Severe Regurgitant Bicuspid Aortic Valve in a Patient with Overlapping Left Ventricular Noncompaction and Asymmetrical Septal Hypertrophy.

Overlapping of left ventricular noncompaction (LVNC) and hypertrophic cardiomyopathy in the same patient is rare and is associated with a more severe clinical course and unfavorable prognosis. The present report describes the case of a severely regurgitant bicuspid aortic valve in a 68-year-old man with overlapping LVNC and asymmetrical septal hypertrophy. Aortic valve replacement controlled the left ventricular dilatation that occurred secondary to the volume overload induced by the valvular disease. However, even 3 years postoperatively, severe systolic dysfunction persisted due to the preexisting myocardial disease, requiring close and lifelong follow-up with special attention to life-threatening arrhythmias and thromboembolism.

Mid-Term Patency of Spiral Saphenous Vein Graft for Malignant Superior Vena Cava Syndrome.

Reports documenting the mid-term patency of spiral saphenous vein grafts for superior vena cava syndrome in patients with advanced thoracic malignancy are, so far, scarce. The present report describes a 69-year-old man who suffered superior vena cava syndrome due to malignant invasion by advanced lung cancer. Since the huge mass in the anterior mediastinum was unresectable, a bypass from the left innominate vein to the right atrium using an autologous spiral saphenous vein graft was surgically created. Postoperatively, the patient received chemoradiotherapy and maintenance anticoagulant therapy, resulting in survival for 4 years without graft occlusion or recurrence of superior vena cava syndrome.

Hybrid Repair for Mega-Aortic Syndrome due to Giant Cell Aortitis in a Heart Failure Patient.

The present report describes a case of mega-aortic syndrome accompanied with severe aortic regurgitation in a 75-year-old man who underwent a two-stage hybrid repair. Intraoperative pathologic findings at the first repair, consisting of Bentall operation and total arch replacement with a Lupiae graft, aided the identification of the giant cell aortitis. Despite complicating hemorrhagic stroke, steroid therapy was initiated and endovascular repair was subsequently completed. Over more than 2 years of follow-up, the patient continued steroid therapy and is doing well without any reintervention.

The RECK tumor-suppressor protein binds and stabilizes ADAMTS10.

The tumor suppressor protein RECK has been implicated in the regulation of matrix metalloproteinases (MMPs), NOTCH-signaling and WNT7-signaling. It remains unclear, however, how broad the spectrum of RECK targets extends. To find novel RECK binding partners, we took the unbiased approach of yeast two-hybrid screening. This approach detected ADAMTS10 as a RECK-interactor. ADAMTS10 has been characterized as a metalloproteinase involved in fibrillin-rich microfibril biogenesis, and its mutations have been implicated in the connective tissue disorder Weill-Marchesani syndrome. Experiments in vitro using recombinant proteins expressed in mammalian cells indicated that RECK indeed binds ADAMTS10 directly, that RECK protects ADAMTS10 from fragmentation following chemical activation and that ADAMTS10 interferes with the activity of RECK to inhibit MT1-MMP. In cultured cells, RECK increases the amount of ADAMTS10 associated with the cells. Hence, the present study has uncovered novel interactions between two molecules of known clinical importance, RECK and ADAMTS10.This article has an associated First Person interview with the first author of the paper.

Five-Year Clinical Outcome of Asymptomatic vs. Symptomatic Severe Aortic Stenosis After Aortic Valve Replacement.

BACKGROUND: There is discordance regarding the effect of symptom status before aortic valve replacement (AVR) on long-term outcome after AVR in severe aortic stenosis (AS).Methods and Results:The CURRENT AS registry is a multicenter retrospective registry enrolling 3,815 consecutive patients with severe AS. Among 1,196 patients managed with the initial AVR strategy, long-term clinical outcomes were compared between the symptomatic patients (n=905), and asymptomatic patients (n=291). Median follow-up interval was 1337 days with a 91% follow-up rate at 2 years. AVR was performed in 886 patients (98%) in the symptomatic group and in 287 patients (99%) in the asymptomatic group. Symptomatic patients were older and more often had comorbidities than asymptomatic patients with similar echocardiographic AS severity. The cumulative 5-year incidences of all-cause death and heart failure (HF) hospitalization were significantly higher in symptomatic patients than in asymptomatic patients (25.6% vs. 15.4%, P=0.001, and 14.2% vs. 3.8%, P<0.001, respectively). On landmark analysis at 30 days after AVR, the differences in mortality and HF hospitalization between the 2 groups were mainly observed beyond 30 days. CONCLUSIONS: When managed with the initial AVR strategy, the long-term outcomes of symptomatic severe AS were worse than those of asymptomatic severe AS. Early AVR strategy might be recommended in some selected asymptomatic severe AS patients with reasonable operative risk.

[Isolation and applications of transformation suppressor genes].

A common strategy to identify tumor suppressor genes has been positional cloning, taking advantages of chromosomal abnormalities, linkage to polymorphic markers, etc. We have been taking another approach, based on shotgun cloning with cDNA-expression library, to isolate genes suppressing an aspect of transformed phenotypes. Genes identified in such an artificial system, however, require subsequent validation for their clinical relevance through independent approaches, such as finding mutations and altered expression in human cancers. Whether the parental genes act as oncogenes or tumor suppressors needs to be deduced from available annotations and/or new experimental data. Once validated, such genes, being isolated by virtue of their biological activities, are likely to be useful in developing new strategies for tumor prognosis, tumor stratification, and drug discovery.

Symmetrical papillary muscle approximation for functional mitral regurgitation with idiopathic dilated cardiomyopathy.

The cases are reported of mitral valve repair with symmetrical papillary muscle approximation from heads to bases close to cardiac apex for functional mitral regurgitation (FMR). The two papillary heads attaching the chordae to both leaflets from the posteromedial papillary muscle were approximated parallel to the solitary head of the anterolateral papillary muscle. This procedure permits an even reduction of lateral shift of the papillary muscle, resulting in an elimination of mitral tethering, and provides a satisfactory and durable mitral valve repair with good outcomes in patients with idiopathic dilated cardiomyopathy and FMR.

The transformation suppressor gene Reck is required for postaxial patterning in mouse forelimbs.

The membrane-anchored metalloproteinase-regulator RECK has been characterized as a tumor suppressor. Here we report that mice with reduced Reck-expression show limb abnormalities including right-dominant, forelimb-specific defects in postaxial skeletal elements. The forelimb buds of low-Reck mutants have an altered dorsal ectoderm with reduced Wnt7a and Igf2 expression, and hypotrophy in two signaling centers (i.e., ZPA and AER) that are essential for limb outgrowth and patterning. Reck is abundantly expressed in the anterior mesenchyme in normal limb buds; mesenchyme-specific Reck inactivation recapitulates the low-Reck phenotype; and some teratogens downregulate Reck in mesenchymal cells. Our findings illustrate a role for Reck in the mesenchymal-epithelial interactions essential for mammalian development.

[Acute aortic dissection with anomalous coronary artery].

A 38-year-old man was diagnosed with acute type A aortic dissection and severe aortic regurgitation, and taken immediately to the operating room for repair of the ascending aorta using the Bentall procedure. The presence of the anomalous right coronary artery was revealed at the time of the procedure, and was repaired with single coronary button technique. Some case reports have described anomalous coronary artery in association with acute myocardiac infarction or angina pectoris. This report describes a case of anomalous coronary artery diagnosed during an emergency operation for aortic dissection.

Early and late results of surgical treatment for ventricular septal rupture with and without use of the infarction exclusion technique--experience with two- and three-sheet modification.

BACKGROUND: Ventricular septal rupture (VSR) is an infrequent but life-threatening situation. Although outcomes have improved with the introduction of infarction exclusion, we have experienced difficulty in determining the optimal patch size and shape for obtaining good outcomes. Therefore, we modified the infarction exclusion technique. Herein, we review our experience on the basis of early closure of VSR with and without use of the infarction exclusion technique. METHODS: We retrospectively analyzed the hospital records of 33 patients who underwent surgical treatment for VSR. We employed Dagget's method from 1982 to 1995, and then introduced the infarction exclusion technique in 1995. We have developed two modifications: the two-sheet single-patch technique and the three-sheet double-patch technique. RESULTS: Overall hospital mortality was 41.9% and that of the infarction exclusion group was significantly lower than the hospital mortality rate of the noninfarction exclusion group (21% and 63%, respectively, p = 0.0266). Late mortality of survivors was low in all groups during the observation period. The three-sheet double-patch group showed no residual shunt. This difference in outcomes between the single-patch and double-patch groups was statistically significant (p = 0.0174). CONCLUSIONS: The two-sheet method facilitates the restoration of ventricular geometry. A double-patch using the three-sheet method may be useful for reducing residual shunt.

Successful closure of a patent ductus arteriosus using an aortic stent graft.

Closure of patent ductus arteriosus (PDA) in the elderly is a high-risk procedure due to the fragility of the aorta and aneurysmal changes in the ductus. Stent grafting has emerged as a method for treating aortic disease. We describe a case in which this endovascular technique was successfully performed for closure of a PDA with aneurismal change in a high-risk patient. This approach may comprise the armamentarium for treating this pathology in adults.

[Application of partial median sternotomy in cardiac surgery in patients with tracheostoma].

Median full-sternotomy carries a risk of sternal infection and lethal mediastinitis in cardiac surgery. We performed open-heart surgery through partial median sternotomy in 5 patients with tracheostomy. Coronary artery bypass grafting (CABG) was performed in 3 patients, aortic valve replacement in 1, and mitral valve replacement in 1. No operative deaths or complications related to wound infection occurred. Partial sternotomy represents a safe alternative in cardiac surgery in patients with tracheostoma.

[Resection and reconstruction of intimal sarcoma of the pulmonary artery with autologous pericardial roll].

Tumors of the pulmonary artery (PA) are rare and their prognosis is poor. Proper diagnosis is often delayed or made post mortem despite diagnostic advances. Although the only treatment of choice is radical surgical resection, local recurrences are soon recognized after the operation. There is no standard regimen of perioperative additional therapy, and its effectiveness is still unknown. We report a case of an 80-year-old male whose PA was almost completely obstructed by the intimal sarcoma. It was resected and reconstructed with autologous pericardial roll. His postoperative course was uneventful.

Involvement of the Reck tumor suppressor protein in maternal and embryonic vascular remodeling in mice.

BACKGROUND: Developmental angiogenesis proceeds through multiple morphogenetic events including sprouting, intussusception, and pruning. Mice lacking the membrane-anchored metalloproteinase regulator Reck die in utero around embryonic day 10.5 with halted vascular development; however, the mechanisms by which this phenotype arises remain unclear. RESULTS: We found that Reck is abundantly expressed in the cells associated with blood vessels undergoing angiogenesis or remodelling in the uteri of pregnant female mice. Some of the Reck-positive vessels show morphological features consistent with non-sprouting angiogenesis. Treatment with a vector expressing a small hairpin RNA against Reck severely disrupts the formation of blood vessels with a compact, round lumen. Similar defects were found in the vasculature of Reck-deficient or Reck conditional knockout embryos. CONCLUSIONS: Our findings implicate Reck in vascular remodeling, possibly through non-sprouting angiogenesis, in both maternal and embyonic tissues.

What we learn from transformation suppressor genes: lessons from RECK.

Expression cloning is a powerful approach to finding genes that induce appreciable changes in cultured cells. One way to use this technique in cancer research is to isolate cDNAs that induce flat reversion in transformed cells. Such screening, however, is inherently artificial, and therefore requires independent validation of the clinical relevance of isolated genes. Studies of the mechanisms of actions, physiological functions and mechanisms of regulation of these genes at various levels may enrich our knowledge of cancer biology and supplement our toolbox in developing new cancer diagnoses and therapies. In this article we discuss the promise, limitations and recent innovations in this approach, taking one transformation suppressor gene, RECK, as an example.

A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs.

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in various types of cancers; the levels of residual RECK in resected tumors often correlate with better prognosis. Forced expression of RECK in cancer cells suppresses tumor angiogenesis, invasion, and metastasis in xenograft models. RECK is therefore a promising marker for benignancy and a potential effector in cancer therapy. We established a cell line containing two transgene systems: (1) the secreted alkaline phosphatase (SEAP) gene fused to Reck promoter and (2) the HRAS(12V) oncogene driven by the Tet-off promoter system. This cell line exhibits transformed phenotype in regular medium and flat morphology with increased SEAP activity in the presence of doxycycline, allowing the assessment of RECK-inducing activity of chemicals in the contexts of both transformed and untransformed cells. Our pilot experiments with 880 known bioactive compounds detected 34 compounds that activate RECK promoter; among these, 10 were authentic anticancer drugs. Four selected compounds up-regulated endogenous RECK protein in several human cancer cell lines. The top-ranking compound, disulfiram, strongly suppressed spontaneous lung-metastasis of human fibrosarcoma cells in nude mice. Our data demonstrate the value of this screen in discovering effective cancer therapeutics.

VNCOP-B plus rituximab therapy in elderly patients with aggressive B-cell non-Hodgkin lymphoma: a multicenter experience.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP.