On-pump transapical cardioscopic mitral valve replacement with cardiac arrest: short-term results in a porcine survival model.

OBJECTIVES: Favourable outcomes with mitral annuloplasty have been achieved with transapical cardioscopic (TAC) surgery in a survival animal model. In addition, experimental TAC on a non-survival animal model also showed adequate access to remove the native mitral valve and implant a prosthetic valve, but the surgical procedure took a long time and lacked follow-up data. The goal of this study was to develop a clinically translatable TAC mitral valve replacement (MVR) procedure using technical and instrumental refinements to reduce the surgical time and to evaluate functional recovery and short-term durability using a survival porcine model. We hypothesized that MVR could be achieved with subannular implantation of the bioprosthesis via the TAC approach. METHODS: TAC MVR using the Hancock II™ (Medtronic)® mitral prosthesis was performed in 6 pigs via an incision over the xiphoid process, under cardiopulmonary bypass and cardiac arrest. COR-KNOT® and minimally invasive cardiac surgery instruments were used. Haemodynamics, echocardiography, cardiac computed tomography, ventriculography and electrocardiography were used to evaluate the function of the mitral prosthesis and left ventricle, coronary system and conduction system in the perioperative period and 4 weeks later. RESULTS: A postimplant examination showed that the mitral prosthesis was competent, without a paravalvular leak. The left ventricular ejection fraction was comparable to preoperative values (65.2 ± 4.1 vs 67.2 ± 7.9). The bypass, cross-clamp and implant times were 177.2 ± 44.2 min, 135.3 ± 47.6 min and 94.0 ± 41.2 min, respectively. The prosthesis was in a good position. The apical scar was intact and not aneurysmal 4 weeks after the implant. The valve was properly sutured to the annulus, without a postimplant paravalvular leak. All animals recovered after 1 month of follow-up with preserved ventricular function and normal wall motion. CONCLUSIONS: We successfully managed to replace the mitral valve with a biological prosthesis via the apex with encouraging bypass and cross-clamp times. This technique may provide an alternative for a selected group of patients with diseased mitral valves who have indications for MVR and still in a high-risk redo setting with conventional sternotomy or minimally invasive cardiac surgery-MVR.

Transapical cardioscopic mitral annuloplasty: a short-term survival study in a porcine model.

OBJECTIVES: The transapical approach provides concurrent surgical access to the mitral and the aortic valves, the root of the aorta and the left atrium. We previously showed the feasibility of transapical cardioscopic (TAC) surgery in a non-survival porcine model. However, reproducibility and feasibility of ring implantation using TAC have not been reported. Therefore, in this study, we hypothesized that implantation of a mitral annuloplasty ring can be feasibly and safely carried out endoscopically via the apex of the heart. METHODS: Using a porcine model in a short-term survival study, TAC mitral annuloplasty was performed in 6 pigs via an incision over the xyphoid, under cardiopulmonary bypass and cardiac arrest. A mitral annuloplasty ring was implanted via the apex to a normal mitral annulus, using a customized set of instruments and techniques. Haemodynamics, echocardiography, cardiac computed tomography, ventriculography, electrocardiography and histopathology studies were used to evaluate the function of the mitral valve and the left ventricle, coronary system and conduction system in the perioperative period and 4 weeks later. RESULTS: All 6 animals survived and recovered from the TAC annuloplasty procedure. Postimplantation examination showed that the mitral valve was competent, left ventricular ejection fraction was 63 ± 4%, left ventricular length was 6.2 ± 0.5 cm and left ventricular end-diastolic volume was 80 ± 10 ml, which were comparable to preoperative values. Apart from a dense scar at the apex, no significant injury was noticed on the ventricle, the chordae and the mitral leaflets. The bypass, cross-clamp and implantation times were 181 ± 55 min, 130 ± 37 min and 47 ± 6 min, respectively. CONCLUSIONS: Despite long surgical times due to the initial learning curve, successful execution of mitral ring annuloplasty could be safely achieved using the TAC approach, via a small incision without the involvement of sternum or the right pleural cavity, thereby potentially expanding the indication to patients with high-risk full sternotomy or right thoracotomy.

TCR-like antibodies mediate complement and antibody-dependent cellular cytotoxicity against Epstein-Barr virus-transformed B lymphoblastoid cells expressing different HLA-A*02 microvariants.

Epstein-Barr virus (EBV) is a common gammaherpesvirus associated with various human malignancies. Antibodies with T cell receptor-like specificities (TCR-like mAbs) provide a means to target intracellular tumor- or virus-associated antigens by recognising their processed peptides presented on major histocompatibility complex (MHC) class I (pMHC) complexes. These antibodies are however thought to be relevant only for a single HLA allele. Here, we show that HLA-A*02:01-restricted EBV antigenic peptides EBNA1562-570, LMP1125-133 and LMP2A426-434 display binding degeneracy towards HLA-A*02 allelic microvariants, and that these pMHC complexes are recognised by anti-EBV TCR-like mAbs E1, L1 and L2 raised in the context of HLA-A*02:01. These antibodies bound endogenously derived pMHC targets on EBV-transformed human B lymphoblastoid cell lines expressing A*02:01, A*02:03, A*02:06 and A*02:07 alleles. More importantly, these TCR-like mAbs mediated both complement-dependent and antibody-dependent cellular cytotoxicity of these cell lines in vitro. This finding suggests the utility of TCR-like mAbs against target cells of closely related HLA subtypes, and the potential applicability of similar reagents within populations of diverse HLA-A*02 alleles.

The genomic landscape of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.

Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies.

Epstein-Barr virus (EBV) is a gamma herpesvirus that causes a life-long latent infection in human hosts. The latent gene products LMP1, LMP2A and EBNA1 are expressed by EBV-associated tumors and peptide epitopes derived from these can be targeted by CD8 Cytotoxic T-Lymphocyte (CTL) lines. Whilst CTL-based methodologies can be utilized to infer the presence of specific latent epitopes, they do not allow a direct visualization or quantitation of these epitopes. Here, we describe the characterization of three TCR-like monoclonal antibodies (mAbs) targeting the latent epitopes LMP1(125-133), LMP2A(426-434) or EBNA1(562-570) in association with HLA-A0201. These are employed to map the expression hierarchy of endogenously generated EBV epitopes. The dominance of EBNA1(562-570) in association with HLA-A0201 was consistently observed in cell lines and EBV-associated tumor biopsies. These data highlight the discordance between MHC-epitope density and frequencies of associated CTL with implications for cell-based immunotherapies and/or vaccines for EBV-associated disease.