Brain metastases are a common occurrence in both non-small cell and small cell lung cancer with the potential to affect quality of life and prognosis. Due to concerns about the accessibility of the central nervous system by systemic chemotherapy agents, the management of brain metastases has historically relied on local therapies including surgery and radiation. However, novel targeted and immune therapies that improve overall outcomes in lung cancer have demonstrated effective intracranial activity. As a result, the management of brain metastases in lung cancer has evolved, with both local and systemic therapies now playing an important role. Factors such as tumor histology , oncogenic driver mutations, and symptom burden from intracranial disease impact treatment decisions. Here, we review the current management of brain metastases in lung cancer, highlighting the roles of stereotactic radiosurgery and novel systemic therapies as well as the ongoing questions that remain under investigation. Thus, surveillance brain imaging is routinely recommended for patients with newly diagnosed lung cancer, regardless of symptoms.Brain metastases are the most common adult intracranial tumor, and their incidence is increasing, driven largely by lung cancer.3 The Graded Prognostic Assessment (GPA) index can help predict prognosis in patients with brain metastases based on age, performance status, number of brain metastases, and the presence of extracranial disease.4 This GPA index has also been updated to incorporate gene alteration data including EGFR and ALK mutations in a modified prognostic index (Lung-molGPA), with the highest scores corresponding to a median survival of nearly 4 years.5The morbidity of brain metastases is related to both the direct neurological complications of the disease as well as the side-effects of local therapy. Depending on the size, location, and extent of edema associated with brain metastases, symptoms can include headache, altered mental status, focal motor or sensory deficits, and ataxia. Although the prognosis of patients with lung cancer brain metastases has historically been poor, outcomes are improving with median survival now reaching 12 months overall and 15 months in patients with adenocarcinoma in particular.The treatment of brain metastases in lung cancer combines both local  and systemic therapies. In this review, we summarize the available literature supporting these therapeutic interventions and describe our evidence-based approach to the management of brain metastases in both non-small cell and small cell lung cancer.The systemic treatment of non-small cell lung cancer (NSCLC) has advanced significantly over the last decade due to the emergence of tyrosine kinase inhibitors (TKI) and immunotherapy. Although the central nervous system (CNS) has been classically considered a protected site due to the presence of the blood-brain barrier, these novel therapies have good intracranial penetration and are changing the management of intracranial disease in lung cancer. In addition, radiotherapy strategies have evolved, with stereotactic radiosurgery (SRS) supplanting whole-brain radiotherapy (WBRT) in most circumstances. As a result, the management of patients with intracranial metastases from NSCLC remains complex and requires multidisciplinary care that takes into account the presence of oncogenic driver alterations, the size, number, and volume of intracranial lesions, and the extent of extracranial disease .6 A more recent prospective study of patients with oligometastatic NSCLC, 44% of whom had brain involvement, reported that the addition of definitive surgery or radiation to both primary and oligometastatic disease sites resulted in a 3-year overall survival rate of 17.5%, which compared favorably to historical controls.7 Factors associated with improved outcomes in this setting include lower primary (T) and lymph node (N) stage within the lung and concurrent definitive management of the primary tumor with complete resection or radiation.8–11 Therefore, any decision to pursue an aggressive, definitive-intent surgical approach for an asymptomatic, solitary brain metastasis must carefully consider a patient’s overall stage of disease and his or her fitness for treatment including surgery and chemotherapy.For patients with large parenchymal brain metastases with symptomatic mass effect and reasonable performance status and prognosis, or when there is diagnostic uncertainty, surgical resection is the preferred initial treatment. Surgery may also be considered as one part of a definitive, multi-modality treatment approach for patients who present with oligometastatic NSCLC in the form of solitary brain metastasis. In an older, randomized trial of patients with single brain metastasis, the majority of whom had lung cancer and no evidence of disease outside of the brain and primary site, the addition of surgical resection to WBRT significantly prolonged overall survival.13 However, the role of WBRT has declined due to advances in systemic therapy as well as radiotherapy delivery. Image-guided systems have enabled stereotactic radiosurgery (SRS), which allows the delivery of high doses of radiation to small targets with high precision. In addition to the improved side effect profile compared to WBRT, the ablative doses of SRS improve local tumor control, particularly for radioresistant histologies. Reducing long-term neurotoxicity and local progression is increasingly important in the setting of improved systemic therapy and survival in patients with lung cancer. Post-operative SRS to the resection cavity has a less deleterious cognitive impact than WBRT in the adjuvant setting and is, therefore, the standard of care for patients with limited brain metastases following resection.14 Further details of radiation modalities and techniques are well-covered in other articles in this issue (“Advances in radiation therapy for brain metastases”).Following surgical resection of brain metastases, postoperative radiation is recommended to reduce the risk of local recurrence. WBRT had previously been the standard treatment as it addresses both gross and microscopic intracranial disease and decreases the risk of local recurrence, distant intracranial recurrence, and neurologic death.Patients with brain metastases from NSCLC without a driver mutation are managed similarly to patients with brain metastases from other primary sites.SRS and WBRT.—Patients with small, asymptomatic brain metastases can be treated with radiation alone without resection. As in the adjuvant radiation setting, SRS is increasingly used for intact brain metastases to balance treatment toxicities with intracranial control. For patients with a limited number of brain metastases, SRS is preferred as it has improved cognitive outcomes compared to WBRT, with no difference in survival.15 While SRS trials have included patients with up to 3–4 brain metastases, there are accumulating prospective data supporting SRS for patients with up to 10–20 brain metastases.17 Additionally, total intracranial tumor volumes are better correlated with survival than is the number of brain metastases.18 However, SRS is not without risk and can result in the development of post-treatment radiation necrosis given the high doses of radiation used. Radiation necrosis is an inflammatory reaction around an irradiated lesion that can be symptomatic and may require management with steroids, bevacizumab, and/or resection.19 Patients with guarded prognosis and poor performance status, however, may derive little benefit from WBRT. The Quality of Life after Treatment for Brain Metastases (QUARTZ) trial randomized patients with advanced NSCLC to best supportive care including dexamethasone with or without WBRT. There was no clinically meaningful benefit in terms of quality of life or survival with the addition of WBRT. Notably, patients on this trial had a median survival of only 2 months.20 Subset analyses suggested improved survival with WBRT for younger patients with higher performance status and controlled primary disease. Thus, for certain patients with limited expected survival, the best supportive care is an acceptable alternative.For patients with brain metastases who are not candidates for radiosurgery, WBRT with hippocampal sparing and memantine to reduce the adverse impact of radiation on quality of life and neurocognition is the new standard of care.21 Leptomeningeal disease can cause significant symptoms including cranial and spinal neuropathies and headaches due to elevated intracranial pressure and hydrocephalus. Focal radiation can be directed to symptomatic, bulky disease in the brain or spine and can lead to symptom improvement. While irradiation of the entire craniospinal axis is not typically recommended due to concern for significant myelosuppression and neurotoxicity, newer techniques using protons can potentially improve the tolerability of craniospinal irradiation.22 Intrathecal methotrexate and cytarabine have also been studied in leptomeningeal disease from solid tumors but are only modestly effective and are limited by side-effects including chemical meningitis.23 Additionally, systemic therapies with intracranial activity, such as pemetrexed, bevacizumab, and targeted therapies, now offer better-tolerated, potentially more effective alternatives beyond intrathecal chemotherapy and WBRT, as discussed below.24For patients with leptomeningeal disease, WBRT is an important palliative treatment option. Although WBRT has not been shown to improve survival in this clinical scenario, its effect on symptoms or quality of life was not evaluated.25–28 RTOG 0214 randomized 356 patients with stage III NSCLC to PCI or observation following initial therapy and found that PCI significantly reduced the incidence of brain metastases (1 year 7.7% versus 18.0 %) but did not improve overall or disease-free survival.28 The long-term update of this trial did find a survival benefit among patients who did not undergo surgery, suggesting that perhaps certain patient subgroups could benefit long-term from PCI.27 A recent phase 2 randomized trial of PCI among 84 patients with Stage IIIB or IV NSCLC at high risk for developing brain metastases (adenocarcinoma subtype with targetable mutation and elevated CEA) did show a survival benefit .29 It is important to note, though, that patients on this study did not have access to third-generation TKIs which have been proven to be highly effective at decreasing the incidence of brain metastases as discussed later in this review. More study is warranted of the benefit of PCI in NSCLC in the setting of newer systemic therapies and in specific patient populations before this treatment can be adopted into standard practice.Finally, prophylactic cranial irradiation (PCI) has also been explored for NSCLC but unlike in small cell lung cancer (SCLC), most studies have failed to show a survival benefit with the addition of PCI.Non-targeted systemic therapy: chemotherapy, immunotherapy & bevacizumab.—Chemotherapeutic agents have traditionally had limited intracranial activity. However, most patients with brain metastases will have concurrent extrathoracic disease that requires systemic therapy. In patients whose tumors lack an oncogenic driver mutation, chemotherapy typically forms the backbone of such therapy. Although several studies did not show a survival benefit with the addition of chemotherapy to radiation in patients with NSCLC brain metastases and limited extracranial disease, these trials primarily evaluated chemotherapy regimens that are not widely used today for the systemic treatment of NSCLC.31 On the other hand, studies of platinum-doublet chemotherapy have demonstrated comparable overall survival and, in some cases, intracranial response rates in patients receiving chemotherapy alone with radiation reserved for the time of progression versus concurrent upfront chemotherapy plus radiation.32–3435 Consistent with pemetrexed’s histology-specific activity, the rate of brain-only metastases at progression was significantly lower in patients with non-squamous cell lung cancer whereas no difference was seen between pemetrexed and other regimens in patients with squamous cell lung cancer. In a prospective study of patients with NSCLC presenting with asymptomatic brain metastases, the combination of cisplatin plus pemetrexed was associated with an intracranial objective response rate (ORR) of 42%.36 However, all patients also received WBRT following up to 6 cycles of cisplatin plus pemetrexed.Pemetrexed is an antimetabolite used in combination with cisplatin or carboplatin for non-squamous cell lung cancer that has shown encouraging intracranial activity. In a retrospective analysis of two-phase 3 trials of metastatic NSCLC, the incidence of brain-only metastases at the time of progression was significantly lower in patients receiving pemetrexed compared to non-pemetrexed chemotherapy (3.2% vs. 6.6%).EGFR mutation or ALK/ROS1 rearrangements. In a recent phase 2 trial assessing the intracranial activity of pembrolizumab monotherapy (PD-1 inhibitor) in patients with NSCLC presenting with asymptomatic, untreated, or progressing intracranial metastases measuring 5–20 mm in size, the intracranial ORR was 30% in patients with PD-L1 expression ≥1%.37 In comparison, no responses were seen in a second, smaller cohort of patients whose tumors were negative or not evaluable for PD-L1. In a separate phase 2 trial of pembrolizumab monotherapy in patients with leptomeningeal metastases from multiple cancer histologies, stable intracranial disease was reported in 55% of the heavily pretreated cohort according to Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria.38 While this suggests possible activity for more advanced intracranial disease, only one patient in this cohort had NSCLC, and further study of leptomeningeal disease is therefore necessary.Immune checkpoint inhibitors targeting the PD-1/PD-L1 and CTLA-4 axes are now routinely used alone or in combination with chemotherapy as first-line treatment of metastatic NSCLC that does not harbor an 39 In addition, studies of pembrolizumab in patients with melanoma suggest that salvage local therapy is frequently required for lesion growth, edema, or hemorrhage even in patients not receiving upfront radiation for lesions measuring 5–20 mm in size.40 Because studies to-date evaluating pembrolizumab in patients with intracranial metastases have had strict inclusion criteria, their findings are also of limited generalizability to patients with larger and/or symptomatic lesions. Consistent with the hypothesis that radiation may augment immune functions such as antigen presentation and T-cell activation, retrospective studies have also suggested a local control and survival benefit for concurrent checkpoint inhibition plus SRS in lung cancer and other malignancies.42 While these studies showed combined checkpoint inhibition and intracranial radiation to be safe without an increased incidence of radiation necrosis or other neurological complications, others have suggested increased rates of radiation necrosis with the combination approach.43 Patients receiving immunotherapy may also develop a transient enlargement of brain metastases following SRS, termed “pseudoprogression”, which may be symptomatic or mistaken for true progression.44 Therefore, as with any other novel therapy, prospective studies are eagerly awaited to define the role and safety of concurrent checkpoint inhibition and radiotherapy and identify predictive factors for their combined use in patients with intracranial metastases.Despite these findings, the brain is still a frequent site of recurrence in patients receiving checkpoint inhibitor therapy. Follow-up analysis of the PACIFIC trial, for example, showed that among patients with extrathoracic disease recurrence, the brain was a site of involvement in 62% of patients receiving durvalumab versus 67% of those receiving placebo.45–47 This paved the way for the phase 2 BRAIN trial, which demonstrated similar rates of response to carboplatin, paclitaxel, and bevacizumab in both intracranial and extracranial lesions  in patients with untreated, asymptomatic brain metastases from NSCLC.48 In a retrospective analysis of the AVAiL trial, the addition of bevacizumab to cisplatin plus gemcitabine in patients without baseline intracranial disease was also associated with a significant reduction in the incidence of intracranial metastases as site of first progression (2.6% vs. 5.8%).49 Similarly, despite not meeting the trial’s primary endpoint, the addition of bevacizumab to adjuvant chemotherapy in the ECOG-ACRIN E1505 trial was associated with a lower risk of brain metastases as the first site of recurrence in subset analyses.50Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has also been studied in patients with brain metastases in combination with both radiotherapy and other systemic agents. Although early trials excluded patients with brain metastases due to concerns about the risk of intracerebral hemorrhage, subsequent analyses showed bevacizumab to be safe in patients with brain metastases from solid tumors.51 In addition, the role of bevacizumab in metastatic NSCLC overall continues to evolve now that targeted therapies and immune checkpoint inhibitors occupy clearly defined roles in the metastatic setting. Therefore, while bevacizumab appears to be safe in combination with intracranial radiation in metastatic solid tumors, further work is needed to determine the most effective and optimal use of bevacizumab in patients with lung cancer intracranial metastases.52On the other hand, the addition of bevacizumab to erlotinib in the NEJ026 trial did not improve PFS compared to erlotinib alone in the subset of patients with baseline brain metastases.Overall, pemetrexed, pembrolizumab, and bevacizumab do not replace the need for local radiotherapy. However, the added intracranial activity with each of these systemic therapies has the potential to improve overall outcomes in combination with radiotherapy. This is particularly important in patients without targetable oncogenic driver mutations who lack oral TKI therapy options and remain at risk for developing intracranial progression during the course of their disease.EGFR-targeted therapies.—Patients with a driver mutation will respond to many of the brain-penetrable TKI therapies, which may allow deferral of local therapy for asymptomatic brain metastases. Although this strategy has not been tested in randomized trials, third-generation TKIs such as osimertinib can achieve high intracranial concentrations53 and have shown intracranial response rates of up to 91%  for new or progressing brain metastases found no statistically significant difference in time to overall progression or time to intracranial progression in patients receiving TKI therapy with or without radiotherapy.57 These results suggest that deferral of upfront radiation may be a safe strategy for carefully selected patients receiving newer-generation therapies, particularly if brain metastases are small and asymptomatic. However, to what extent lesion size, number of metastases, and/or presence of symptoms should impact therapeutic decision-making remains unclear. Additionally, deferral of radiotherapy may also not be appropriate for patients with limited oligometastatic disease for whom an aggressive local ablative approach is considered. Prospective confirmation is therefore awaited, with the phase II OUTRUN trial (NCT03497767) currently underway to evaluate osimertinib versus osimertinib plus SRS in patients with ≤10 intracranial metastases. In the meantime, while the optimal combination and sequencing of TKI and SRS and impact of treatment strategies on outcomes such as quality of life remain to be clarified prospectively, patients who are managed with TKI alone and deferral of radiotherapy upfront should get short-interval imaging to confirm the response of intracranial disease.p to 91% .54 AlthoALK-rearrangements and other oncogenic drivers.—Although EGFR serves as the paradigm for driver mutated lung cancer, brain metastases are also frequently seen in lung cancers harboring less common targetable alterations such as ALK, ROS1, or RET rearrangements or BRAF, HER2, or MET exon 14 skipping mutations.63–68 In ALK-rearranged lung cancer, three FDA-approved, first-line inhibitors  demonstrate high intracranial response rates ranging from 78–82% in patients with measurable intracranial disease  may provide a rationale for using lorlatinib in the relapsed, refractory setting regardless of baseline CNS metastases.69 disease .58–62 WhEGFR-mutant lung cancer, a remaining question with highly effective ALK inhibitors is when to use them alone versus in combination with radiotherapy for intracranial metastases at diagnosis. In a secondary analysis of the ALEX trial, the superiority of alectinib over crizotinib was maintained regardless of prior intracranial radiotherapy, with comparable intracranial response rates among patients with measurable CNS disease who did and did not receive prior radiotherapy (86% vs. 79%).59 However, the cumulative incidence rate (CIR) of intracranial metastases was lower in those patients with baseline CNS metastases who received alectinib plus radiotherapy compared to alectinib alone , suggesting that long-term intracranial disease control may be improved with radiotherapy compared to the use of ALK-directed TKI therapy alone. In one multi-center retrospective analysis, neither time to overall progression nor time to intracranial progression was statistically different in patients receiving alectinib, lorlatinib, brigatinib, or ensartinib alone versus in combination with radiotherapy.57 However, among those patients receiving radiation, there was a trend toward having larger and/or symptomatic intracranial metastases. Therefore, ongoing studies are needed to define which patients with ALK-rearranged NSCLC in the era of brain-penetrable TKI therapy will continue to benefit from upfront radiotherapy due to being at higher risk for intracranial progression.As with ROS1-rearranged NSCLC, lorlatinib had an intracranial response rate of 64% in patients who were TKI-naïve.70 Capmatinib and tepotinib are both active in lung cancer harboring MET exon 14 skipping mutations, with associated intracranial response rates of ~50%.72 Finally, selpercatinib has been reported to have an intracranial response rate of 91% in patients with RET-fusion-positive NSCLC.73 In many of these trials, however, the number of patients with evaluable CNS disease was small, and therefore, as these and other novel targeted therapies continue to be studied, intracranial activity should remain an important benchmark in clinical trials.Brain-penetrable therapies are also emerging for other infrequent driver mutations. In Leptomeningial disease.—Patients with driver-mutated lung cancer are also at risk of leptomeningeal metastases during their disease course. For EGFR-mutant NSCLC, the incidence of leptomeningeal disease has been reported to be higher than that of wild-type EGFR cohorts (9.4% versus 1.7%).74 Fortunately, osimertinib appears to be active in this setting as described in the phase I BLOOM trial, which reported a leptomeningeal ORR of 62% according to RANO criteria and complete cytologic clearance from the CSF in 28% of patients receiving osimertinib 160 mg daily.75 Notably, response rates were numerically similar (55% versus 57%) in patients receiving or not receiving prior intracranial radiotherapy. Whether high-dose osimertinib is required to achieve intracranial concentrations sufficient to treat leptomeningeal disease has come into question as standard-dose osimertinib 80 mg daily has also shown activity in a retrospective series and may therefore represent a better-tolerated option.76 Collectively, these results suggest that osimertinib represents a potential radiation-sparing treatment option in patients with EGFR-mutant lung cancer metastatic to the leptomeninges. Prospective trials of other brain-penetrable TKI therapies targeting driver mutations beyond EGFR are needed to confirm whether a similar approach can be taken in these patients with leptomeningeal disease as well, as has been suggested by early case reports.77Post-progression management after TKI therapy.—Patients managed with TKIs can also develop isolated intracranial progression while on therapy. It is unclear whether this is due to acquired resistance versus the brain being a “sanctuary” site. This underscores the need for brain-penetrable TKI therapies that not only effectively treat existing intracranial metastases but also lower the cumulative incidence of subsequent metastases. For patients who develop new or progressing intracranial metastases on TKI therapy, radiotherapy at the time of progression remains an effective option enabling continued use of post-progression TKI therapy.78 Alternatively, the systemic therapies described above for patients without a driver mutation  can also be considered in the later-line setting following TKI therapy especially if there is concurrent extracranial progression as well. Some TKI therapies such as osimertinib have also been safely used in combination with carboplatin-doublet chemotherapy.79 The choice to continue TKI therapy while also adding chemotherapy may be particularly advantageous in patients who experience extracranial progression but are considered to have ongoing control of intracranial disease from their TKI therapy.Future directions: genetic drivers of brain metastases.—Driver alterations such as those occurring in EGFR and ALK are responsible for tumorigenesis and therefore represent early, seminal genetic events in lung cancer development. Branched evolution of lung tumors over time, however, may lead to the development of additional genetic alterations that differ between metastases and primary tumors, thereby contributing to genetic heterogeneity across sites of disease.80 In the case of lung adenocarcinoma, sequencing analyses comparing primary tumor versus metastatic brain sites have identified alterations that are more common in brain metastases such as amplification of MYC and mutations in TP53.82 If such alterations underlie the ability of tumors to metastasize to the brain, development of therapies targeting these alterations could eventually enable a systemic treatment approach that is specifically tailored to the genetic environment driving lung cancer brain metastases.Small cell lung cancer differs from NSCLC in that its natural history reflects more rapid growth and dissemination. Given concern for high rates of occult brain metastases among patients with SCLC, brain management has typically included WBRT for patients with known brain metastases and PCI for patients without known brain metastases. However, this paradigm has been shifting with improved imaging surveillance and radiation technology .83 Patients with ES-SCLC treated with PCI following chemotherapy also had decreased incidence of symptomatic brain metastases and increased survival on the EORTC trial.84 However, these trials were conducted in an era prior to routine brain imaging. A more recent trial from Japan of patients with ES-SCLC who had a response to chemotherapy required brain MRIs prior to randomization and randomized patients to PCI or active surveillance with brain MRIs every 3 months during the first year followed by every 6 months during the second year.85 The trial was stopped early due to futility. While PCI did decrease incidence of brain metastases (1-year cumulative incidence of brain metastases 33% with PCI versus 59% without PCI), the trial failed to show a survival benefit with the addition of PCI.PCI has been studied in the randomized setting in both limited-stage (LS) and extensive stage (ES) SCLC. A meta-analysis of 7 randomized trials showed that among patients with LS-SCLC who achieved a complete remission to chemotherapy, PCI decreased the incidence of brain metastases by almost half and improved 3-year survival by 5%.Thus, for patients with ES-SCLC who have good response to chemotherapy, both PCI and active surveillance with brain MRIs and early salvage are appropriate, and shared decision-making to evaluate risks and benefits of either approach is warranted. PCI reduces the incidence of brain metastases but at the cost of neurocognitive function and quality of life, and its survival benefit has been questioned in the context of improved brain surveillance imaging. A phase 3 trial  is ongoing to evaluate MRI surveillance with and without PCI in both LS- and ES-SCLC.19 memantine, and hippocampal-sparing radiation techniques can be considered. A Dutch randomized trial of hippocampal-sparing PCI (25 Gy in 10 fractions) for 168 patients with SCLC was recently published. In contrast with NRG-CC001, this trial did not demonstrate lower probability of cognitive decline with hippocampal-sparing technique as measured by the Hopkins Verbal learning test.86 Critiques of the trial have included its small sample size and limited power to detect small changes, and several other larger trials are still ongoing . Radiation dose and patient age should also be considered as factors impacting tolerability of PCI. The preferred dose of PCI is 25 Gy in 10 fractions, with higher doses associated with increased toxicity and mortality.87 Older patients are more vulnerable to PCI as 83% of patients older than 60 years developed chronic neurotoxicity at 1 year following PCI compared to 56% of patients younger than 60 on RTOG 0214.88For patients who do proceed with PCI, several strategies can be similarly employed as with WBRT to mitigate neurotoxicity. Extrapolating from the NRG-CC001 trial,15 However, retrospective series have suggested that as with other histologies, SRS may be a reasonable alternative to WBRT for SCLC brain metastases with less adverse effect and no detriment to survival. One of the first studies looking at this retrospectively compared 34 patients with SCLC brain metastases to 211 patients with NSCLC brain metastases treated with radiosurgery.89 There was no difference between the two groups in terms of tumor control, neurological survival, or overall survival. Outcomes with first-line SRS for SCLC brain metastases were recently reported in a large international multicenter “First-line Radiosurgery for Small-Cell Lung Cancer Brain Metastases (FIRE-SCLC)” cohort study.90 This cohort included 710 patients treated with SRS at 28 centers in 6 countries between 1994 and 2018. Median overall survival and time to central nervous system progression were 8.5 and 8.1 months, respectively. One-year cumulative incidence of distant intracranial failure was 41.6%; of patients who received salvage treatment, 33.5% received salvage SRS and only 16.1% received salvage WBRT. Concerning outcomes that may be associated with omission of WBRT were uncommon, with these including leptomeningeal progression (10.8%) and neurological death (12.4%). Finally, the authors compared this cohort with individual patient data (219 patients) from a large published data set of first-line WBRT for SCLC using propensity-score matching. As expected, WBRT was associated with improved intracranial control, but without an improvement in overall survival.WBRT has long been considered standard therapy for SCLC brain metastases due to concern for rapid and diffuse intracranial progression. SCLC was excluded from many of the landmark trials showing superiority of SRS over WBRT in terms of cognitive function for patients with limited brain metastases.With improved systemic therapy  and prognoses for patients with SCLC, the value of long-term neurocognitive preservation maybe even more important. Further, systemic therapy may help control microscopic intracranial disease that previously required WBRT. Based on the above accumulating data suggesting that SRS may be safe and efficacious for some patients with SCLC, there are several ongoing trials evaluating the role of SRS in SCLC. One of these includes a German randomized trial of WBRT versus SRS for 1–20 SCLC brain metastases .91–93 In addition, the immune checkpoint inhibitors, atezolizumab, and durvalumab, are now approved for use in ES-SCLC in combination with cisplatin or carboplatin plus etoposide. However, trials leading to these approvals included only patients with asymptomatic and/or treated brain metastases, and determining whether the addition of immunotherapy changes the natural history of intracranial disease in SCLC requires further assessment.95Given the high risk of brain metastases in SCLC, systemic therapy plays a secondary role in radiation with respect to the management of intracranial disease. However, intracranial activity has been demonstrated in SCLC with regimens that include etoposide, irinotecan/topotecan, and temozolomide.The management of brain metastases in lung cancer requires a collaborative, multidisciplinary approach among radiation oncologists, medical oncologists, and neurosurgeons. Given the impact of brain metastases on both prognosis and quality of life, the effective coordination of local and systemic therapies remains a priority, especially as extracranial disease control in lung cancer improves. To fully optimize the tools currently available for treating intracranial metastases, further prospective studies are needed to evaluate the most effective combinations of local radiotherapy and novel systemic therapies. In the same way that systemic therapy for metastatic lung cancer has evolved from a one-size-fits-all approach to one that accounts for molecular and pathologic tumor features, the goal for intracranial management should be better understand how tumor mutations, immune markers, extent of intracranial disease burden, and other patient- and tumor-specific factors might inform clinical decision-making in the modern treatment era.


Sepsis is triggered by infection-induced immune alteration and may be theoretically improved by pharmacological and extracorporeal immune modulating therapies. Pharmacological immune modulation may have long lasting clinical effects, that may even worsen patient-related outcomes. On the other hand, extracorporeal immune modulation allows short-term removal of inflammatory mediators from the bloodstream. Although such therapies have been widely used in clinical practice, the role of immune modulation in critically ill septic patients remains unclear and little evidence supports the role of immune modulation in this clinical context. Accordingly, further research should be carried out by an evidence-based and personalized approach in order to improve the management of critically ill septic patients. Sepsis  represenSepsis is a life-threatening organ dysfunction, which is caused by dysregulated host response to infection . Sepsis Immune response to pathogen invasion is initiated by the recognition of highly conserved pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), which belong to microorganisms and injured tissues of the host, respectively. These molecules are recognized by specific receptors  that activate multiple intracellular pathways. Specifically, the activation of selective receptors induces the phosphorylation of mitogen-activated protein kinases (MAPKs), Janus kinases (JAKs), or signal transducers and activators of transcription (STATs) . These mThe physiological inflammatory response to pathogen invasion of the body implies immune activation and immune suppression, while sepsis occurs when the balance between these pathways is lost . TraditiIn the last few years, an increasing body of evidence has demonstrated that immune activation and immune suppression happen concurrently and cause organ dysfunction, and the severity of which may be evaluated by the Sequential Organ Failure Assessment (SOFA) score  Table 1Table 1. Immune alteration represents the main pathological pathway that causes and sustains sepsis. Accordingly, immune modulation has appeared as a promising adjuvant therapy in patients who suffer from such disease. Immune modulation may be carried out by specific interventions with the aim to mitigate both pro- and anti-inflammatory bursts, thus allowing for an appropriate and protective response to microbial threat. Immune modulation should be considered as a complementary therapy and should be used with the aim of limiting infection-induced inflammatory alteration by the time appropriate etiologic therapies  are delivered to the patient .In order to limit immune alteration caused by host response to infection, the microbiological threat must be identified and treated. Such an approach implies the identification of both source (organ or system) and agent  that cause infection. The source of infection must be determined by clinical assessment  of the patient and possibly confirmed by radiological examination  . The ideMany different drugs have been tested with the aim to provide immune modulation in patients with sepsis .The pathophysiological hypothesis beyond the administration of immune modulating drugs in patients with sepsis relies on the concept of smoothing both hyper- and hypo-inflammation via synthetic analogues of cytokines that are intended to hold such features. As an example, IFN-γ and the granulocyte-macrophage colony-stimulating factor (GM-CSF) have been investigated in order to provide immune modulation due to pleiotropic effects on innate inflammation. The administration of these drugs has shown controversial efficacy and no significant adverse events ,21. HoweRecently, complement manipulation may play a role in the development of sepsis-associated immune alteration. Specifically, C5a activity has been demonstrated as crucial in the development of inflammatory mediated tissue damage and its inhibition via selective antibodies was demonstrated effective to mitigate sepsis severity in animal models . HoweverIn the last decades, the administration of intravenous immunoglobulins (IVIg) has been increasing in patients with sepsis and such therapy appears characterized by multiple mechanisms of action that include pathogen recognition and killing, toxin scavenging, inflammatory genes-reduced transcription, and anti-apoptosis effects on immune cells . Both poMoreover, glucocorticoids are drugs with immune-modulating properties and mimic hormones that are released by adrenal glands when the organism in under stress . GlucocoFinally, many drugs have been tested with the aim to provide immune modulation via the interaction with ultra-specific pathways of inflammatory host response to infection. As an example, the administration of Sivelestat, a neutrophil elastase inhibitor, may play some role to improve the outcome of septic patients with acute respiratory distress syndrome and disseminated intravascular coagulation . MoreoveExtracorporeal removal of PAMPs, DAMPs, and cytokines is considered the new frontier of immune modulation in patients with sepsis. Such interventions allow mediators removal from the bloodstream via specific characteristics of the internal surface of membranes. Moreover, their application in critically ill patients with sepsis appeared feasible and was made easy by the significant rate of acute kidney injury that required continuous renal replacement therapy (CRRT) . AccordiEBPT are characterized by important features that should be considered when prescribing such interventions . First, Main Application of Extracorporeal Immune Modulation in Critically Ill Septic PatientsMediators removal via extracorporeal therapy may be selective or non-selective  Table 2Table 2. ▪Non selective extracorporeal removal of inflammatory mediators-electrostatic interactions between soluble molecules and the internal surface of the membrane (adsorption);-trans-membrane flux via gradient  and pressure (convection via hemofiltration) concentration, according to the cut-off of the device.PAMPs and cytokines may be non-selectively removed by EBPT via:®, Baxter, IL, USA) are devices for CRRT that are characterized by heparin-coated polymers of sodium methallylsulfonate and polyethyleneimine. They allow adsorption of both pro- and anti-inflammatory cytokines  as well as endotoxin (Oxiris®), both in vitro [® was associated with significant reduction of IL-6 blood level concentration in critically ill patients admitted to the ICU for COVID-19 [Electrostatic interactions regulate mediator removal of many different devices for EBPT. Specifically, acrylonitrile-69 surface-treated  and surface modified membranes , a device made by polymethylmethacrylate that was demonstrated as effective in the removal of IL-8 and IL-6 by in-vitro study [Another EBPT which allows for CRRT and mediators removal by adsorption is Hemofeelro study . However® represented a promising tool to deliver immune modulation in patients with sepsis. This cartridge is made by highly porous polystyrene divinylbenzene copolymer covered with a biocompatible polyvinylpyrrolidone coating and in-vitro studies demonstrated a certain degree of efficacy to remove pro- and anti-inflammatory cytokines [® hemoperfusion compared with standard care on IL-6 blood level concentration and 60-day mortality [Among EBPT that allow mediators removal via adsorption, Cytosorbytokines . Howeverortality .®-100 is a sorbent made by polyethylene beads, whose internal surface contains heparin. Although in vitro studies have shown some efficacy of this EBPT on cytokines (TNF-α), bacteria (Staphylococcus Aureus) and viruses  by adsorption [Moreover, the Seraphsorption , no clinOn the other hand, Coupled Plasma Filtration and Adsorption (CPFA) represents a hybrid EBPT which allows mediator removal via plasma filtration and adsorption by styrene resin. Although in vitro studies demonstrated a direct relationship between cytokines removal and volume of plasma cleared by such device, a recent randomized controlled trial was stopped because of futility. Furthermore, this trial observed a significant rate of clotting (48% of the treatments) despite anticoagulation with heparin .▪Selective extracorporeal removal of inflammatory mediatorsFinally, immune modulation may be performed by trans-membrane removal of mediators via gradient  and pressure (convection via hemofiltration) concentration. However, only membranes with a large pore size (20 nm) , namely ®  hemoperfusion. Toraymyxin® is a cartridge made by polystyrene fibers and Polymyxin-B, a cationic antibiotic that is characterized by high affinity for endotoxin via ionic and hydrophobic bonds [® was demonstrated as effective to improve the outcome patients at high risk of mortality (above 30%) [® has shown immune modulating effect beyond endotoxin removal and very recently it was demonstrated effective as to improve immune suppression by allowing Monocyte Human Leukocyte Antigen-DR increase [® hemoperfusion was used in a cohort of critically ill patients admitted to the ICU for COVID-19 [To the best of our knowledge, endotoxin is the only PAMP that may be selectively removed via adsorption by Toraymyxinic bonds . This deic bonds ,62, althic bonds . Howeverove 30%)  and for ove 30%) . Moreoveincrease . FinallyCOVID-19  who deveImmune modulation offers enticing perspectives of treatment for critically ill septic patients. However, the real application of this complementary treatment is still a matter of debate due to controversial results between laboratory and clinical trials. Sepsis is a clinical syndrome, which complex pathophysiology may be explained by the multifaced genetic  and epigenetic  interplay that characterizes each single patient. Accordingly, a personalized approach to sepsis may address such a gap via the clinical application of biomarkers of single-cell transcriptomics , big datImmune modulation represents a complementary therapy for critically ill patients with sepsis. Among immune modulating strategies, EBPT appear safe and timely targeted compared with longer lasting pharmacological therapies. However, little evidence supports the efficacy of immune modulation in critically ill patients with sepsis. Accordingly, immune modulation remains a matter of debate and further research, carried out by evidence-based and personalized approaches, is warranted in order to improve the management of critically ill septic patients.


Stereotactic body radiation therapy (SBRT) is a promising new method for non-invasive management of life-threatening ventricular arrhythmias. Numerous case reports and case series have provided encouraging short-term results suggesting good efficacy and safety, but randomized data and long-term outcomes are not yet available. The primary hypothesis as to the mechanism of action for SBRT relates to the development of cardiac fibrosis in arrhythmogenic myocardial substrate; however, limited animal model data offer conflicting insights into this theory. The use of SBRT for patients with refractory ventricular arrhythmias is rapidly increasing, but ongoing translational science work and randomized clinical trials will be critical to address many outstanding questions regarding this novel therapy. Standard ablation may employ both an endocardial and an epicardial access approach and require mapping during hemodynamically unstable arrhythmias, and the case may take several hours to achieve a successful outcome. Many patients may also require multiple procedures. Additionally, patients with these arrhythmias often suffer from multiple comorbid conditions, further increasing the peri-procedural risk. In recent years, stereotactic body radiation therapy (SBRT) as a non-invasive treatment option for recalcitrant ventricular arrhythmias has garnered much attention. Multiple case reports and case series have been published, with promising, although variable, degrees of success.7Modern techniques and technology for the catheter ablation of ventricular tachycardia (VT) continue to improve and remain a cornerstone of therapy for the management of these life-threatening arrhythmias.8 Catheter ablation targets these critical isthmuses, and a comprehensive scar homogenization approach that aims to eliminate all potential VT circuits may result in improved outcomes based on the available data.9 Whether and how SBRT exerts its anti-arrhythmic mechanism of action similar to catheter ablation is not yet known.Ionizing radiation has long been used in cancer therapeutics, and, for many years, the focus on SBRT delivery has been to minimize cardiac exposure to radiation. As such, insights as to the potential antiarrhythmic benefits of SBRT are not yet fully understood. Scar-mediated VT depends on surviving myocyte bundles within the regions of fibrosis, which serve as the substrate for unidirectional conduction block to promote reentrant arrhythmia mechanisms.10 The primary histopathological observation in these cases was the widespread myocardial fibrosis. It stands to reason that a primary hypothesis for the SBRT mechanism of action in the elimination of VT is therefore a scar-homogenization effect and elimination of VT isthmuses, similar to that achieved with catheter ablation. A number of animal model studies have supported this hypothesis.12 A recent human study examined 4 previously irradiated explanted hearts following cardiac transplantation.13 Subendocardial necrosis with surrounding fibrosis was seen on histopathological analysis, lending further support to this theory.Early autopsy data have demonstrated the long-term effects of excessive radiation inadvertently delivered to the heart during cancer treatments.14 interest in SBRT as a treatment for refractory ventricular arrhythmias has grown. The capability of SBRT to be delivered in an ambulatory, non-sedated patient in a single fraction during a session of 15–30 minutes is an incredibly attractive option. As such, there are few circumstances that might prevent a patient from feasibly undergoing SBRT. Exclusions include pregnancy, hemodynamic instability, or excessive risk to nearby organs . In general, SBRT is very well tolerated and can even be performed on an outpatient basis.Since the first case report of a patient at prohibitive risk for catheter ablation due to numerous medical comorbidities,Until more data about long-term safety and efficacy become available, it is prudent to limit this novel, palliative therapy to patients who have exhausted options of traditional, proven therapies for ventricular arrhythmias, including heart failure optimization, anti-arrhythmic medications, catheter ablation, and autonomic modulation. Furthermore, it is our practice at our institution to engage in an interdisciplinary discussion with the advanced heart failure team, as recalcitrant ventricular arrhythmias generally warrant consideration of heart transplantation or left ventricular assist device should SBRT fail to control the arrhythmia.2 Other investigators have relied on invasive electroanatomic mapping data during catheter ablation procedures to identify the critical sites for targeting.3 Additionally, the integration of cardiac magnetic resonance imaging (MRI) data with late gadolinium enhancement for detailed scar delineation can also help guide the planning process.5 The readily available 17-segment model, often employed in cardiac imaging, can be utilized to streamline the targeting process and provide a common vocabulary between radiation experts and cardiac electrophysiologists.15The generally accepted dose for radiation therapy is 25 Gy delivered in a single fraction. The ability to target the correct arrhythmogenic substrate is of paramount importance and one that requires an interdisciplinary approach combining cardiac electrophysiology, radiology, and radiation oncology. A number of different methods have been reported to localize ventricular arrhythmias and correlate these to available cardiac imaging studies. Some centers utilize non-invasive electrocardiogram (ECG) imaging (ECGi) with a 256-electrode vest, which the patient wears during programmed stimulation via a previously placed cardiac implantable electronic device (CIED) in order to induce and map the arrhythmia.Figure 1 shows an example of a patient with PTV delineated on planning CT images after the incorporation of surface 12-lead ECG morphology of VT, electroanatomic mapping, and late gadolinium–enhanced cardiac MRI.The patient undergoes a computed tomography (CT) simulation scan with a 1.5-mm slice thickness as well as a 4-dimensional CT for respiratory motion assessment. These images are then combined with the reference data , and the gross target volume is identified on the simulation images via discussion between radiation physicians and electrophysiologists. This is then used to generate the planning target volume (PTV), which is typically expanded slightly beyond the target region in order to account for motion and other uncertainties. The radiation treatment plan is optimized to deliver the prescribed radiation dose to PTV while minimizing exposure to organs at risk (OARs). 16 As multiple case series have followed, nearly all have followed suit with a similar regimen of 25-Gy dose selection.6 Limited animal model data have suggested this as the optimal dose; however, it is important to note that these studies were primarily investigating the effects on atrial tissue.17 Other animal studies have suggested that higher doses may in fact be required to achieve the desired electrophysiologic effect.19 Data from lung cancer studies have indicated that cardiac radiation doses of 40 Gy or more have been associated with reduced overall survival and should therefore be avoided.20 However, it is important to note that the radiation delivery strategy for lung cancer (radiation dose divided over multiple fractions) is much different than that employed for arrhythmia therapeutics (single fraction).The first-in-man report of SBRT for ventricular arrhythmias utilized 25 Gy delivered in a single fraction.21 Vacuum cushions, such as the BodyFix system reported by the original Electrophysiologic-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia (ENCORE-VT) trial, are commonly used to immobilize the patient during radiation delivery.2 An onboard image guidance system, such as cone-beam CT, is necessary for accurate patient positioning before beam delivery. Abdominal compression can be used to reduce organ respiratory motion. The CyberKnife  technology utilizes a fiducial marker such as a temporary pacing wire or the lead of a CIED with gating of radiation delivery to ensure accuracy.4 Patients with a CIED should have their devices interrogated and reprogrammed as appropriate before and after SBRT delivery, in accordance with task force recommendations.22Various methods have been developed to ensure accurate delivery to the targeted tissue and are reviewed extensively elsewhere.23 Restrictive cardiomyopathy, likely owing to myocardial fibrosis, can result in worsening heart failure with preserved ejection fraction, though systolic dysfunction can also occur. Valvular dysfunction due to worsening thickening and calcification of heart valves can cause worsening stenosis or regurgitation. Pericardial disease can result in both acute and chronic pericardial calcification, and thickening can lead to constrictive physiology. Vasculopathy may also occur, classically affecting the ostia or proximal coronary arteries. Finally, radiation can also affect the conduction system, causing anything from sinus node dysfunction to infra-Hisian conduction blocks. With the exception of acute pericarditis, many of these radiation-associated cardiac diseases develop years or decades after exposure. Thus, while faced with the more acute life-threatening consequences of ventricular arrhythmias, the risk–benefit profile may favor SBRT, though these are important considerations when applying this novel therapy to potentially younger, healthier patients. Adverse events of published clinical case series to date are included in Table 1.Radiation-associated cardiac disease has been well described, owing to the off-target effects of cancer radiation therapy such as for breast cancer, lymphoma, or lung cancer. Radiation-associated cardiac disease can present with various manifestations.24 The maximum point doses for these organs are included in Table 2. Pericarditis and pneumonitis are common early adverse effects, which have been reported in multiple case series. In the longer-term report of the ENCORE-VT trial, which is the largest series to date consisting of 19 patients, at a median follow-up of 23.5 months, 1 patient developed pericarditis within 90 days, 2 patients developed pericardial effusions >2 years after SBRT, and 1 patient developed a gastropericardial fistula 2.4 years after SBRT which required surgical correction.25 These toxicities, both cardiac and non-cardiac, will be important to keep in mind as more long-term data become available on patients receiving SBRT for cardiac arrhythmias.OARs are an important consideration when targeting the cardiac tissue for SBRT. Adjacent organs vulnerable to the off-target effects of radiation therapy include the gastrointestinal organs , lung, bronchi, spinal cord, ribs, and pericardium. Taskforce consensus recommendations should be followed to ensure that these OARs do not receive an excessive dose within the field of SBRT.4 3 patients underwent repeat catheter ablation procedures after SBRT. In all patients, there were low-voltage, fractionated potentials within the dense scar regions, which should have theoretically been eliminated with SBRT. If not by myocardial tissue destruction and fibrosis, then alternative hypotheses must be considered.Published case series have reported variable degrees of success with varying time courses of efficacy. The presumed mechanism of action has been principally myocardial necrosis with subsequent fibrosis, thus eliminating critical VT circuits. However, multiple studies have reported early efficacy almost immediately after SBRT delivery, which contradicts this hypothesis. In the case series published by Gianni et al.,26 Conduction slowing was also evidenced by surface ECG characteristics. This might serve as a potential explanation for the early benefits of SBRT reported in certain studies.6 These findings are supported by histopathologic findings of 3 patients after explantation during heart transplant showing minimal fibrosis but significant compromise of intercalated discs.7In a rat model, ionizing radiation was delivered in escalating doses and a histopathological analysis was performed within 4 weeks of exposure. While myocardial necrosis and apoptosis were not observed, disruption of intercalated discs with myocyte vacuolization and intracellular and extracellular edema occurred.12C radiation resulted in the reversal of conduction slowing and reduction in VT/ventricular fibrillation inducibility, with the upregulation of connexin 43.27 Left ventricular systolic function was also improved with radiation delivery compared to the untreated animals with myocardial infarction, which was thought to be due to increased connexin 43 expression within the infarcted regions.Another recent animal study offers an explanation that conflicts with the scar-homogenization theory of SBRT. In a canine infarct model, delivery of 15 Gy via SBRT is an emerging therapy that shows great promise in the management of ventricular arrhythmias. While initial case series have demonstrated encouraging results, many questions remain as to the mechanism of action, time course of benefit, optimal method of delivery, dose selection, and long-term efficacy and safety. Thoughtful, rigorous randomized clinical trials and continued translational work will be critical to answer many of these important questions.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 is the virus responsible for the 2019 global pandemic. Pulmonary complications of COVID-19 are well established in the literature. However, the virus causes numerous extrapulmonary manifestations, notably acute aortic occlusion (AAO). COVID-19 creates a hypercoagulable state via the upregulation of numerous procoagulant cytokines in endothelial cells of blood vessels. We present a case of a 63-year-old patient without a previous history of prothrombotic disorders who developed AAO in the distal abdominal aorta and bilateral common iliac arteries after contracting COVID-19. The patient was a poor surgical candidate and was treated with fibrinolytics that were administered via an EkoSonic™ Endovascular System (EKOS) catheter using a bilateral transfemoral approach. This case highlights a unique treatment option for non-surgical candidates with AAO. Acute aortic occlusion (AAO) has a multitude of etiologies including aortic emboli, thrombosis of an atherosclerotic plaque, aortic stent occlusion and aortic dissection ,2. AcuteAcute aortic occlusion can be managed surgically or non-surgically depending on the health status of the patient. Bilateral transfemoral embolectomy, aortobifemoral bypass and thrombolysis are all viable treatment options that are well described in the literature ,2.We present a case of a 63-year-old patient that developed AAO secondary to COVID-19 infection. This case represents a unique way of treating AAO using fibrinolytics administered through an EKOS catheter using a bilateral transradial approach. A 63-year-old female with newly diagnosed atrial fibrillation with rapid ventricular response (RVR), history of type 2 diabetes, hypertension, and deep venous thrombosis six years ago presented to the emergency department with paresthesia of the left lower extremity. She had been feeling sick over the last few days with a sore throat, cough, and shortness of breath. She denied any chest pain.Physical examination revealed absence of pulses in the left lower extremity and coolness to the touch. Initial laboratory workup in the emergency department was performed, and significant findings are illustrated in table A chest radiograph demonstrated asymmetric haziness in the right lower lateral lung field. A Computed Tomography (CT) scan of the thorax was obtained and showed bilateral pulmonary ground glass opacities and basilar atelectasis, but demonstrated no evidence of pulmonary embolism. Next, a CT of the abdomen was obtained and showed a 1.7 x 1.0 cm filling defect superior to the celiac artery in the abdominal aorta as well as a large occlusive filling thrombus defect just inferior to the renal artery to the level of the common femoral artery bilaterally Figure .In this case, the patient was deemed a poor surgical candidate due to disease severity and comorbid conditions. Therefore, a treatment approach via thrombolysis was elected over traditional surgical bypass or thrombectomy.Bilateral percutaneous radial artery access was obtained because the common femoral arteries were nearly completely occluded with thrombus. This approach was unique because access is traditionally gained via the femoral arteries. Angiography of the abdominal aorta demonstrated patent suprarenal segment with good perfusion to the patient's bilateral renal arteries. However, complete thrombotic occlusion below the level of the renal arteries was present. No flow was visualized into the pelvic arteries. Selective angiography of the bilateral external iliac arteries demonstrated stasis of flow. Bilateral transradial EKOS thrombolysis catheters were placed within the aorta, extending into the lower extremities Figure . The infThe patient expired hours later from cardiopulmonary arrest, likely from severe COVID-19 infection and multiorgan dysfunction but also exacerbated by reperfusion injury. It is unknown whether or not the patient was vaccinated against COVID-19.COVID-19 patients are at increased risk of vascular complications such as arterial and venous thrombi as well as cardiac dysfunctions including arrhythmias and myocarditis ,5. COVIDWhile in-situ aortic thromboses are exceedingly rare, there have been increased reports of COVID-19 resulting in thrombi in abnormal locations such as the aorta . The patAcute aortic occlusion can be treated medically, surgically, or percutaneously. Often, a combination of these techniques is employed. For patients diagnosed with AAO, heparin therapy is initiated as soon as possible . The estReperfusion injury results from the reintroduction of oxygen into a previously ischemic environment. This leads to the activation of endothelial cells and generation of free radicals by leukocytes, which together damages tissue. The inflammatory response causes a hypercoagulable state and vascular permeability. Electrolyte imbalances include hyperkalemia and acidosis. This leads to multisystem organ damage and cardiac arrhythmias . AlthougCOVID-19 can cause thrombus formation in unusual locations like the abdominal aorta. The in-situ thrombi can propagate to the point of causing complete vessel occlusion. EKOS thrombolysis serves as an effective alternative treatment to restore blood flow to previously ischemic tissue in patients who are poor surgical candidates. However, clinicians must be conscientious of reperfusion injury and potential sequelae.


Serum proteins can be readily assessed during routine clinical care. However, it is unclear to what extent serum proteins reflect the molecular dysregulations of peripheral blood cells (PBCs) or affected end-organs in systemic sclerosis (SSc). We conducted a multiomic comparative analysis of SSc serum profile, PBC, and skin gene expression in concurrently collected samples.Global gene expression profiling was carried out in skin and PBC samples obtained from 49 SSc patients enrolled in the GENISOS observational cohort and 25 unaffected controls. Levels of 911 proteins were determined by Olink Proximity Extension Assay in concurrently collected serum samples.Both SSc PBC and skin transcriptomes showed a prominent type I interferon signature. The examination of SSc serum profile revealed an upregulation of proteins involved in pro-fibrotic homing and extravasation, as well as extracellular matrix components/modulators. Notably, several soluble receptor proteins such as EGFR, ERBB2, ERBB3, VEGFR2, TGFBR3, and PDGF-Rα were downregulated. Thirty-nine proteins correlated with severity of SSc skin disease. The differential expression of serum protein in SSc vs. control comparison significantly correlated with the differential expression of corresponding transcripts in skin but not in PBCs. Moreover, the differentially expressed serum proteins were significantly more connected to the Well-Associated-Proteins in the skin than PBC gene expression dataset. The assessment of the concordance of between-sample similarities revealed that the molecular profile of serum proteins and skin gene expression data were significantly concordant in patients with SSc but not in healthy controls.SSc serum protein profile shows an upregulation of profibrotic cytokines and a downregulation of soluble EGF and other key receptors. Our multilevel comparative analysis indicates that the serum protein profile in SSc correlates more closely with molecular dysregulations of skin than PBCs and might serve as a reflection of disease severity at the end-organ level.The online version contains supplementary material available at 10.1186/s13075-021-02633-5. Systemic sclerosis (SSc) is a complex, multisystem disease, characterized by an interplay of immune dysregulation, vasculopathy, and fibrosis . Its cliOur recent study in the Scleroderma: Cyclophosphamide or Transplant Trial (SCOT) comparing the serum protein profile to PBC gene expression of enrolled patients in the concomitantly collected samples based on a panel of 230 measured proteins indicated that the differential expression of most serum proteins in SSc is likely to originate outside the PBCs ), and  cohort . All patPBC RNA collected in PAXgene tubes were obtained from the same participants included in our previously reported SSc skin gene expression study  at the tAs described previously, global gene expression profiling  was perfA total of 981 proteins were assessed in concurrently collected serum samples by Olink Proximity Extension Assay (PEA) technology using 11  biomarker panels. Seventy proteins with more than 50% of observations below the lower limit of detection (LLOD) across the entire study cohort were excluded from the analyses . For the remaining 911 unique serum proteins  quantifies whether the samples that are more similar to each other by one set of measurements  are also more similar to each other in another measurement space . The advantage of this approach is that it can examine relationships between gene (or protein) modules even if they are composed of non-identical / non-overlapping genes (and/or proteins corresponding to them). A Mantel test -based pen = 49) and healthy controls of similar demographic background (n = 25) included in this multiomic study. The majority of patients had diffuse cutaneous involvement (65%) and a large portion of patients (40%) had clinically significant interstitial lung disease.Table Comparison of SSc to control PBC gene expression profiles revealed 78 differentially expressed transcripts after correction for multiple comparisons  list of serum proteins potentially reflecting SSc-Cont differences. As shown in Fig. A concurrently collected serum sample was available in almost all samples , and the proteomic profile of these serum samples was characterized by Olink technology resulting in assessment of 911 distinct proteins. Principal component analysis (PCA) plot . Assessp < 0.05) is provided in Additional file As shown in Fig. ρ = 0.59, permutation p < 0.0001; additional details can be found in Additional file Several serum proteins positively correlating with mRSS that were also upregulated in SSc vs. control comparison, include ECM proteins NOV and THBS4. Similarly, several proteins negatively correlating with mRSS were also significantly downregulated in SSc, such as EGF growth factor receptor (EGFR), EGF-related receptor DNER, and the integrin subunit alpha V (ITGAV). Overall, on the entire set of serum proteins, as shown in Fig. ρ = 0.21, permutation p = 0.012; Fig. ρ = 0.11) which did not reach statistical significance (permutation p = 0.25).In order to compare the SSc serum protein profile with the SSc skin and PBC transcript profiles, we first examined the correlation of serum protein differential expression in SSc vs. control comparison to the differential expression of corresponding transcripts in the examined gene expression datasets. Of the 911 proteins measured in serum, 314 had corresponding transcripts present in PBC, and 448 in skin gene expression data  for the serum proteins with significant SSc-Cont differences, as well as for a wider range of serum proteins , differentially expressed serum proteins were several orders of magnitude more significantly connected to differentially expressed transcripts in skin as compared to PBCs  in these two tissues types in SSc and/or control samples. As shown in Additional file ρ = 0.2, p = 0.002). This suggests strong influence of PBC transcriptional profile onto the levels of circulating proteins in serum for healthy controls. The correlation of similarities between PBC and skin transcriptional profiles for the healthy controls was not significant  and comparable to the correlation observed between serum proteome and skin transcriptional profile observed in the same study group . These two observations taken together suggest that, for healthy controls, the genome-wide similarity of skin transcriptional levels has very little, if any, relevance to the genome-wide similarity of PBC transcriptional levels and to serum protein level similarities. Conversely, the correlation of similarities between molecular profiles of PBC transcriptome and serum proteins in SSc patients is lower in magnitude  compared to correlation between the same compartments in healthy controls. This correlation in SSc patients is also similar to that observed between skin transcriptome profile and serum protein in the same study group . Both correlations are statistically significant with respect to permutation, indicative of the comparable impacts of both skin and PBC transcriptional composition on the levels of circulating proteins in serum of SSc patients. The similarities among gene expression profiles in skin and in PBCs in SSc patients showed the weakest correlation  among all six performed comparisons.Lastly, we focused on the concordance of between-samples similarities at the entire dataset level. Of note, we anticipated a priori that the correlations in this comparison will be weaker than the aforementioned methods because this comparison goes beyond differentially expressed molecules and examines the entire dataset that includes many genes/proteins which are unaltered in the disease state, including housekeeping genes/proteins. However, such agnostic evaluation across all analytes characterized for each pairwise comparison eliminates the potential of introducing the bias associated with variable selection based on intensity, variability or differential expression. Figure In the present study, the comparison of skin and PBC transcriptomic data to serum protein profile in concurrently collected samples examining differential expression, WAP analysis, and overall between-sample concordance showed consistently that the serum proteome reflects molecular dysregulation in the skin tissue, in SSc patients. These results are consistent with our previous findings in the baseline line samples of the SCOT study, in which only a small portion of differentially expressed serum proteins (15.5%) was also differentially expressed in the concurrently collected PBC transcriptome, supporting the notion that differential expression for most serum proteins in SSc is likely to originate outside the PBCs. This finding might be counterintuitive as PBCs and serum proteins are proximally located in the intravascular compartment. The correlative analysis of between sample similarities in the present study indicates that the correlation between the PBC gene expression profile and serum proteome in SSc patients, contrary to healthy controls, is weakened by the spillover effect of molecular dysregulation in the skin tissue. The observed prominent correlations between serum proteins and the extent of SSc skin involvement as assessed by mRSS further supports a link between molecular dysregulation at the serum protein and skin levels in SSc. Consistent with our results, two previous proteomic studies have also shown a large number of serum proteins correlating with mRSS in patients with diffuse cutaneous involvement , 27. CumIn the present study, the Olink platform enabled an interrogation of a large number of serum proteins across broad variety of cardiovascular, metabolic, inflammatory, immune, developmental, neurological, and carcinogenic pathways. Focusing on the biological pathways, one of the notable findings was the downregulation of several soluble growth factor receptors involved in fibrosis including four EGF receptors . EGFR also showed a strong negative correlation with mRSS. These findings are consistent with findings in the SCOT cohort in which soluble EGFR was significantly downregulated in SSc and showed the strongest negative correlation with mRSS . SpecifiThe number of differentially expressed transcripts in the PBC in the present study was lower than previously observed in patients with early diffuse disease with severe internal organ involvement in the SCOT study . HoweverIn relation to SSc pathophysiology, consistently with previously published data –49, inteThe present study has several strengths. To our knowledge, it represents the first, multi-level examination of serum proteome, PBC, and skin gene expression data in concurrently collected samples in patients with SSc. Furthermore, the utilized proteomic platform enabled reliable assessment of a large panel of serum proteins involved in various disease processes. Moreover, the utilized analytic approach goes beyond assessment of differentially expressed proteins and included examination of networks of connected proteins and concordance of between sample similarities. As a result, we have provided three lines of evidence supporting the plausibility of serum proteome reflecting disease process at the end-organ level in SSc: (1) globally, the correlation of the differences between SSc and Cont is more pronounced for serum proteins and corresponding skin, rather than PBC transcripts; (2) serum proteins differentially expressed in SSc are more significantly connected on the pathway network to the skin, than to PBC transcripts dysregulated in disease; and (3) overall concordance of between-subject similarities across the entire serum protein and skin transcript datasets is more pronounced in SSc patients than in healthy controls.However, our study also has some limitations. While it is limited to cross-sectional samples and does not enable evaluation of the longitudinal aspect of SSs pathogenesis, future studies can longitudinally investigate the relationship between PBC, skin, and serum molecular profiles in SSc patients. Additionally, although we used a large-scale, robust platform, comparisons involving serum proteins were limited to the proteins included in Olink PEA panels and could be potentially impacted by expanding these analyses to a wider range of serum proteins. Moreover, the present study was not confined to patients with early diffuse disease, molecular characterization of patients with early severe disease in similar manner represents an exciting possibility that can be pursued in future studies. However, our results are in agreement with the PBC gene expression and serum protein comparative analysis in the SCOT trial which included only patients with early diffuse cutaneous involvement .In conclusion, our study expands the findings of previous reports of the upregulated profibrotic cytokines and downregulated soluble EGF and other key receptors in serum proteome of SSc patients. Furthermore, SSc PBC and skin transcriptome both showed a prominent type I IFN signature. Most notably, the present study represents the first, multi-level examination of serum proteome, PBC, and skin gene expression data in concurrently collected samples in patients with SSc. This enabled a direct comparison of these three sample types and revealed that the primary contributor to SSc serum protein profile is diseased tissue rather than PBCs. This finding underscores the potential utility of serum proteins as attractive surrogate markers for tracking disease severity at the diseased organ level in SSc.Additional file 1. Supplementary Materials; Figures S1-S11.Additional file 2. Tables S1-S8.


Shape memory self-soldering tape used as conductive interconnecting material.Perfect shape and conductivity memory performance and anti-fatigue performance.Reversible strong-to-weak adhesion switched by temperature.−1 and a maximum tensile strain of ~ 100%. The maximum conductivity could be increased to 5446 S cm−1 by decreasing the strain to 17%. Meanwhile, SMSC tape can easily realize a heating induced reversible strong-to-weak adhesion transition for self-soldering circuit. The combination of stable conductivity, excellent shape memory performance, and temperature-switching reversible adhesion enables SMSC tape to serve two functions of electrode and solder simultaneously. This provides a new way for conductive interconnecting materials to meet requirements of modern electronic devices in the future.With practical interest in the future applications of next-generation electronic devices, it is imperative to develop new conductive interconnecting materials appropriate for modern electronic devices to replace traditional rigid solder tin and silver paste of high melting temperature or corrosive solvent requirements. Herein, we design highly stretchable shape memory self-soldering conductive (SMSC) tape with reversible adhesion switched by temperature, which is composed of silver particles encapsulated by shape memory polymer. SMSC tape has perfect shape and conductivity memory property and anti-fatigue ability even under the strain of 90%. It also exhibits an initial conductivity of 2772 S cmThe online version contains supplementary material available at 10.1007/s40820-021-00652-0. In recent decades, modern electronic devices are developing toward integration, miniaturization, flexibility, scalability and biocompatibility –4. ExtenThe most direct method to develop conductive interconnecting materials is to improve the existing interconnecting materials according to the demands of modern electronic devices. For example, tin-bismuth alloy solder with lower melting temperature can be used at processing temperature below 200 °C –23. Howe−1 and a maximum tensile strain of ~ 100%. The maximum conductivity could be increased to 5446 S cm−1 by decreasing the strain to 17%. It also had a perfect shape memory performance with strain fixation ratio and recovery ratio of 100%. Meanwhile, there was no obvious degradation of shape memory performance after repeated stretching-recovery cycles. Thanks to the temperature induced shape recovery property, SMSC tape easily enabled reversible strong to weak adhesion transition. The combination of stable conductivity, excellent shape memory performance and reversible adhesion gives SMSC tape versatility to independently finish the collaborative work of multiple materials or cannot be completed by existing interconnecting materials.In this work, we reported highly stretchable shape memory self-soldering conductive tape (SMSC tape) with reversible adhesion switched by temperature. The SMSC tape exhibited an initial conductivity of 2772 S cmSilver acetate (99%) was obtained from Adamas-beta, saturated ammonia solution (AR 25–28%), formic acid aqueous solution (AR 88%) and stearyl acrylate (SA) (> 96.0% GC) were purchased from Aladdin. Urethane diacrylate (UDA) (CN9021 NS) was acquired from Sartomer. Benzoyl peroxide (BPO) (98%) was purchased from MERYER. They were not purified before use.Ag NPs were prepared by thermal reduced method following a previous report . Silver SMSC tape was prepared by in situ formation of SA-UDA copolymer in blended composite under the condition of anaerobic heating. SA, UDA, BPO, and thermal reduced Ag NPs were proportionally mixed by vortex mixing using as the precursor of SMSC tape. After that, the precursor was degassed in a vacuum oven at 50 °C. Then, the precursor was injected between a pair of warm glass sheets spaced with Kapton tape of 280 μm. The precursor was subsequently cured at 80 °C for 80 min. Finally, the film was cooled to room temperature and gently peeled off from the glass sheets. The film can be further cut into required shape.−1. The tensile strain of SMSC tape was achieved by a home-made stress–strain test system, which was connected with a Keithley 2182A/6221 system to record all the electric signals in real-time. Two quantities, namely strain fixation ratio (Rf) and strain recovery ratio (Rr), were used to evaluated the shape memory performance of SMSC tape. They were, respectively, calculated as following:L0, Ls, Lf, and Lr are original length, tensile length, temporarily fixing length and final recovery length of SMSC tape, respectively. The shear adhesive strength of SMSC tape was also measured using home-made stress–strain measuring system. SMSC tape (5 × 5 mm2) is sandwiched between two copper (Cu) plates by pressing (preloading force of ~ 4 kPa) at the heating state. Two Cu plates are fixed by the clamps in the measuring system, where the adhesive interface is parallel to the tensile direction. The load is recorded in real-time with the increase in distance between two clamps. The recorded maximum load before separation of two Cu plates is the corresponding shear strength. The output voltage and current of TENG made of SMSC tape were measured with a digital oscilloscope  and a low noise electrometer .The morphology of Ag NPs and SMSC tape was observed by SEM . The structural information of Ag NPs and SMSC tape was characterized by XRD (Rigaku Smart Lab SE). DSC analysis was performed by the thermogravimetric analyzer (Netzsch STA 449F5) with a heating rate of 0.5 °C minTm), it is easily deformed to the desired shape. The temporary shape is maintained at room temperature until it is reheated to the melting temperature  is greatly reduced. The former shows that Ag NPs do not decrease the crystallinity of SA-UDA copolymer, while the latter is due to the low specific heat of Ag NPs . Under the condition of anaerobic heating, BPO induces radical reaction between SA and UDA to form the SMP in situ in composite. Meanwhile, the uniformly distributed Ag NPs construct a conductive network in the polymer. Annealing treatment further improves the electric conductivity of SMSC tape  rises, the initial conductivity increases, but the maximum strain decreases  and strain recovery ratio (Rr) are two important quantities for evaluating shape-memory performance. They are calculated using equations described in experimental methods. The former has the ability of switching segments (SA) to fix the temporary shape, while the latter is used to describe the ability of the shape-memory segment (UDA) to memorize the permanent shape. Figure Rf and Rr of SMSC tape as a function of tensile strain. Under different strains from 10 to 90%, the SMSC tape shows perfect ability of shape-fixation and shape-recovery, namely almost 100% Rf and 100% Rr (Video S1). The insets in Fig. SMSC tape containing SA-UDA copolymer encapsulated Ag NPs exhibits almost perfect shape memory performance. Here, 150 °C annealed SMSC tape containing 19.86 wt% SARf has always maintained 100% after 200 cycles, which indicates that the SMSC tape has near perfect anti-fatigue performance in shape-fixation ability. Meanwhile, when the number of cycles is less than 100 times, Rr is also 100%. And from 100 to 200th cycles, the degradation of Rr decreases from 100 to 99.93%. However, due to the recoverable conductivity and near perfect shape memory performance, SMSC tape can be easily reused many times in practice.SMSC tape shows good recovery capacity of conductivity thanks to its excellent shape memory performance. As shown in Fig. 2) attached on Cu plate can withstand a load of 1.252 kg in the shear direction (corresponding to 0.50 MPa). The site of fracture is located at the interface between SMSC tape and Cu plate, not the SMSC tape. This may be due to the fact that the maximum tensile strength of SMSC tape is much larger than the adhesive strength between Cu plate and SMSC tape [Besides good conductivity and perfect shape memory performance, SMSC tape also shows temperature-dependent reversible adhesion. SMSC tape is rigid at room temperature, which is unable to obviously wet the surface. Thus, it has no adhesion ability. When the SMSC tape is heated above the melting temperature, the SMSC tape softens and gradually wets the surface under a moderate pressure, resulting in sharp increase in adhesion upon cooling Fig. a. FigureMSC tape . The adhMSC tape , 44.Fig.The content of each component in SMSC tape and annealing temperature can directly affect the intrinsic adhesive strength. Shear adhesive strength of SMSC tape synthesized by different formulations has been compared in Fig. S9. When the mass ratio between SA and UDA changes from 40:60 to 90:10, the adhesive strength increases first and then decreases. Similarly, it also increases first and then decreases with the increase of Ag NPs content in the polymer. On the other hand, with the increase in BPO content and annealing temperature, the shear adhesive strength of SMSC tape decreases. However, both the optimization of component content and the change of annealing temperature essentially change the wetting behavior of SMSC tape in the heating state, thus determining the intrinsic adhesive strength of SMSC tape.Because of the advantages of stable conductivity, perfect shape memory property and temperature switching reversible adhesion, SMSC tape can independently accomplish the task that requires cooperation of multiple materials or cannot be finished by existing electronic interconnecting materials. In general, a conductor is fixed between two terminals by solder or silver paste to make electric current conduct, while SMSC tape can fix itself on the Cu plate by its own adhesion to conduct the circuit Fig. a. The soSMSC tape is also able to handle the responsibility of electrode by itself. A SMSC tape-based triboelectric nanogenerator (TENG) working in two-electrode mode is prepared. SMSC tape and polytetrafluoroethylene (PTFE) film are used as negative and positive triboelectric layer, respectively. Moreover, SMSC tape is used as an electrode due to its conductivity. A Cu plate is attached on the back of PTFE film to collect the current from the PTFE film Fig. e. SMSC t−1 and a maximum strain of ~ 100%. With the increase in Ag NPs content, the initial conductivity could be increased to 5446 S cm−1 by decreasing the strain to 17%. Meanwhile, SMSC tape has the perfect shape memory performance and fatigue resistance ability. The perfect shape memory effect gives SMSC tape a temperature-determined reversible strong–weak adhesion transition. The adhesive strength of SMSC tape can be compared with the commercial conductive tape, where the adhesive mechanism is from the embedded structure rather than the molecular interaction. Thanks to the stable conductivity, perfect shape memory performance and reversible self-adhesion, SMSC tape can serve two functions of electrode and solder simultaneously. As a new type of conductive interconnecting material, SMSC tape possesses the characteristics of no adhesive residue and low processing temperature, and has promising compatibility with modern electronic devices. It also provides a unique idea for the development of electronic devices in the future.In summary, we designed a highly stretchable shape memory self-soldering conductive tape with reversible adhesion switched by temperature. The tape is prepared by anaerobic curing of well blended precursors, including SA, UDA, BPO and Ag NPs. A series of experimental results show that SMSC tape exhibits an initial conductivity of ~ 2772 S cmSupplementary file1 (PDF 514 kb)Supplementary file2 (MP4 13955 kb)Supplementary file3 (MP4 11015 kb)Supplementary file4 (MP4 4612 kb)Below is the link to the electronic supplementary material.


Remdesivir is an antiviral, nucleoside analog used extensively during the coronavirus-disease 2019 (COVID-19) pandemic with proven efficacy against COVID-19-induced acute respiratory distress syndrome (ARDS). Our case report details the clinical course of a 50-year-old, COVID-19-positive patient who developed sinus arrest after being treated with remdesivir. Within 24 hours of discontinuing remdesivir therapy, the patient’s sinus arrest resolved to a normal sinus rhythm. The findings from our case report add to a growing body of evidence on the cardiotoxic profile of remdesivir. Remdesivir’s ability to cause bradyarrhythmias, and specifically sinus arrest, should be acknowledged when considering the use of this drug in at-risk patients. Remdesivir is an antiviral agent that has been Remdesivir-Associated Sinus Arrest in COVID-19: A Potential Indication for Close Cardiac Monitoring (FDA)-approved for the treatment of COVID-19 in hospitalized patients . However2 saturation 78% on room air). The physical exam was unremarkable aside from the lung exam, which revealed bilateral bibasilar crackles. The patient was requiring supplemental oxygen at the time of the initial encounter with 2L via nasal cannula. An electrocardiogram (ECG) at the time of presentation revealed a normal sinus rhythm, as demonstrated in Figure A 50-year-old female with a known history of coronary artery disease (CAD), hypertension, atrial fibrillation (AF), and chronic obstructive pulmonary disease (COPD) presented to the emergency department (ED) with a two-week history of worsening dyspnea. She also had complaints of mild dry cough and intermittent nausea at the time. She had a known smoking history, but no family history of any arrhythmias was reported. The patient denied any use of rate-controlling medications besides metoprolol for AF. On presentation, the patient was normotensive (blood pressure 137/84 mmHg), had a slightly elevated heart rate (92 beats/min), afebrile (temperature 98.6 degrees Fahrenheit), tachypneic (respiratory rate 24), and hypoxic (OLab evaluation revealed normal results for a complete blood count and chemistry panel. However, imaging findings of the chest were consistent with bilateral ground-glass infiltrates without any evidence of pulmonary embolism, as shown in Figure The patient was started on dexamethasone 6mg daily and was treated empirically with intravenous ceftriaxone 1g daily and azithromycin 250mg for a possible superimposed bacterial infection. The patient also met our hospital criteria for remdesivir therapy. She was initiated on a standard remdesivir dose of 200mg IV on day 1, followed by 100mg IV daily for four days to complete a five-day total course of remdesivir.One day after the initiation of the treatment regimen, the patient was found to have severe sinus bradycardia of 30 to 40 bpm. Metoprolol was identified as a potential culprit and was abruptly discontinued due to the bradyarrhythmia potential of beta-blockers. Despite the discontinuation of the beta-blocker, the patient later developed sinus arrest of three seconds duration, as demonstrated in Figure After reviewing current literature on the cardiotoxic effects of remdesivir, the decision was made to stop remdesivir. The patient’s bradycardia and sinus arrest ultimately resolved within 24 hours of remdesivir discontinuation, as demonstrated in Figure Remdesivir is an antiviral agent which works by inhibiting viral RdRp . OriginaRemdesivir is an antiviral agent structurally analogous to adenosine triphosphate . AdenosiReportedly, remdesivir has been recently associated with sinus bradycardia. One such study was completed using the World Health Organization Global Individual Case Safety Reports database . The incA literature review of PubMed and Embase found only one similar case of remdesivir-associated sinus arrest as depicted in the chart below.In the light of the above discussion on the cardiotoxic profile of this widely used drug during the ongoing COVID-19 pandemic, we suggest close rhythm monitoring of all patients started on remdesivir to avoid any fatal arrhythmias. After carefully ruling out all potential causes of bradyarrhythmias, abrupt discontinuation can be beneficial in such cases. In patients with existing cardiac conduction abnormalities or medications that can induce bradyarrhythmias, the benefits, and risks of remdesivir need to be calculated on an individual basis before initiating treatment. Our case is an excellent contribution to the existing literature on remdesivir adverse effect profiles. Further studies are warranted to learn more about the adverse effects of remdesivir and best practices in management.Remdesivir should be acknowledged for its bradyarrythmic potential and should be employed tactically in patients with pre-existing cardiac conditions. Although rare, remdesivir has been shown to cause sinus arrest in some patients. Intensive cardiac rhythm monitoring should be considered for all patients taking remdesivir. In patients who develop sinus arrest or significant bradycardia due to remdesivir, discontinuation of the drug can reduce the risk of potentially fatal arrhythmias and cardiac arrest.