Preclinical development of a humanized neutralizing antibody targeting HGF

Hepatocyte growth factor (HGF) and its receptor, cMET, play critical roles in cell proliferation, angiogenesis and invasion in a wide variety of cancers. We therefore examined the anti-tumor activity of the humanized monoclonal anti-HGF antibody, YYB-101, in nude mice bearing human glioblastoma xenografts as a single agent or in combination with temozolomide. HGF neutralization, The extracellular signal-related kinases 1 and 2 (ERK1/2) phosphorylation, and HGF-induced scattering were assessed in HGF-expressing cell lines treated with YYB-101. To support clinical development, we also evaluated the preclinical pharmacokinetics and toxicokinetics in cynomolgus monkeys, and human and cynomolgus monkey tissue was stained with YYB-101 to test tissue cross-reactivity. We found that YYB-101 inhibited cMET activation in vitro and suppressed tumor growth in the orthotopic mouse model of human glioblastoma. Combination treatment with YYB-101 and temozolomide decreased tumor growth and increased overall survival compared with the effects of either agent alone. Five cancer-related genes (TMEM119, FST, RSPO3, ROS1 and NBL1) were overexpressed in YYB-101-treated mice that showed tumor regrowth. In the tissue cross-reactivity assay, critical cross-reactivity was not observed. The terminal elimination half-life was 21.7 days. Taken together, the in vitro and in vivo data demonstrated the anti-tumor efficacy of YYB-101, which appeared to be mediated by blocking the HGF/cMET interaction. The preclinical pharmacokinetics, toxicokinetics and tissue cross-reactivity data support the clinical development of YYB-101 for advanced cancer.

Systolic Long Axis Function of the Left Ventricle, as Assessed by 2-D Strain, is Reduced in the Patients Who Have Diastolic Dysfunction and a Normal Ejection Fraction

BACKGROUND AND OBJECTIVES: Echocardiographic evaluation of the long axis left ventricle (LV) function has been reported to be useful for understanding heart failure in those patients with a preserved ejection fraction (EF). The global and segmental peak LV systolic longitudinal strain (PSLS), as determined by the 2D speckle tracking method, may be related with the conventional diastolic parameters. We sought to determine whether the PSLS could reveal LV systolic dysfunction in those patients who have a normal EF and diastolic dysfunction. SUBJECTS AND METHODS: A total of 168 patients who underwent a routine echocardiographic examination were evaluated. Echocardiographic evaluations were performed and the patients were grouped according to the grade of their diastolic dysfunction. The global and segmental PSLS were analyzed off-line. RESULTS: Measurements of the LV PSLS were successfully obtained in 83% of the patients. The mid and basal PSLS values were significantly lower in the patients with grade I and II diastolic dysfunction (-17.5+/-2.0% and -17.5+/-2.3%, respectively) versus the normal healthy controls (-20.6+/-1.9%, p<0.001). The mid and basal PSLS values were found to be well related to the early diastolic mitral annular velocity (r=0.510, p<0.001) and the left atrial volume index (r=-0.422, p<0.001). CONCLUSION: The systolic LV long-axis function, as determined by 2D strain and especially in the mid and basal LV segments, is reduced in the patients with diastolic dysfunction in spite of their normal LV EF.

Medico-Surgical Cooperative Treatment of Pulmonary Atresia with Intact Ventricular Septum

PURPOSE: The actual clinical examples of co-appliance of catheter intervention with surgical procedures in the treatment of pulmonary atresia with an intact ventricular septum(PA/IVS) which we have experienced in our institution are here shown, and the anatomical and hemodynamical profiles between each method is compared. METHODS: Medical records of 33 patients with PA/IVS who underwent various treatment from January, 1995 to December, 2000 were reviewed for a retrograde study. RESULTS: In three out of 10 patients who underwent percutaneous balloon pulmonary valvotomy (PPV), residual pulmonary stenosis were observed in their out patient department(OPD) follow-ups, eventually necessitatig balloon pulmonary valvuloplasty(BPV). One out of three patients exhibited deterioration of tricuspid regurgitation after BPV, requiring surgical tricuspid annuloplasty(TAP). Two out of the seven patients who received primarily surgical right ventricle outlet tract(RVOT) repair without any systemic-pulmonary shunt or intervention needed additional intervention employing cardiac catheterization after operation. Two patients received interventional catheterization before surgical RVOT repair. In five out of 11 cases of Fontan type operation, coil embolization of collateral circulation was done before total cavo-pulmonary connection(TCPC), and in three cases, interventional catheterization was needed after TCPC. CONCLUSION: Both medical and surgical treatment modalities are widely used in management of PA/IVS patients, and recent results prove that medico-surgical cooperative treatment is essential.

Postoperative Progress and Influencing Factors in Patients after Rastelli Procedure

PURPOSE: We have performed an analysis on patients who received Rastelli operation in our institute and reviewed their progress postoperatively. Various factors with suspected relationship to the outcome have been considered to help in future treatment and follow-up. METHODS: We analyzed retrospectively 43 patients who either received Rastelli operation in Yonsei University Cardiovascular Center from March 1995 to April 1997 or who received post-procedural cardiac catheterization and follow-up echocardiography in the out-patient department after the procedure. RESULTS: No statistically valid relationships were found between the age of the patient, their body weight, preoperative pulmonary arterial index and pressure, presence of pulmonary branchial stenosis and postoperative results. Cases with atrioventricular concordance showed lower age and body weight, and discordant cases exhibited lower ejection fraction 3 days postoperatively. Upon follow up, lower NYHA score was seen in patients with severe residual stenosis. In the group that received cardiac catheterization after the procedure, residual stenosis and right ventricular pressure measurement in echocardiography showed good correlation with the catheterization data. CONCLUSION: In cases where conduit insertions of the right ventricular outflow tract are required to achieve total correction in complex cardiac deformity, early operation does not seem to provide a clear risk to the patient. In patients with atrioventricular discordance, careful postoperative observation of the ventricular function seems to be needed. Also, echocardiography appears to be a sound method in follow-up of patients after the correctional procedure.

Conversion of Total Atrio-pulmonary Connection to Total Cavo-pulmonary Connection-Review of Indications and Hemodynamic Characteristics-

PURPOSE: Since the successful application of total atrio-pulmonary connection(TAPC) to patients with various types of physiologic single ventricles in 1971, post-operative survival rates have reached more than 90%. However some patients have been shown to present with late complications such as right atrial thrombosis, atrial fibrillation and protein losing enteropathy eventually leading to re-operation to control the long-term complications. The aim of this study is to review the results of total cavo-pulmonary connection(TCPC) in cases with late complications after TAPC. METHODS: Between Jan. 1995 and Dec. 2000, 6 patients(5 males and 1 female) underwent cardiac catheterization 11+/-3 months after conversion of previous TAPC to TCPC. We compared the hemodynamic and morphologic parameters before and after TCPC and also assessed the clinical outcomes. The indications for TAPC were tricuspid atresia in 4 cases and complex double-outlet right ventricle with single ventricle physiology in 2 cases. RESULTS: There was no peri-operative mortality and all patients were clinically and hemodynamically improved at a mean follow-up of 11 months(range: 4 to 13). However, protein losing enteropathy recurred in 2 patients; this was were successfully treated with subcutaneous administration of heparin. Right atrial pressure before TCPC was 18.0+/-3.6 mmHg, but baffle pressure, corresponding to right atrial pressure decreased to 14.8+/-3.6 mmHg after TCPC. The size of the pulmonary arteries did not regress after TCPC. CONCLUSION: The conversion of TAPC to TCPC improves clinical and hemodynamic status by decreasing the right atrial pressure and by providing a laminar cavo-pulmonary flow which enhances the effective pulmonary circulation in the so-called Fontan circulation.

Surgical Repair of Isolated Ventricular Septal Defect in Infancy Guided by Echocardiography

BACKGROUND: Echocardiographic examination is universally considered as an established method for the diagnosis of congenital heart disease, and as a result of many technological advancements in information processing, its utility is being emphasized much more. Cardiac catheterization, by comparison, is usually performed in the past for the purpose of diagnosis and preoperative assessment of infants with isolated ventricular septal defect (VSD), and the risks and complications of cardiac catheterization have been more frequent in the younger ages. Accordingly, we present in this study the effectiveness and safety of echocardiography on the diagnosis and treatment of infants who met the indications of early correction and underwent operations. METHODS: Between May 1994 and April 1997, 66 infants with isolated VSD were submitted for primary correction in the Yonsei Cardiovascular Center. Among the 66 infants (36 males and 30 females), 33 (group 1) underwent surgery on the basis of echocardiography alone and another 33 (group 2), on the basis of cardiac catheterization in addition to echocardiography. The two groups were compared for the diagnostic sensitivity, specificity, complication after surgical correction and frequency of re-operation. RESULTS: 1) The average age was 5.4+/-3.3 months in group 1 and 5.7+/-2.2 months in group 2. 2) There was no significant difference between the two groups in terms of the sensitivity and specificity of diagnostic tools. 3) There was no post-operative death in either group and no significant difference in postoperative hospital stay between the two groups. 4) There was no significant difference between the two groups in complications such as sepsis, pneumonia after surgical correction. CONCLUSION: We concluded that after an accurate selection, most infants with isolated VSD can safely undergo primary repair on the basis of echocardiography alone.