspnea (23.8% vs. 5.7%, P < 0.001) and fevers/chills (23.3% vs. 5.7%, P = 0.005) was significantly higher in patients with unavoidable visits. Patients with avoidable visits had a significantly greater proportion of visits for dehydration (13.2% vs. 2.1%, P = 0.002). Notably, although hospital stay was significantly longer in the unavoidable group (P = 0.045), mortality for palliative care patients-regardless of whether their ED visit was avoidable or unavoidable-was not statistically different (P=-0.069). CONCLUSION: To our knowledge, this is the largest and most comprehensive study from Saudi Arabia and the Middle East providing insights into the utilization of palliative care services in the region and the propensity of advanced cancer patients towards visiting the ED. Future studies ought to explore interventions to reduce the frequency of avoidable ED visits.

Cellular senescence in brain aging and cognitive decline.

Cellular senescence is a biological aging hallmark that plays a key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate the effectiveness of senotherapies for these diseases. However, the impact of senescence on brain aging and cognitive decline in the absence of neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic brain injury survivors, obese individuals, obstructive sleep apnea patients, and chronic kidney disease patients can suffer age-related brain changes like cognitive decline prematurely, suggesting that they may suffer accelerated senescence in the brain. Understanding the role of senescence in neurocognitive deficits linked to these conditions is crucial, especially considering the rapidly evolving field of senotherapeutics. Such treatments could help alleviate early brain aging in these patients, significantly reducing patient morbidity and healthcare costs. This review provides a translational perspective on how cellular senescence plays a role in brain aging and age-related cognitive decline. We also discuss important caveats surrounding mainstream senotherapies like senolytics and senomorphics, and present emerging evidence of hyperbaric oxygen therapy and immune-directed therapies as viable modalities for reducing senescent cell burden.

Neutrophil extracellular traps and long COVID.

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan. In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID. Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can drive NET formation through their pro-inflammatory secretome in long COVID. Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.

Bispecific Antibodies in Hematological Malignancies: A Scoping Review.

Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.

Corrigendum: Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

[This corrects the article DOI: 10.3389/fimmu.2023.1200941.].

Reprogramming the immunosuppressive tumor microenvironment: exploiting angiogenesis and thrombosis to enhance immunotherapy.

This review focuses on the immunosuppressive effects of tumor angiogenesis and coagulation on the tumor microenvironment (TME). We summarize previous research efforts leveraging these observations and targeting these processes to enhance immunotherapy outcomes. Clinical trials have documented improved outcomes when combining anti-angiogenic agents and immunotherapy. However, their overall survival benefit over conventional therapy remains limited and certain tumors exhibit poor response to anti-angiogenic therapy. Additionally, whilst preclinical studies have shown several components of the tumor coagulome to curb effective anti-tumor immune responses, the clinical studies reporting combinations of anticoagulants with immunotherapies have demonstrated variable treatment outcomes. By reviewing the current state of the literature on this topic, we address the key questions and future directions in the field, the answers of which are crucial for developing effective strategies to reprogram the TME in order to further the field of cancer immunotherapy.

Comparison of a modified pediatric protocol versus a hyper-CVAD protocol in adolescents and young adults with Philadelphia-negative acute lymphoblastic leukemia: A multicenter retrospective analysis.

BACKGROUND: The outcomes of Pediatric acute lymphoblastic leukemia (ALL) have improved dramatically whereas outcomes for ALL amongst adolescents and young adults (AYA) have lagged behind. The introduction of pediatric-like regimens to manage adult ALL has shown promising outcomes across several analyses. MATERIALS AND METHODS: In this analysis, we aimed to retrospectively compare the differences in outcomes among patients aged 14-40 years with Philadelphia-negative ALL treated with a Hyper-CVAD protocol versus a modified pediatric protocol. RESULTS: A total of 103 patients were identified with 58 (56.3%) in the modified ABFM group and 45 (43.7%) in the hyper-CVAD group. The median duration of follow-up for the cohort was 39 months (range 1-93). There were significantly lower rates of MRD persistence after consolidation (10.3% vs. 26.7%, P = 0.031) and transplantation (15.5% vs. 46.6%, P < 0.001) in the modified ABFM group. 5-year OS rates (83.9% vs. 65.3%, P = 0.036) and DFS rates (67.4% vs. 44%, P = 0.014) were higher in the modified ABFM groups. The incidence of grade 3 and 4 hepatotoxicity (24.1% vs. 13.3%, P < 0.001) and osteonecrosis (20.6% vs. 2.2%, P = 0.005) were higher in the modified ABFM group. CONCLUSION: Our analysis demonstrates that the use of a pediatric modified ABFM protocol demonstrated superior outcomes compared to the hyper-CVAD regimen in the treatment of Philadelphia-negative ALL amongst AYA patients. However, the modified ABFM protocol was associated with an increased risk of certain toxicities including high grade liver toxicity and osteonecrosis.

SARS-CoV-2 epitopes inform future vaccination strategies.

All currently approved COVID-19 vaccines utilize the spike protein as their immunogen. SARS-CoV-2 variants of concern (VOCs) contain mutations in the spike protein, enabling them to escape infection- and vaccination-induced immune responses to cause reinfection. New vaccines are hence being researched intensively. Studying SARS-CoV-2 epitopes is essential for vaccine design, as identifying targets of broadly neutralizing antibody responses and immunodominant T-cell epitopes reveal candidates for inclusion in next-generation COVID-19 vaccines. We summarize the major studies which have reported on SARS-CoV-2 antibody and T-cell epitopes thus far. These results suggest that a future of pan-coronavirus vaccines, which not only protect against SARS-CoV-2 but numerous other coronaviruses, may be possible. The T-cell epitopes of SARS-CoV-2 have gotten less attention than neutralizing antibody epitopes but may provide new strategies to control SARS-CoV-2 infection. T-cells target many SARS-CoV-2 antigens other than spike, recognizing numerous epitopes within these antigens, thereby limiting the chance of immune escape by VOCs that mainly possess spike protein mutations. Therefore, augmenting vaccination-induced T-cell responses against SARS-CoV-2 may provide adequate protection despite broad antibody escape by VOCs.

Unmasking of Brugada syndrome by lamotrigine in a patient with pre-existing epilepsy: A case report with review of the literature.

Brugada syndrome is an inherited cardiac channelopathy arising from mutations in voltage-gated cardiac sodium channels. Idiopathic epilepsy portrays a coalescent underlying pathophysiological mechanism pertaining to the premature excitation of neuronal voltage-gated ion channels resulting in the disruption of presynaptic neurons and the unregulated release of excitatory neurotransmitters. The coexistence of epilepsy and Brugada syndrome may be explained by mutations in voltage-gated ion channels, which are coexpressed in cardiac and neural tissue. Moreover, the incidence of sudden unexpected death in epilepsy has been associated with malignant cardiac arrhythmias in the presence of mutations in voltage-gated ion channels. Lamotrigine is an antiepileptic drug that inhibits neuronal voltage-gated sodium channels, thus stabilizing neural impulse propagation and controlling seizure activity in the brain. However, lamotrigine has been shown to inhibit cardiac voltage-gated sodium channels resulting in a potential arrhythmogenic effect and the ability to unmask Brugada syndrome in genetically susceptible individuals. We are reporting a case of a 27-year-old male patient with a background of presumed idiopathic epilepsy who was initiated on lamotrigine therapy resulting in the unmasking of Brugada syndrome and the onset of syncopal episodes. This case provides further evidence for the arrhythmogenic capacity of lamotrigine and highlights the relationship between epilepsy and Brugada syndrome. In this report, we aim to review the current literature regarding the associations between epilepsy and Brugada syndrome and the impact of lamotrigine therapy on such patients.

Lupus Anticoagulant-Hypoprothrombinemia Syndrome and Pseudotumor Cerebri as an Initial Presentation of Systemic Lupus Erythematosus in a 16-Year-Old Male Patient: A Case Report and Literature Review.

BACKGROUND Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is an exceptionally rare disease caused by prothrombin antibodies, resulting in reduced factor II levels. This disease can present with significant bleeding and is usually associated with autoimmune disorders, particularly systemic lupus erythematosus (SLE). There are currently no guidelines for the treatment of LAHPS, and corticosteroids remain the criterion standard therapy. Pseudotumor cerebri is a disease that involves an idiopathic rise in intracranial pressure in association with papilledema. The coexistence of pseudotumor cerebri with SLE is rare, with an overall incidence of 0.7%. CASE REPORT A 16-year-old male initially presented to our hospital with nausea, headaches, and decreased visual acuity. He was diagnosed with pseudotumor cerebri based on the findings of papilledema and a raised opening pressure on lumbar puncture. Three months later, he presented with macroscopic hematuria and persistent epistaxis. Further investigation revealed a prolonged activated partial thromboplastin time and prothrombin time, along with positive LA and reduced Factor II levels, resulting in a diagnosis of LAHPS. The patient received a dose of 1 mg/kg/day of prednisolone along with hydroxychloroquine, and he had a complete recovery with cessation of bleeding and normalization of laboratory parameters. CONCLUSIONS We are reporting a case of pseudotumor cerebri with a further presentation of LAHPS in a patient found to have SLE. As both associations are rare in the presence of SLE, it is vital to recognize them early to initiate adequate management and intervention to avoid life-threatening complications.

Erdheim-Chester Disease Successfully Treated with Front-Line Single-Agent Dabrafenib.

BACKGROUND Erdheim-Chester disease (ECD) is a clonal disease characterized by histiocytic infiltration of multiple organ systems. As ECD is a rare disorder with variable presentations, its diagnosis and management can present a significant clinical challenge. The diagnosis of ECD requires several clinical, radiological, and histological criteria. Since approximately 75% of ECD patients harbor a mutation in the proto-oncogene BRAF V600E, inhibition of BRAF activation by BRAF inhibitors has significantly improved the management of ECD. Vemurafenib was approved by the U.S. Food and Drug administration for treatment of BRAF-mutated ECD. Another BRAF inhibitor, dabrafenib, has been used in some cases as a single agent and was associated with a lower toxicity profile. CASE REPORT We report the case of a 30-year-old Saudi Arabian woman who initially presented with a history of diffuse abdominal pain and fever. The patient had elevated inflammatory markers, and radiological investigations revealed hypermetabolic regions in the frontoparietal brain lobe, anterior pericardium, kidneys, and the anterior abdominal wall. Histological investigations from the right perinephric soft-tissue mass revealed foamy histiocytes associated with mild chronic inflammation. Furthermore, BRAF V600E was mutated in the biopsy sample, leading to a diagnosis of BRAF-mutated ECD. The patient began single-agent dabrafenib therapy at 75 mg twice daily and experienced an excellent clinical and radiological response with no reported toxicity. CONCLUSIONS Single-agent dabrafenib is effective and well tolerated among ECD patients; therefore, it might be considered as a first-line option for the treatment of BRAF-mutated ECD.