Checking the Checkpoint Inhibitors: A Case of Autoimmune Diabetes After PD-1 Inhibition in a Patient with HIV.
Journal of the Endocrine Society
2020; 4 (12): bvaa150
Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice.
2017; 7 (1): 12351
Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a known immune-related adverse event (irAE) following treatment with programmed cell death protein 1 (PD-1), with a reported 0.9% incidence. We hereby present the first case, to our knowledge, of ICI-DM following ICI use in a human immunodeficiency virus (HIV) patient. In this case, a 48-year-old man with HIV stable on highly active antiretroviral therapy (HAART) was diagnosed with Hodgkin lymphoma and initiated treatment with the PD-1 inhibitor nivolumab. His lymphoma achieved complete response after 5 months. However, at month 8, he reported sudden polydipsia and polyuria. Labs revealed a glucose level of 764 mg/dL and glycated hemoglobin A1c (HbA1c) of 7.1%. Low C-peptide and elevated glutamic acid decarboxylase 65 (GAD65) antibody levels confirmed autoimmune DM, and he was started on insulin. Major histocompatibility complex class II genetic analysis revealed homozygous HLA DRB1*03-DQA1*0501-DQB1*02 (DR3-DQ2), which is a known primary driver of genetic susceptibility to type 1 DM. Autoimmune DM has been reported as an ICI-associated irAE. However, patients with immunocompromising conditions such as HIV are usually excluded from ICI trials. Therefore, little is known about such irAEs in this population. In this case, risk of ICI-DM as an irAE was likely increased by several factors including family history, a high-risk genetic profile, islet-related immunologic abnormalities, active lymphoma, and HIV infection with a possible immune reconstitution event. Clinicians should maintain a high index of suspicion for development of irAEs associated with ICI, particularly as use of these therapies broadens. Thorough investigation for presence of higher-risk features should be conducted and may warrant inclusion of pre-therapy genetic and/or autoantibody screening.
View details for DOI 10.1210/jendso/bvaa150
View details for PubMedID 33225197
View details for PubMedCentralID PMC7660136
Valve-sparing aortic root replacement: early and midterm outcomes in 83 patients.
The Annals of thoracic surgery
2014; 97 (4): 1267?73; discussion 1273?74
Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency (Adamts-4-/-) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4-/- mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.
View details for DOI 10.1038/s41598-017-12248-z
View details for PubMedID 28955046
View details for PubMedCentralID PMC5617887
Outcomes of open distal aortic aneurysm repair in patients with chronic DeBakey type I dissection.
The Journal of thoracic and cardiovascular surgery
2014; 148 (6): 2986?93.e1?2
Valve-sparing aortic root replacement (VSARR) is an alternative to traditional composite valve graft (CVG) root replacement. We examined early and midterm outcomes after VSARR.A combined retrospective/prospective study was performed in 83 patients who underwent VSARR (16%) among 515 patients who underwent aortic root replacement during a nearly 12-year period. Thirty-six patients (43%) had a connective tissue disorder, 3 patients (4%) had acute aortic dissection, and 40 (48%) patients had at least moderate aortic regurgitation (AR). Twenty-eight patients (34%) had left ventricular hypertrophy or dilatation. The reimplantation VSARR technique was used in 82 patients (99%), and the Florida sleeve technique was used in 1 patient. Thirty-two patients (39%) underwent concomitant aortic arch replacement. For early survivors, the median duration of follow-up was 3.5 years (range, 5 days-12.2 years).One patient had severe AR after VSARR that necessitated intraoperative conversion to a mechanical CVG. The 1 operative death and 1 stroke occurred in a patient with acute dissection. Actuarial survival was 96.4%±2.0% at 2 years and 86.9%±5.6% at 8 years. Six patients (7%) had late valve-related complications: 1 died of endocarditis, 4 underwent reoperation for severe AR and received replacement valves, and 1 had severe AR and is being monitored. Freedom from repair failure (reoperation, endocarditis, or severe AR) was 94.8%±2.6% at 2 years and 87.3%±5.7% at 8 years.Valve-sparing aortic root replacement can have excellent early and respectable midterm outcomes, even when combined with arch repair. Further follow-up remains necessary to evaluate the long-term durability of VSARR.
View details for DOI 10.1016/j.athoracsur.2013.10.076
View details for PubMedID 24424011
In patients with acute DeBakey type I dissection, endovascular repair of the descending thoracic aorta during proximal aortic repair is an increasingly popular approach to preventing distal aortic sequelae and subsequent repair. To better define the risks and outcomes associated with these secondary operations, we examined our contemporary experience with open distal aortic repair in patients with chronic type I aortic dissection.Data were collected between January 2005 and June 2013 regarding 198 consecutive open descending thoracic (n = 27) or thoracoabdominal (n = 171) aortic repairs performed in patients with chronic type I dissection. The median interval between the dissection onset and the subsequent distal operation was 5.0 years (interquartile range, 2.4-10.5 years). A total of 110 repairs (56%) were performed in patients with genetic disorders.There were 14 early deaths (7%). Permanent paraplegia developed in 2 patients (1%), 5 patients (3%) had permanent stroke, and 9 patients (5%) had permanent renal failure. Factors associated with early death included greater age (P = .01), chronic obstructive pulmonary disease (P = .01), clamping proximal to the left subclavian artery (P = .004), and use of hypothermic circulatory arrest (P = .002). The use of cold renal perfusion (P < .001) was associated with early survival. Early death was not associated with genetic disorders, emergency surgery, or extent of aortic repair. There were 36 late deaths, yielding an actuarial 8-year survival of 65.6% ± 5.9%. At 7 years, freedom from repair failure was 95.7% ± 1.7%, and freedom from subsequent repair for disease progression was 84.8% ± 4.6%.In survivors of DeBakey type I aortic dissection with distal aneurysm, open repair of the descending thoracic or thoracoabdominal aorta can be performed with excellent early survival, acceptable morbidity, and relatively few late aortic events.
View details for DOI 10.1016/j.jtcvs.2014.07.048
View details for PubMedID 25212053