Infective endocarditis of quadricuspid aortic valve.

BACKGROUND: Infective endocarditis of the aortic valve is a relatively common disease presentation, with surgical intervention a mainstay of treatment in severe cases. Quadricuspid aortic valves are a rare spontaneous developmental anomaly that are more likely to be asymptomatic, and less likely to require a full valve replacement than their hypocuspid counterparts. However, there is very little literature addressing infective endocarditis of this valve variant. CASE PRESENTATION: This case report presents a case of infective endocarditis of a quadricuspid aortic valve that required replacement with a surgical bioprosthetic valve. The patient is a 30 year old male with a history of polysubstance use, upper extremity aneurysm, and prior tricuspid valve endocarditis. Surgical aortic valve replacement was performed with a 25 mm tissue valve via median sternotomy. CONCLUSIONS: The patient made a full recovery after surgical aortic valve replacement and a course of antibiotics and was discharged home without any complications. This supports that surgical aortic valve replacement is feasible and safe in patients with polycuspid aortic valve endocarditis.

Pectus Bar Displacement Causing Right Ventricular Outflow Tract Obstruction.

Pectus excavatum is the most common congenital anomaly of the chest wall. Surgical management of this problem has evolved to encompass many modifications of Dr Ravitch's initial groundbreaking repair to include the insertion of mesh, metal struts, and bars to bolster the repair through open and minimally invasive approaches. This report presents a case of right ventricular outflow tract obstruction from a dislodged pectus bar after a modified Ravitch procedure. The presentation, diagnosis, and management of this exceedingly rare complication are described, and the discussion also provides clinical pearls and inspiration for future research directions that are based on this experience.

Totally percutaneous endovascular repair of HeartMate 3 ventricular assistive device outflow graft pseudoaneurysm.

The rate of heart failure and subsequent placement of left ventricular assistive devices (LVADs) has been increasing. The extra-anatomic placement of the LVAD and outflow graft presents a challenging problem for repair when complications arise. The present report describes a case of a 63-year-old man who had presented with acute pseudoaneurysm of the outflow graft of his recently placed LVAD. Percutaneous access of the left subclavian artery and percutaneous, transthoracic access of the outflow graft was obtained to allow for sheath placement and stent deployment within the outflow graft. The patient underwent successful endovascular repair of the defect without complications.

Single-dose del Nido Cardioplegia in Minimally Invasive Aortic Valve Surgery.

del Nido cardioplegia (DC) offers prolonged cardiac protection with single-dose administration and has been shown to be safe in adult CABG surgery. We set out to evaluate the efficacy of cardiac protection and clinical outcomes of DC versus standard blood cardioplegia (BC) in minimally invasive aortic valve surgery. From August 2011 to May 2016, 178 patients underwent minimally invasive aortic valve replacement (mini-AVR) with BC (n = 101) or DC (n = 77). Ministernotomy or right minithoracotomy was utilized for surgical access. Clinical patient characteristics and data were extracted from our local Society of Thoracic Surgeons (STS) database and the electronic medical record. Patients were propensity matched for age, gender, body mass index, valve size and type, STS score, surgical access, preop creatinine, diabetes, and chronic obstructive pulmonary disease, yielding 63 well-matched pairs. There was no difference in patient age, preoperative creatinine, body mass index, diabetes, chronic obstructive pulmonary disease, or STS score between BC and DC before or after propensity matching. BC patients received both anterograde and retrograde cardioplegias in multiple doses, whereas DC was delivered almost entirely anterograde with 95% of the patients (73/77) receiving a single dose only. DC was associated with decreased cardiopulmonary bypass time (108 ± 24 vs 135 ± 43 minutes, P = 0.001) and aortic cross-clamp time (80 ± 16 vs 102 ± 30 min, P = 0.001) and maximal glucose levels during cardiopulmonary bypass (165 ± 39 vs 202 ± 49 mg/dL, P = 0.001), whereas troponin T level did not differ between DC and BC (0.3 ± 0.29 vs 0.44 ± 1.7 ng/mL, P = 0.7). Preoperative ejection fraction did not change in either BC (64% ± 12% vs 61% ± 10%, P = 0.09) or DC (58% ± 14% vs 57% ± 14%, P = 0.4) after AVR. In minimally invasive AVR surgery, DC provided equivalent myocardial protection and clinical outcomes to BC while simplifying cardioprotective regimen and reducing aortic cross-clamp time. DC was associated with lower cardiopulmonary bypass glucose levels and demonstrated the feasibility of a single-dose administration.

WITHDRAWN: Single-dose del Nido cardioplegia in minimally invasive aortic valve surgery.

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RalA is overactivated in medulloblastoma.

Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies. We have studied an important effector down-stream of Ras, namely RalA (Ras-Like), for the first time and revealed overactivation of RalA in MDB. Affinity precipitation analysis of active RalA (RalA-GTP) in eight MDB cell lines (DAOY, RES256, RES262, UW228-1, UW426, UW473, D283 and D425) revealed that the majority contained elevated levels of active RalA (RalA-GTP) as compared with fetal cerebellar tissue as a normal control. Additionally, total RalA levels were shown to be elevated in 20 MDB patient samples as compared to normal brain tissue. The overall expression of RalA, however, was comparable in cancerous and normal samples. Other important effectors of RalA pathway including RalA binding protein-1 (RalBP1) and protein phosphatase A (PP2A) down-stream of Ral and Aurora kinase A (AKA) as an upstream RalA activator were also investigated in MDB. Considering the lack of specific inhibitors for RalA, we used gene specific silencing in order to inhibit RalA expression. Using a lentivirus expressing anti-RalA shRNA we successfully inhibited RalA expression in MDB and observed a significant reduction in proliferation and invasiveness. Similar results were observed using inhibitors of AKA and geranyl-geranyl transferase (non-specific inhibitors of RalA signaling) in terms of loss of in vivo tumorigenicity in heterotopic nude mouse model. Finally, once tested in cells expressing CD133 (a marker for MDB cancer stem cells), higher levels of RalA activation was observed. These data not only bring RalA to light as an important contributor to the malignant phenotype of MDB but introduces this pathway as a novel target in the treatment of this malignancy.

Significant Differences in the Development of Acquired Resistance to the MDM2 Inhibitor SAR405838 between In Vitro and In Vivo Drug Treatment.

SAR405838 is a potent and specific MDM2 inhibitor currently being evaluated in Phase I clinical trials for the treatment of human cancer. Using the SJSA-1 osteosarcoma cell line which harbors an amplified MDM2 gene and wild-type p53, we have investigated the acquired resistance mechanisms both in vitro and in vivo to SAR405838. Treatment of SJSA-1 cells with SAR405838 in vitro leads to dose-dependent cell growth inhibition, cell cycle arrest and robust apoptosis. However, prolonged treatment of SJSA-1 cells in vitro with SAR405838 results in profound acquired resistance to the drug. Analysis of in vitro-derived resistant cell lines showed that p53 is mutated in the DNA binding domain and can no longer be activated by SAR405838. Treatment of the parental SJSA-1 xenograft tumors with SAR405838 in mice yields rapid tumor regression but the tumors eventually regrow. Culturing the regrown tumors established a number of sublines, which showed only modest (3-5 times) loss of sensitivity to SAR405838 in vitro. Sequencing of the p53 showed that it retains its wild-type status in these in vivo sublines, with the exception of one subline, which harbors a single heterozygous C176F p53 mutation. Using xenograft models of two in vivo derived sublines, which has either wild-type p53 or p53 containing a single heterozygous C176F mutation, we showed that while SAR405838 effectively achieves partial tumor regression in these models, it no longer induces complete tumor regression and tumors resume growth once the treatment is stopped. Harvesting and culturing tumors obtained from a prolonged treatment with SAR405838 in mice established additional in vivo sublines, which all contain a single heterozygous C176F mutation with no additional p53 mutation detected. Interestingly, SAR405838 can still effectively activate p53 in all sublines containing a single heterozygous C176F mutation, with a moderately reduced potency as compared to that in the parental cell line. Consistently, SAR405838 is 3-5 times less effective in all the in vivo derived sublines containing a single heterozygous C176F p53 mutation than in the SJSA-1 parental cell line in assays of cell growth and apoptosis. Computational modeling suggested that a p53 tetramer containing two wild-type p53 molecules and two C176F mutated molecules can maintain the structural stability and interactions with DNA by formation of additional hydrophobic and cation-π interactions which compensate for the loss of sulphur-zinc coordination. Our data thus show that SJSA-1 tumor cells acquire very different levels of resistance in vitro and in vivo to the MDM2 inhibitor SAR405838. Our present study may have a significant implication for the investigation of resistant mechanisms for other classes of anticancer drugs.

Elucidation of Acquired Resistance to Bcl-2 and MDM2 Inhibitors in Acute Leukemia In Vitro and In Vivo.

PURPOSE: Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance. Elucidation of acquired resistance mechanisms and development of strategies to overcome the resistance are critical for their successful clinical development. EXPERIMENTAL DESIGN: We employed RS4;11 and MV4;11 cell lines, two acute leukemia models, to investigate acquired resistance mechanisms for both drugs in vitro and in vivo and evaluated several treatment regimens in xenograft mouse models to improve long-term, complete tumor regression. RESULTS: Resistance to either SAR405838 or ABT-263 (or its analogue ABT-737) develops in acute leukemia models in vitro and in vivo. RS4;11 and MV4;11 tumors treated with SAR405838 acquire resistance to the drug by mutation of the TP53 gene or compromise of p53 protein function. RS4;11 tumors treated with either ABT-263 or ABT-737 acquire resistance primarily through downregulation of BAX but not BAK. When acute leukemia cells become highly resistant to the MDM2 inhibitor, they retain their sensitivity to the Bcl-2 inhibitors, or vice versa. Certain sequential or combination treatment of SAR405838 and ABT-263 can achieve longer-term tumor regression than treatment with either agent alone. CONCLUSIONS: Our study provides new insights into the mechanisms of acquired resistance of Bcl-2 and MDM2 inhibitors in acute leukemia models and suggests that certain sequential or combination treatment of these two distinct classes of apoptosis-inducing agents should be tested as new treatment strategies for acute leukemia in the clinic.

An integrated cellular and sub-cellular model of cancer chemotherapy and therapies that target cell survival.

Apoptosis resistance is a hallmark of human cancer, and tumor cells often become resistant due to defects in the programmed cell death machinery. Targeting key apoptosis regulators to overcome apoptotic resistance and promote rapid death of tumor cells is an exciting new strategy for cancer treatment, either alone or in combination with traditionally used anti-cancer drugs that target cell division. Here we present a multiscale modeling framework for investigating the synergism between traditional chemotherapy and targeted therapies aimed at critical regulators of apoptosis.