Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

Lepidic predominant adenocarcinoma with aerogenous spread of mucin in a young patient -- a case report.

We present a unique case of a 26 year-old female non-smoker who expired following treatment for presumed pneumonias. At autopsy, lepidic predominant adenocarcinoma with aerogenous spread of mucin without evidence of invasion, a rare diagnosis that previously would have fallen under the umbrella of "bronchioloalveolar carcinoma," was found. Histopathology showed mucin-secreting neoplastic cells lining the alveolar walls, as well as exfoliated and dense aggregates of mucinous debris filling the alveoli. The immediate cause of death was respiratory failure, most likely due to the significant amount of tumor-produced mucin that filled the alveolar spaces, which literally drowned the patient.

Electrophysiologic and Cardiovascular Manifestations of Duchenne and Becker Muscular Dystrophies.

BACKGROUND: There have been significant advances in the diagnosis and management of the hereditary muscular disorders Duchenne and Becker Muscular Dystrophy (DMD and BMD). Cardiac electrophysiologic and Cardiovascular involvement has long been important in the surveillance, care, and prognosis of patients with both BMD and DMD, and is the leading cause of mortality in patients with DMD. With improved long-term prognosis, rhythm disorders and progressive cardiomyopathy with resultant heart failure are increasingly common. OBJECTIVES: This review aims to provide an overview to electrophysiologists and cardiologists of the cardiac electrophysiologic phenotypes and genetics of the BMD and DMD and highlight the recent discoveries that have advanced clinical course and management. METHODS: A systematic review was performed in the diagnosis and management of Duchenne and Becker muscular dystrophies. The Cochrane Library, PubMed, MEDLINE, the Europe PubMed Central, AMED, and EMBASE database were accessed for available evidence. The research reported in this paper adhered to PRISMA guidelines. RESULTS: Evidence from randomized control trials and studies cited in expert consensus and practice guidelines are examined. Advanced imaging techniques and a spectrum of rhythm disorders associated with the progressive cardiomyopathy are presented. Early initiation of heart failure therapies, the role of cardiac implantable devices, and novel gene therapies approved for use with the potential to alter the disease course are discussed. CONCLUSION: DMD and BMD patients may have profound cardiac and cardiac electrophysiologic involvement, which when diagnosed and treated earlier, could lead to improved outcomes.

Implantation of a Dual-chamber Pacemaker in a Patient with Dextrocardia, Situs Inversus, and Sick Sinus Syndrome.

Situs inversus with dextrocardia is a rare congenital anomaly that presents a unique challenge for the consultant electrophysiologist. Implantation of cardiac device in these patients may be challenging owing to their individual cardiac and vascular anatomy. Consequently, adverse procedural outcomes are more common in this group and an informed pre- and intraoperative approach is critical. In this article, we present the relevant patient findings and implications for the electrophysiologist, including operative approaches. We then examine them in the context of an actual case, having implanted an intracardiac permanent pacemaker with a right-sided approach via the conventional method in a patient with dextrocardia situs inversus who had undergone multiple surgeries for structural heart disease.

Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population.

BACKGROUND: Human neutrophil peptides 1-3 are endogenous cationic antimicrobial peptides implicated in host defense against microbes. The genes encoding human neutrophil peptides 1-3 (DEFA1/DEFA3) exhibit copy number variations. This study was designed to determine whether DEFA1/DEFA3 copy number variations conferred susceptibility to infection-induced complications such as severe sepsis. METHODS: This case-control study was performed in 179 patients with severe sepsis and 233 healthy blood donors and was replicated in an independent cohort of 112 cases and 118 controls. Plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 were detected. RESULTS: The genotype of DEFA1/DEFA3 with more than eight copies was more frequent in patients with severe sepsis than in controls (55.9% vs. 31.3%; P = 1.13 x 10, odds ratio 2.77, 95% confidence interval 1.85-4.16). After adjustment for age and gender, logistic regression analysis confirmed the association of the genotype of more than eight copies with an increased risk of severe sepsis (P = 2.25 x 10, odds ratio 2.66, 95% confidence interval 1.69-4.19). This established association was replicated in a second age- and gender-matched case-control cohort (P = 0.02, odds ratio 1.90, 95% confidence interval 1.11-3.27). Furthermore, compared with those with fewer copies, the patients carrying more than eight copies of DEFA1/DEFA3 presented significantly lower plasma levels of human neutrophil peptides 1-3, tumor necrosis factor-alpha, interleukin-6, and interleukin-10 (P = 0.039, 0.017, 0.030, and 0.029, respectively). CONCLUSIONS: DEFA1/DEFA3 is an important genetic component participating in host immune response to severe sepsis. A higher copy number of DEFA1/DEFA3 (>8 copies) is significantly associated with the risk of severe sepsis.