Risk factors for reduced function in women with a history of breast cancer.

PURPOSE: People with a history of breast cancer are at risk of losing function during and after treatment. Unfortunately, little is known about the individual and additive effects of specific treatment, disease-related, and demographic factors that may contribute to functional decline. This manuscript reports the results of a multi-center study to evaluate the effects of these factors on function. METHODS: In this cross-sectional study, women with a history of breast cancer referred to physical medicine and rehabilitation cancer rehabilitation clinics were administered the PROMIS® Cancer Function Brief 3D Profile to evaluate function in the domains of physical function, fatigue, and social participation. Clinical and demographic information, including treatment history and disease status, was recorded by clinicians. Patients were analyzed in two groups: those with active disease on antineoplastic treatment, and those with no evidence of disease (NED). A multivariable model was constructed to detect associations between clinical and demographic factors. RESULTS: In patients with NED, the presence of chemotherapy-induced peripheral neuropathy (CIPN) was strongly associated with reduced function in all three domains. In those with active disease, having brain metastases was significantly associated with reduced function in all domains and CIPN with reduced physical function. Radiation was associated with improved function in both cohorts. CONCLUSIONS: Among women seeking rehabilitative care, CIPN and the presence of brain metastases were most strongly associated with a decline in function. The effects of radiation on function were unexpected and may be partially explained by the treatment's role in symptom management. Clinicians who treat breast cancer should consider a patient's functional status when providing supportive care.

Recellularization of a novel off-the-shelf valve following xenogenic implantation into the right ventricular outflow tract.

Current research on valvular heart repair has focused on tissue-engineered heart valves (TEHV) because of its potential to grow similarly to native heart valves. Decellularized xenografts are a promising solution; however, host recellularization remains challenging. In this study, decellularized porcine aortic valves were implanted into the right ventricular outflow tract (RVOT) of sheep to investigate recellularization potential. Porcine aortic valves, decellularized with sodium dodecyl sulfate (SDS), were sterilized by supercritical carbon dioxide (scCO2) and implanted into the RVOT of five juvenile polypay sheep for 5 months (n = 5). During implantation, functionality of the valves was assessed by serial echocardiography, blood tests, and right heart pulmonary artery catheterization measurements. The explanted valves were characterized through gross examination, mechanical characterization, and immunohistochemical analysis including cell viability, phenotype, proliferation, and extracellular matrix generation. Gross examination of the valve cusps demonstrated the absence of thrombosis. Bacterial and fungal stains were negative for pathogenic microbes. Immunohistochemical analysis showed the presence of myofibroblast-like cell infiltration with formation of new collagen fibrils and the existence of an endothelial layer at the surface of the explant. Analysis of cell phenotype and morphology showed no lymphoplasmacytic infiltration. Tensile mechanical testing of valve cusps revealed an increase in stiffness while strength was maintained during implantation. The increased tensile stiffness confirms the recellularization of the cusps by collagen synthesizing cells. The current study demonstrated the feasibility of the trans-species implantation of a non-fixed decellularized porcine aortic valve into the RVOT of sheep. The implantation resulted in recellularization of the valve with sufficient hemodynamic function for the 5-month study. Thus, the study supports a potential role for use of a TEHV for the treatment of valve disease in humans.

Xenoantigenicity of porcine decellularized valves.

BACKGROUND: The xenoantigenicity of porcine bioprosthetic valves is implicated as an etiology leading to calcification and subsequent valve failure. Decellularization of porcine valves theoretically could erase the antigenicity of the tissue leading to more durable prosthetic valves, but the effectiveness of decellularization protocols in regard to completely removing antigens has yet to be verified. Our hypothesis was that decellularization would remove the more abundant α-gal antigens but not remove all the non α-gal antigens, which could mount a response. METHODS: Porcine aortic valves were decellularized with 1% sodium dodecyl sulfate for 4 days. Decellularized cusps were evaluated for α-gal epitopes by ELISA. To test for non α-gal antigens, valves were implanted into sheep. Serum was obtained from the sheep preoperatively and 1 week, 1 month, and 2 months postoperatively. This serum was utilized for anti-porcine antibody staining and for quantification of anti-pig IgM and IgG antibodies and complement. RESULTS: Decellularized porcine cusps had 2.8 ± 2.0% relative α-gal epitope as compared to fresh porcine aortic valve cusps and was not statistically significantly different (p = 0.4) from the human aortic valve cusp which had a 2.0 ± 0.4% relative concentration. Anti-pig IgM and IgG increased postoperatively from baseline levels. Preoperatively anti-pig IgM was 27.7 ± 1.7 µg/mL and it increased to 71.9 ± 12.1 µg/mL average of all time points postoperatively (p = 0.04). Preoperatively anti-pig IgG in sheep serum was 44.9 ± 1.5 µg/mL and it increased to 72.6 ± 6.0 µg/mL average of all time points postoperatively (p = 0.01). There was a statistically significant difference (p = 0.00007) in the serum C1q concentration before valve implantation (2.5 ± 0.2 IU/mL) and at averaged time points after valve implantation (5.3 ± 0.3 IU/mL). CONCLUSIONS: Decellularization with 1% sodium dodecyl sulfate does not fully eliminate non α-gal antigens; however, significant reduction in α-gal presence on decellularized cusps was observed. Clinical implications of the non α-gal antigenic response are yet to be determined. As such, evaluation of any novel decellularized xenografts must include rigorous antigen testing prior to human trials.

Supercritical carbon dioxide-based sterilization of decellularized heart valves.

OBJECTIVE: The goal of this research project encompasses finding the most efficient and effective method of decellularized tissue sterilization. BACKGROUND: Aortic tissue grafts have been utilized to repair damaged or diseased valves. Although, the tissues for grafting are collected aseptically, it does not eradicate the risk of contamination nor disease transfer. Thus, sterilization of grafts is mandatory. Several techniques have been applied to sterilize grafts; however, each technique shows drawbacks. In this study, we compared several sterilization techniques: supercritical carbon dioxide, electrolyzed water, gamma radiation, ethanol-peracetic acid, and hydrogen peroxide for impact on the sterility and mechanical integrity of porcine decellularized aortic valves. METHODS: Valve sterility was characterized by histology, microbe culture, and electron microscopy. Uniaxial tensile testing was conducted on the valve cusps along their circumferential orientation to study these sterilization techniques on their integrity. RESULTS: Ethanol-peracetic acid and supercritical carbon dioxide treated valves were found to be sterile. The tensile strength of supercritical carbon dioxide treated valves (4.28 ± 0.22 MPa) was higher to those valves treated with electrolyzed water, gamma radiation, ethanol-peracetic acid and hydrogen peroxide (1.02 ± 0.15, 1.25 ± 0.25, 3.53 ± 0.41 and 0.37 ± 0.04 MPa, respectively). CONCLUSIONS: Superior sterility and integrity were found in the decellularized porcine aortic valves with supercritical carbon dioxide sterilization. This sterilization technique may hold promise for other decellularized soft tissues. SUMMARY: Sterilization of grafts is essential. Supercritical carbon dioxide, electrolyzed water, gamma radiation, ethanol-peracetic acid, and hydrogen peroxide techniques were compared for impact on sterility and mechanical integrity of porcine decellularized aortic valves. Ethanol-peracetic acid and supercritical carbon dioxide treated valves were found to be sterile using histology, microbe culture and electron microscopy assays. The cusp tensile properties of supercritical carbon dioxide treated valves were higher compared to valves treated with other techniques. Superior sterility and integrity was found in the decellularized valves treated with supercritical carbon dioxide sterilization. This sterilization technique may hold promise for other decellularized soft tissues.

Computed Tomography and Magnetic Resonance Imaging for Longitudinal Characterization of Lung Structure Changes in a Yucatan Miniature Pig Silicosis Model.

Medical imaging is a rapidly advancing field enabling the repeated, noninvasive assessment of physiological structure and function. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In addition, swine may serve as a human surrogate, facilitating the development and comparison of new imaging protocols for translation to humans. This study presents methods for pulmonary imaging developed for monitoring pulmonary disease initiation and progression in a pig exposure model with computed tomography and magnetic resonance imaging. In particular, a focus was placed on systematic processes, including positioning, image acquisition, and structured reporting to monitor longitudinal change. The image-based monitoring procedure was applied to 6 Yucatan miniature pigs. A subset of animals (n= 3) were injected with crystalline silica into the apical bronchial tree to induce silicosis. The methodology provided longitudinal monitoring and evidence of progressive lung disease while simultaneously allowing for a cross-modality comparative study highlighting the practical application of medical image data collection in swine. The integration of multimodality imaging with structured reporting allows for cross comparison of modalities, refinement of CT and MRI protocols, and consistently monitors potential areas of interest for guided biopsy and/or necropsy.