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.

RNAi screen identifies essential regulators of human brain metastasis-initiating cells.

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

Racial disparities in characteristics and outcomes of patients undergoing mitral transcatheter edge-to-edge repair.

Background: There are scarce data regarding the post-mitral transcatheter edge-to-edger repair (TEER) course in different racial groups. Objective: To assess the impact of race on outcomes following TEER for mitral regurgitation (MR). Methods: This is a single-center, retrospective analysis of consecutive TEER procedures performed during 2013-2020. The primary outcome was the composite of all-cause mortality or heart failure (HF) hospitalizations along the first postprocedural year. Secondary outcomes included individual components of the primary outcome, New York Heart Association (NYHA) class, MR grade, and left ventricular mass index (LVMi). Results: Out of 964 cases, 751 (77.9%), 88 (9.1%), 68 (7.1%), and 57 (5.9%) were whites, blacks, Asians, and Hispanics, respectively. At baseline, non-whites and blacks were younger and more likely be female, based in lower socioeconomic areas, not fully insured, diagnosed with functional MR, and affected by biventricular dysfunction. Intra-procedurally, more devices were implanted in blacks. At 1-year, non-whites (vs. whites) and blacks (vs. non-blacks or whites) experienced higher cumulative incidence of the primary outcome (32.9% vs. 22.5%, p = 0.002 and 38.6% vs. 23.4% or 22.5%, p = 0.002 or p = 0.001, respectively), which were accounted for by hospitalizations in the functional MR sub-cohort (n = 494). NYHA class improved less among blacks with functional MR. MR severity and LVMi equally regressed in all groups. White race (HR 0.62, 95% CI 0.39-0.99, p = 0.047) and black race (HR 2.07, 95% CI 1.28-3.35, p = 0.003) were independently associated with the primary outcome in functional MR patients only. Conclusion: Mitral TEER patients of different racial backgrounds exhibit major differences in baseline characteristics. Among those with functional MR, non-whites and blacks also experience a less favorable 1-year clinical outcome.

Development of a Patient-Derived Xenograft Model Using Brain Tumor Stem Cell Systems to Study Cancer.

Patient-derived xenograft (PDX) models provide an excellent platform to understand cancer initiation and development in vivo. In the context of brain tumor initiating cells (BTICs), PDX models allow for characterization of tumor formation, growth, and recurrence, in a clinically relevant in vivo system. Here, we detail procedures to harvest, culture, characterize, and orthotopically inject human BTICs derived from patient samples.