Aortic rupture following acute aortitis in a patient with head and neck carcinoma treated with nivolumab: a rare but severe immune-related adverse event.

INTRODUCTION: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors may lead to discontinuation and treatment-related death. Acute aortitis is a rare but severe irAE. CASE PRESENTATION: A 67-year-old man with recurrent lower gingival carcinoma received nivolumab therapy. Twenty-three months later, he experienced chest compression, which resulted in syncope. Following a whole-body computed tomography (CT) scanning, which revealed diffuse thickening of the aorta, and systemic assessments of the causes of aortitis, he was diagnosed with acute aortitis due to irAE. Nivolumab discontinuation and oral steroids improved CT findings. However, 11 months after nivolumab discontinuation, he developed an aortic aneurysmal rupture. Endovascular aortic repair rescued him. A durable anti-cancer response was still observed 4 months after the aortic rupture. CONCLUSION: Although severe irAE, such as acute aortitis, occurred, the patient may still achieve a durable response. A broad examination and prompt treatment of irAE can help improve the patient's survival.

Aortitis after administration of pegfilgrastim to a healthy donor for peripheral blood stem cell collection.

A 45-year-old man who was a sibling donor for allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was administered 7.2 mg of pegfilgrastim for stem cell collection. Peripheral blood stem cells were collected 4 days after administration of pegfilgrastim (Day 4) and 4.32 × 106 /kg of CD34-positive cells per recipient body weight were obtained. Fever of 38 ℃ or higher and left submandibular pain appeared on Day 6. Ultrasonography and contrast-enhanced computed tomography (CT) showed wall thickening of the carotid artery and the abdominal aorta. We carefully excluded the possibilities of cardiovascular and autoimmune diseases by thorough examination, and ultimately diagnosed pegfilgrastim-induced aortitis. The patient's fever resolved rapidly after treatment with prednisolone (PSL) 1 mg/kg. We began to taper PSL after eight days. Sixty-one days after starting PSL, we confirmed that abdominal aortic wall thickening had improved by contrast-enhanced CT. We continued to taper off PSL and stopped 141 days later with no relapse thereafter. This is the first case report of pegfilgrastim-induced aortitis in an allo-PBSCT donor. Careful monitoring is warranted when administering pegfilgrastim to donors even without past medical history.

Aortitis Associated with Prophylactic Short-acting Granulocyte Colony-stimulating Factor Administration: A Case Report and Review of the Literature.

We herein report an 83-year-old woman with filgrastim-associated aortitis during chemotherapy for relapsed diffuse large B-cell lymphoma. She had been treated with filgrastim as a prophylaxis for neutropenia during the fourth cycle of chemotherapy from day 9 to 18. On day 21, she developed a fever. Contrast-enhanced computed tomography revealed aortitis of the descending aorta. The fever abated with non-steroidal anti-inflammatory drug treatment. A literature review identified a small number of aortitis cases all caused by prophylactic use of granulocyte colony-stimulating factors (G-CSFs), among which short-acting filgrastim was rarely encountered. The present and previous findings imply a possible relationship between aortitis and prophylactic G-CSF usage.

Granulocyte Colony-stimulating Factor-associated Aortitis on Gallium Scintigraphy.

Aortitis is a rare adverse event associated with granulocyte colony-stimulating factor (G-CSF). Contrast-enhanced computed tomography (CECT) is widely used to diagnose G-CSF-associated aortitis. However, the usefulness of gallium scintigraphy for the diagnosis of G-CSF-associated aortitis is unknown. We herein report a set of pre- and post-treatment gallium scintigrams of a patient with G-CSF-associated aortitis. During the diagnosis, gallium scintigraphy revealed hot spots on the arterial walls that appeared inflamed on CECT. Both the CECT and gallium scintigraphy findings disappeared. Gallium scintigraphy can be a supportive diagnostic tool for G-CSF-associated aortitis, especially in patients with an impaired renal function or allergy to iodine contrast.

Granulocyte colony-stimulating factor-induced aortitis with temporal arteritis and monoarthritis.

We present the case of a patient in his 80s receiving gemcitabine-cisplatin therapy for bladder cancer who developed neutropenia and was treated with filgrastim. In 10 days, the patient developed a mild fever with left jaw claudication and right knee arthritis. Contrast-enhanced CT findings indicated aortitis. Prednisolone was started for granulocyte colony-stimulating factor (G-CSF)-induced aortitis, and symptoms and elevated serum inflammatory markers resolved rapidly, allowing early discontinuation of prednisolone. Right knee arthritis relapsed at the initial follow-up. Contrast-enhanced CT revealed aortitis had disappeared. Therefore, recurrence of G-CSF-induced arthritis was suspected; prednisolone was resumed for 29 days without relapse. Most previous reports of G-CSF-induced aortitis have described inflammation of the aorta, carotid arteries and subclavian arteries; however, G-CSF-induced aortitis may present with more peripheral symptoms, such as temporal arteritis and knee arthritis. Furthermore, G-CSF-induced aortitis reportedly responds well and rapidly to prednisolone, although early discontinuation may lead to relapse.

[Two Cases of Aortitis Caused by Pegfilgrastim Administered during Chemotherapy for Breast Cancer].

Granulocyte colony-stimulating factor(G-CSF)is known to cause bone pain, headache, and fatigue as side effects. We experienced 2 cases of aortitis caused by pegfilgrastim(PEG-G)administration. Case 1: A 50s woman with breast cancer started FEC therapy with PEG-G as neoadjuvant chemotherapy. She developed a fever in the 38℃ range, and chest CT showed wall thickening in the aortic arch. She was diagnosed with aortitis and administration of prednisolone was started, and the fever resolved and the general condition improved dramatically. Case 2: A 70s woman was started TC therapy with PEG-G as adjuvant chemotherapy after surgery. Fever, anorexia, and epigastralgia appeared. A CT scan of the abdomen revealed thickening of the abdominal aortic wall from the thoracoabdominal transition area to the renal artery bifurcation. She was diagnosed with PEG-G-induced aortitis, and administration of prednisolone was started. The fever resolved and the pain disappeared. Although the symptoms of G-CSF-induced aortitis are nonspecific, it is relatively easy to diagnose by CT and should be considered when a fever develops after G-CSF administration.

Single-Center Analysis of Pegfilgrastim-induced Aortitis Using a Drug Prescription Database and CT Findings.

Background Pegfilgrastim-induced aortitis is a rare but serious adverse event in patients undergoing anticancer therapy with granulocyte colony-stimulating factor analogs. Despite previous case series and systemic reviews, the exact incidence, clinical presentation, and CT manifestations of pegfilgrastim-induced aortitis remain unclear. Purpose To clarify the incidence and clinicoradiologic characteristics of pegfilgrastim-induced aortitis. Materials and Methods Pegfilgrastim administration records from January 2015 to March 2021 were retrospectively collected from the drug prescription database of a single center and were matched with the relevant findings in the CT database. Corresponding CT images within 6 months were available for a total of 1462 doses of pegfilgrastim in 674 patients. Four radiologists reviewed the CT images for the presence of aortitis in two steps. Clinical information and the distribution of aortitis on CT images were examined for patients with a diagnosis of pegfilgrastim-induced aortitis. Results Pegfilgrastim-induced aortitis was observed in 18 of 674 patients (mean age, 62 years ± 13 [SD]; 424 men), resulting in incidence rates of 2.7% per patient (95% CI: 1.6, 4.2) and 1.2% per dose (95% CI: 0.7, 1.9). The most common original primary malignancies were esophageal cancer (n = 10, 9%), breast cancer (n = 3, 4%), and pancreatic cancer (n = 2, 2%). The most common anticancer drugs used at onset were 5-fluorouracil, cisplatin, and docetaxel. Seven cases were symptomatic, while the remaining 11 (61%) were asymptomatic. CT findings indicated that aortitis involved branches of the aortic arch in 13 cases (72%), aortic arch in 10 cases (56%), and abdominal aorta in two cases (11%). Conclusion Pegfilgrastim-induced aortitis may be more prevalent than previously reported and may be more common in patients with esophageal cancer and those who received 5-fluorouracil, cisplatin, and docetaxel as anticancer drugs. The findings also suggest that pegfilgrastim-induced aortitis is often characterized by aortic arch and proximal branch involvement at CT. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Krinsky in this issue.

[A Case of Aortitis Caused by Pegfilgrastim Use during Neoadjuvant Chemotherapy for Treating Breast Cancer].

Granulocyte colony-stimulating factor(G-CSF)is useful for preventing febrile neutropenia induced by chemotherapy. Recently, some cases of aortitis have been reported following administration of G-CSF. Here, we present a case of aortitis induced by pegfilgrastim(peg-G)use during neoadjuvant chemotherapy for treating breast cancer. A 61-year-old woman with breast cancer(cT2N1M0, stage ⅡB, triple negative)started neoadjuvant chemotherapy FEC(100). Eleven days after the third course of peg-G administration, the patient developed a fever and general malaise. Blood test results showed an increase in inflammatory markers and severe anemia. The symptoms were not controlled with antibiotics. Blood and urine culture test results were negative. Computed tomography revealed remarkable wall thickening of the aorta. Therefore, we suspected aortitis induced by peg-G. The symptoms rapidly improved with prednisolone therapy. The possibility of aortitis should be considered for those with fever or raised inflammatory markers following the use of G-CSF. Steroids can be used for the treatment of G-CSF-induced aortitis.

Granulocyte colony stimulating factor (G-CSF)-induced aortitis in a patient undergoing adjuvant chemotherapy for breast cancer.

Granulocyte colony stimulating factor (G-CSF) is used to prevent febrile neutropenia post chemotherapy. Usually well tolerated with minimal side effects but aortitis is an extremely rare side effect previously reported. A 64-year-old woman treated with adjuvant chemotherapy including G-CSF for left breast cancer was admitted with fevers, neutropenia and markedly raised inflammatory markers after 7 days of her first cycle. Initially diagnosed with neutropenic sepsis, she did not respond to broad spectrum antibiotics with subsequent CT imaging revealing marked periaortic inflammatory changes consistent with aortitis and periaortitis. Extensive investigations for other causes of large vessel vasculitis were negative and G-CSF was the only causative factor. She rapidly responded to steroids with almost complete resolution of inflammatory changes on repeat imaging within 4 weeks and no recurrence on tapering of steroids. This diagnosis must be considered in patients presenting with fever and raised inflammatory markers post G-CSF treatment.

[A Case of Granulocyte Colony-Stimulating Factor-Associated Aortitis during Neoadjuvant Chemotherapy for Esophageal Cancer].

A 71-year-old man with middle thoracic esophageal cancer was treated with neoadjuvant chemotherapy using docetaxel plus 5-FU plus cisplatin therapy and was also administered pegfilgrastim. Blood tests showed elevated white blood cell counts and C-reactive protein levels before the start of the third course. Contrast-enhanced computed tomography revealed wall thickening of the aortic arch. We diagnosed this as aortitis due to pegfilgrastim. Inflammation was improved with conservative treatment. We then performed video-assisted thoracoscopic esophagectomy. Drug-induced vasculitis should be included in the differential diagnosis of patients with elevated inflammation markers of unknown cause following the administration of granulocyte colony-stimulating factor preparations.

Fine particulate matter (PM2.5) inhalation-induced alterations in the plasma lipidome as promoters of vascular inflammation and insulin resistance.

Fine particulate matter (PM2.5) air pollution exposure increases the risk of developing cardiovascular disease (CVD). Although the precise mechanisms by which air pollution exposure increases CVD risk remain uncertain, research indicates that PM2.5-induced endothelial dysfunction contributes to CVD risk. Previous studies demonstrate that concentrated ambient PM2.5 (CAP) exposure induces vascular inflammation and impairs insulin and vascular endothelial growth factor (VEGF) signaling dependent on pulmonary oxidative stress. To assess whether CAP exposure induces these vascular effects via plasmatic factors, we incubated aortas from naïve mice with plasma isolated from mice exposed to HEPA-filtered air or CAP (9 days) and examined vascular inflammation and insulin and VEGF signaling. We found that treatment of naïve aortas with plasma from CAP-exposed mice activates NF-κBα and induces insulin and VEGF resistance, indicating transmission by plasmatic factor(s). To identify putative factors, we exposed lung-specific ecSOD-transgenic (ecSOD-Tg) mice and wild-type (WT) littermates to CAP at concentrations of either ∼60 µg/m3 (CAP60) or ∼100 µg/m3 (CAP100) and measured the abundance of plasma metabolites by mass spectrometry. In WT mice, both CAP concentrations increased levels of fatty acids such as palmitate, myristate, and palmitoleate and decreased numerous phospholipid species; however, these CAP-induced changes in the plasma lipidome were prevented in ecSOD-Tg mice. Consistent with the literature, we found that fatty acids such as palmitate are sufficient to promote endothelial inflammation. Collectively, our findings suggest that PM2.5 exposure, by inducing pulmonary oxidative stress, promotes unique lipidomic changes characterized by high levels of circulating fatty acids, which are sufficient to trigger vascular pathology.NEW & NOTEWORTHY We found that circulating plasma constituents are responsible for air pollution-induced vascular pathologies. Inhalation of fine particulate matter (≤PM2.5) promotes a unique form of dyslipidemia that manifests in a manner dependent upon pulmonary oxidative stress. The air pollution-engendered dyslipidemic phenotype is characterized by elevated free fatty acid species and diminished phospholipid species, which could contribute to vascular inflammation and loss of insulin sensitivity.

Gal-1 (Galectin-1) Upregulation Contributes to Abdominal Aortic Aneurysm Progression by Enhancing Vascular Inflammation.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a vascular degenerative disease causing sudden rupture of aorta and significant mortality in elders. Nevertheless, no prognostic and therapeutic target is available for disease management. Gal-1 (galectin-1) is a ß-galactoside-binding lectin constitutively expressed in vasculature with roles in maintaining vascular homeostasis. This study aims to investigate the potential involvement of Gal-1 in AAA progression. Approach and Results: Gal-1 was significantly elevated in circulation and aortic tissues of Ang II (angiotensin II)-infused apoE-deficient mice developing AAA. Gal-1 deficiency reduced incidence and severity of AAA with lower expression of aortic MMPs (matrix metalloproteases) and proinflammatory cytokines. TNFα (tumor necrosis factor alpha) induced Gal-1 expression in cultured vascular smooth muscle cells and adventitial fibroblasts. Gal-1 deletion enhanced TNFα-induced MMP9 expression in fibroblasts but not vascular smooth muscle cells. Cysteinyl-labeling assay demonstrated that aortic Gal-1 exhibited susceptibility to oxidation in vivo. Recombinant oxidized Gal-1 induced expression of MMP9 and inflammatory cytokines to various extents in macrophages, vascular smooth muscle cells, and fibroblasts through activation of MAP (mitogen-activated protein) kinase signaling. Clinically, serum MMP9 level was significantly higher in both patients with AAA and coronary artery disease than in control subjects, whereas serum Gal-1 level was elevated in patients with AAA but not coronary artery disease when compared with controls. CONCLUSIONS: Gal-1 is highly induced and contributes to AAA by enhancing matrix degradation activity and inflammatory responses in experimental model. The pathological link between Gal-1 and AAA is also observed in human patients. These findings support the potential of Gal-1 as a disease biomarker and therapeutic target of AAA.

Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.

OBJECTIVE: Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. APPROACHES AND RESULTS: In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. CONCLUSIONS: Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.

Granulocyte Colony-stimulating Factor-induced Aortitis with Lung Injury, Splenomegaly, and a Rash During Treatment for Recurrent Extraosseous Mucinous Chondrosarcoma.

We herein report a case of aortitis induced by granulocyte colony-stimulating factor (G-CSF) that coincided with lung injury, splenomegaly, and cutaneous manifestations during treatment for recurrent extraosseous mucinous chondrosarcoma. Computed tomography revealed large-vessel vasculitis, splenomegaly, and pulmonary interstitial changes. Treatment with prednisolone was successful. Because sarcoma is a rare disease, this case is valuable for showing clinicians that G-CSF preparations could cause aortitis regardless of the patient's underlying diseases or therapeutic pharmacological backgrounds.

The incidence and clinical features of PEGylated filgrastim-induced acute aortitis in patients with breast cancer.

Although PEGylated filgrastim-induced aortitis is very rare and unknown clinically, some cases were reported and increasing, especially in breast cancer patients. The present study investigated the prevalence, clinical features and treatment of aortitis induced by PEGylated filgrastim in patients with breast cancer. A total of 2068 consecutive patients who underwent neoadjuvant/adjuvant chemotherapy with PEGylated filgrastim for breast cancer were enrolled. From the medical record, clinical, laboratory, medication, and imaging evaluation findings were collected. PEGylated filgrastim-induced aortitis was established in 0.3% of the study population. Common clinical presentations included extremely high fever and chest/back pain with high levels of inflammatory markers without any signs of infection. Contrast-enhanced computed tomography scans revealed typical enhancing wall thickening and periaortic soft tissue infiltration at various levels of aorta. All patients improved rapidly after treatment with modest doses of prednisolone (0.5 mg/kg/day) without any complications. Clinicians should be aware of aortitis as a possible complication of granulocyte-colony stimulating factor therapy, especially PEGylated filgrastim, given the frequent misdiagnoses in neutropenic patients undergoing chemotherapy.