Inhibition of Notch4 using Novel Neutralizing Antibodies Reduces Tumor Growth in Murine Cancer Models by Targeting the Tumor Endothelium.

Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed on tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancer. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Safe Use of Glutaraldehyde to Repair the Destroyed Valve in Active Infective Mitral Valve Endocarditis.

BACKGROUND: The aim of this study was to review our experience of mitral valve (MV) repair for acute and active infective endocarditis (AAIE) and to identify the feasibility of a new approach together with the mid-term results. Methods and Results: A retrospective analysis was performed on 35 consecutive AAIE patients surgically treated in the isolated mitral position. Mean follow-up after the surgery was 4.3±3.7 years. 30 of the 35 patients were successfully treated by MV plasty (MVP); however, MV replacement (MVR) was necessary in the remaining 5 patients. Our novel approach included resection of the infective lesion, approximation with direct suture and/or patch repair with bovine or autopericardium after 2-min treatment of it and the defective leaflet edge(s) with 0.625% glutaraldehyde solution, reconstruction with artificial chordae and ring annuloplasty. The success rate of MVP was 85.7%. The longest postoperative follow-up echocardiography showed no mitral regurgitation (MR) in 4, trivial MR in 4, mild MR in 16 and moderate MR in 5 patients in the MVP group. The 5-year survival rate in the MVP group was 89±6%. MVR was required in 1 patient 2 months after MVP because of increasing MR. Recurrence of endocarditis has not been observed in any case. CONCLUSIONS: Glutaraldehyde was safely used in a surgical intervention for AAIE in the mitral position with acceptable early and mid-term results.

Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1.

Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (mDA) neurons for cell replacement therapy for Parkinson's disease (PD). However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. To eliminate these unwanted cells, cell sorting using antibodies for specific markers such as CORIN or ALCAM has been developed, but neither marker is specific for ventral midbrain. Here we employ a double selection strategy for cells expressing both CORIN and LMX1A::GFP, and report a cell surface marker to enrich mDA progenitors, LRTM1. When transplanted into 6-OHDA-lesioned rats, human iPSC-derived LRTM1+ cells survive and differentiate into mDA neurons in vivo, resulting in a significant improvement in motor behaviour without tumour formation. In addition, there was marked survival of mDA neurons following transplantation of LRTM1+ cells into the brain of an MPTP-treated monkey. Thus, LRTM1 may provide a tool for efficient and safe cell therapy for PD patients.

Choice of Aortic Valve Prosthesis in a Rapidly Aging and Long-Living Society.

PURPOSE: The aim of this study was to evaluate the long-term results of aortic valve replacement (AVR) with mechanical (M) and bioprosthetic (B) valves as recommended by the Japanese guidelines. METHODS: From April 1995 to March 2014, 366 adult patients underwent AVR. Of these, 127 (35%) patients received M and 239 patients (65%) received B valves. A retrospective analysis of the entire and the selected 124 patients aged 60 to 70 years was carried out. RESULTS: In patients aged 60 to 70 years, the 15-year survival and freedom from reoperation were 88% ± 7% and 100% for the M group and 34% ± 25% (p <0.001) and 73% ± 14% (p = 0.059) for the B group, respectively. Among propensity score matching of the subgroup, there was no significant difference in survival and freedom from reoperation. The rate of thromboembolism was higher in the M (M: 0.58% vs B: 0.35% patient per year, p <0.001) and the rate of hemorrhage was higher in the M group (M: 0.34% vs B: 0.12% patient per year, p <0.001). CONCLUSION: The current strategy of aortic valve choice based on the Japanese guidelines has provided excellent long-term results so far.

[Atrial Septal Defect with Hereditary Deficiency of Antithrombin III].

A 41-year-old female with hereditary deficiency of antithrombin III (ATIII) was diagnosed with atrial septal defect( ASD) and scheduled for the closure of ASD. She had been taking warfarin since she suffered from deep vein thrombosis 10 years ago. Preoperative management of anticoagulation included discontinuation of warfarin, and supplementation of antithrombin with heparin infusion. On the day of operation, antithrombin activity was maintained above 80% by administering antithrombin, and closure of ASD was carried out under standard cardiopulmonary bypass support using heparin. Heparin infusion was continued with antithrombin supplementation until prothrombin time-international normalized ratio(PT-INR) recovered to around 2.5 with warfarin. Her intra-and postoperative courses did not show any thromboembolic events, and she was discharged 20 days after the surgery.

Spontaneous closure of a large left ventricular pseudoaneurysm after mitral valve replacement.

Left ventricular pseudoaneurysm is a rare, but potentially fatal, condition that generally occurs as a complication of myocardial infarction, infective endocarditis, or cardiac surgery. Surgical repair is the treatment of first choice because of the marked risk of rupture, but deteriorated hemodynamics and complicated procedures to treat the pseudoaneurysm may lead to a high mortality rate. We report a 62-year-old woman with a large left ventricular pseudoaneurysm after mitral valve replacement for rheumatic mitral valve stenosis. Surgical repair was not performed due to the patient's refusal, but her pseudoaneurysm resolved spontaneously by 2 years after mitral valve replacement. Spontaneous obliteration of a large left ventricular pseudoaneurysm is very rare in a patient on warfarin therapy. This case suggests that a left ventricular pseudoaneurysm with a narrow neck may resolve spontaneously in rare settings.

Left ventricular pseudoaneurysm after reimplantation procedure.

Postoperative left ventricular pseudoaneurysm is a rare, but potentially lethal, complication because of the high risk of rupture and high mortality of repair. We report a 64-year-old man with Marfan syndrome who underwent the reimplantation valve-sparing aortic root replacement complicated by a postoperative left ventricular pseudoaneurysm that required urgent repair. Careful handling of the aortic root is required to avoid a left ventricular pseudoaneurysm, particularly in patients with connective tissue disorder.

[Mitral valve surgery after aortic valve replacement].

The causes of mitral valve operation for patients who underwent aortic valve replacements (AVR)are rheumatic heart diseases, nonrheumatic insufficiency, infective endocarditis, prosthetic valve dysfunction and so on. No specific recommendation for surgical strategy of mitral valve surgery for those patients has been described and surgical strategy should be selected to each patient. The patients with rheumatic heart disease had higher risk for reoperation as compared with those with nonrheumatic heart disease and majority of patients with AVR who need reoperation because of mitral valve diseases had history of open or closed mitral commissurotomy. Therefore, mitral valve repair should be limited to lesions in which excellent durability of the repair can be expected to prevent re-operation.

[Lower body ischemia due to bending of the stent after hybrid treatment for chronic stanford type B aortic dissection].

Lower body ischemia due to bending of a stented graft at the thoracic aorta was rare, particularly when it occurred in several days after surgery. We experienced this complication and performed the 3rd-time thoracic endovascular repair( TEVAR).A 49-year-old man with a chronic aortic dissection of Stanford type B underwent TEVER;however we failed to close the entry because of the tortuously bended distal arch of the aorta. Then it was decided the patient undergo a hybrid treatment with arch replacement and frozen elephant trunk. Seventeen days after the surgery, the blood pressure of the patient's lower limb was reduced rapidly and his renal function deteriorated. Bending of the stent was revealed by computed tomography( CT). The patient underwent the 3rd-time emergency TEVAR, and his symptoms improved.

Update on aortic valve prosthesis-patient mismatch in Japan.

The influence of aortic valve prosthesis-patient mismatch (VP-PM) on the clinical outcome has been an ongoing controversy. The reported prevalence of VP-PM after aortic valve replacement (AVR) ranges widely between 20 and 70 %. The inconsistent impact of VP-PM on short-term and long-term mortality, regression of left ventricular (LV) hypertrophy, and exercise capacity may be explained by differences of the patient populations, the definition of VP-PM, and the use of different prostheses. Moreover, many factors other than the severity of VP-PM should be taken into account when considering its impact on individual patients after AVR. Although the concept of VP-PM is easy to understand, it cannot be applied to the whole patient population. In Japan, the age of the candidates for AVR has increased markedly in recent years, but almost all elderly patients with a small BSA (<1.6 m(2)) have received newer-generation prostheses with a small outer diameter and large effective orifice area. Indeed, previous studies of Japanese patients have demonstrated that VP-PM was no more than moderate in most cases and its impact on clinical outcomes was generally acceptable. Although severe VP-PM is infrequent and its clinical implications are still unproven in elderly Japanese patients, it would seem reasonable to try to prevent severe VP-PM. Thus, VP-PM itself cannot be accepted as an independent risk factor in Japanese patients, but the useful preventive strategies for severe VP-PM in inactive very elderly persons remain controversial. The implantation of newer-generation biological or mechanical prostheses with or without aortic annular enlargement should be considered according to the characteristics of the patient and the risk-benefit ratio for carrying out a particular procedure in an individual patient.

Technique of managing periprosthetic leakage due to mitral prosthetic valve endocarditis: report of a case.

A patient with multiple leaks caused by active mitral prosthetic valve endocarditis with an annular abscess underwent repeat mitral valve replacement. To secure the new mitral prosthesis, sutures were placed through the healthy interatrial septal wall from right to left at the posteromedial region and then to the new prosthetic valve sewing cuff. In the anterolateral region, sutures were placed through the reconstructed annulus after debridement of the abscess and then reinforced with a pericardial xenograft patch. Postoperatively, the perivalvular leakage stopped and the patient recovered uneventfully.

[Leaflet resection for the degenerative mitral valve regurgitation; early/long-term assessment].

Leaflet resection for posterior leaflet prolapse has been a standard repair procedure with good longterm durability. The aim of this study was to review our experience of mitral valve repair, in which resection of the anterior and/or posterior leaflets was performed. Between October 1991 and December 2010, 172 patients with degenerative mitral valve regurgitation underwent mitral valve reconstruction,including 98 patients with the posterior leaflet prolapse, 47 patients with the anterior leaflet prolapse, 17 patients with both leaflets and 10 patients with the commissure prolapse. Most patients in this study were supposed to be caused by fibroelastic deficiency and we have not experienced systolic anterior motion after repair. The mean follow-up period was 8.7 ± 5.5 years. The freedom from reoperation rates at 15 years in 88.7 ± 5.3% of the anterior leaflet procedure, 96.6 ± 2.5% of the posterior leaflet, and 100% of both leaflets. The results of resection of a diseased prolapsed mitral leaflet have been promising so far. However, reoperation was required in 7 patients (4.1%) and reoperation rate was higher in patients with anterior prolapse and longer follow-up will evaluate precisely be benefit.

Cryosurgical left-sided maze procedure in patients with valvular heart disease: medium-term results.

PURPOSE: We evaluated medium-term results of the left-sided maze procedure using cryoablation in patients with valvular heart disease. METHODS: We retrospectively evaluated 111 patients with valvular heart disease who underwent the cryosurgical left-sided maze procedure. The mean follow-up period was 36.8 ± 24.9 months, and the mean duration of atrial fibrillation was 5.6 ± 6.0 years. The primary surgical procedure was mitral valve replacement in 42 patients, mitral valve plasty in 28, aortic valve replacement in 25, and combined aortic and mitral replacement or plasty in 16. RESULTS: The 7-year actuarial survival rate was 82.9 ± 11.4% for patients in sinus rhythm and 87.0 ± 7.0% for patients with atrial fibrillation, showing no difference between the two groups (p = 0.236). At final follow-up, 86 out of 111 patients (77.5%) remained free from atrial fibrillation. Sinus rhythm was maintained in 26 of 42 patients (61.9%) in the mitral valve replacement group, 26 of 28 patients (92.9%) in the mitral valve plasty group, 15 of 17 patients (88.2%) in the aortic valve replacement group, and 18 of 24 patients (75.0%) in the combined aortic and mitral replacement or plasty group. The overall actuarial rate of freedom from atrial fibrillation at 5 years after surgery was 70.4 ± 6.0%. CONCLUSION: The cryosurgical left-sided maze procedure is a safe, simple, and excellent operation for medically refractory atrial fibrillation.

Reconsideration of patient-prosthesis mismatch definition from the valve indexed effective orifice area.

BACKGROUND: The objective of this study was to reassess the validity of defining patient-prosthesis mismatch (PPM) in the aortic position on the basis of an indexed effective orifice area (iEOA) less than 0.85 cm(2)/m(2). METHODS: From June 1996 to March 2008, 342 patients underwent aortic valve replacement with a Carpentier-Edwards Perimount valve. From the data collected, the transvalvular pressure gradient was determined by the modified Bernoulli equation, and EOA was calculated from the standard continuity equation. RESULTS: The actuarial survival rate at 10 years after surgery was 84.0% +/- 8.2%. The prevalence of PPM was 6.1% when a projected iEOA less than 0.85 cm(2)/m(2) was defined as indicating significant PPM. There was no difference between patients with moderate PPM (85.2% +/- 9.8%) and patients without PPM (81.0% +/- 8.7%; p = 0.44). The relation between mean transvalvular pressure gradient and iEOA demonstrated a gentler slope than that reported previously. Postoperative mean transvalvular pressure gradient was 17.4 +/- 5.6 mm Hg and 14.5 +/- 5.6 mm Hg in patients with an iEOA less than 0.85 and 0.85 or greater, respectively. Most patients had a postoperative mean transvalvular pressure gradient more than 10 mm Hg regardless of PPM. CONCLUSIONS: Our analysis suggested that an iEOA less than 2.0 cm(2)/m(2) might be the threshold for PPM, which should not be passed to achieve a low mean transvalvular pressure gradient (less than 10 mm Hg) with the Carpentier-Edwards Perimount valve. The implications of these findings include the necessity for reassessing the hemodynamic performance of each type of prosthesis when attempting to define PPM, to avoid residual significant transvalvular pressure gradient.

Active infective endocarditis: management and risk analysis of hospital death from 24 years' experience.

BACKGROUND: This study was performed to identify risk factors for hospital death in patients with acute and active infective endocarditis (AAIE) after surgical intervention. METHODS AND RESULTS: From 1980 to 2004, 94 patients underwent surgery for AAIE (age range, 3-77 years; 76% males). Congestive heart failure (CHF) was present in 44 patients, as well as vegetations in 64, septicemia in 16, abscesses in 17, and emboli in 22; 16 patients had prosthetic valve endocarditis. Streptococci were the most common bacteria (34 patients), followed by staphylococci (17 patients). Mechanical valves were selected for 73 patients and bioprosthetic valves for 16. Mitral valve plasty was performed in 4 patients. Aortic root or aorto-mitral discontinuity was repaired in 17 patients, including Manouguian's double valve replacement in 6 and aortic root replacement in 4. Overall hospital mortality was 15% (14 patients). Univariate analysis identified CHF (p=0.016), abscess (p=0.014), and prosthetic valve endocarditis (p=0.043) as risk factors. However, multivariate analysis only identified CHF (p=0.019) as an independent risk factor. CONCLUSION: In AAIE, early surgical intervention is advisable before the occurrence of complications such as root abscess and CHF, particularly before the onset of CHF.

Validity of identifying patient-prosthesis mismatch from the indexed effective orifice area.

The main problem that arises from patient-prosthesis mismatch after aortic valve replacement is a residual high transvalvular pressure gradient, resulting in left ventricular overload. It was demonstrated by Pibarot and Dumesnil that the indexed effective orifice area should be larger than 0.85-0.90 cm2/m2 to prevent any significant transvalvular pressure gradient after operation. However, we have encountered a higher residual transvalvular pressure gradient than expected in some patients with an aortic stented bioprosthesis with an indexed effective orifice area greater than 0.85 cm2/m2. Based on our data, an indexed effective orifice area of less than 1.25 cm2/m2 might be considered the threshold for patient-prosthesis mismatch in patients with a stented bioprosthesis because this indexed effective orifice area is associated with a low mean transvalvular pressure gradient (less than 10 mmHg). The practical implications include the necessity to consider the hemodynamic performance of each prosthesis type when seeking to define patient-prosthesis mismatch and abnormally or significant high postoperative gradients that lead to an increased left ventricular workload, so as to avoid residual significant transvalvular pressure gradients and higher rates of morbidity and mortality.

Mitral valve reconstruction: long-term results of triangular resection for degenerative prolapse.

OBJECTIVES: Surgical treatment of a prolapsed anterior leaflet of the mitral valve is relatively difficult and controversial compared with management of a prolapsed posterior leaflet. The aim of this study was to assess the long-term results of mitral valve repair, focusing on triangular resection of the anterior leaflet. METHODS: Between October 1991 and December 2006, surgical treatment for a prolapsed anterior leaflet was performed in 57 patients with degenerative mitral valve disease, including 49 patients who had anterior leaflet resection. Patients with mitral stenosis, ischemic mitral regurgitation, and congenital valvular disease were excluded. The mean age of the patients was 51.7 +/- 15.9 years, and the mean follow-up period was 6.2 +/- 3.8 years. RESULTS: The overall actuarial survival rate and noreoperation rate at 10 years were 91.7% +/- 4.1% and 92.3% +/- 3.7%, respectively. Reoperation was performed in 2 (4%) of 49 patients who had anterior leaflet resection. All patients survived after reoperation, which involved mitral valve replacement. Postoperative echocardiographic studies showed that the mitral valve area was significantly smaller after repair in patients with anterior leaflet resection, but the area was still large enough for a functional valve. Among the 57 patients, 42 had no mitral regurgitation, whereas it was mild in 7 patients and moderate in 3 patients. CONCLUSION: Triangular resection of a prolapsed anterior leaflet of the mitral valve provides durable and reliable long-term results.