Convection-enhanced delivery of polyethylene glycol-coated liposomal doxorubicin: characterization and efficacy in rat intracranial glioma models.

OBJECT: The characteristics of polyethylene glycol-coated liposomal doxorubicin (PLD), the only liposomal drug now clinically available for intravenous injection, were investigated after convection-enhanced delivery (CED) into the rat brain parenchyma. METHODS: The distribution, tissue retention, and toxicity profile were evaluated after CED into the rat brain parenchyma. The antitumor efficacy was also determined in rodent intracranial U-251MG and U-87MG glioma models. RESULTS: Convection-enhanced delivery of PLD achieved wider distributions and delayed onset of toxicity in the brain parenchyma compared with CED of free doxorubicin infusion. Fluorescence generated from doxorubicin infused as PLD was detected until at least 30 days after infusion. Local toxicity was not observed when a 10% dilution of the commercially available PLD solution was used (0.2 mg/ml doxorubicin), but was significant at higher concentrations. Results after 10% PLD was delivered locally with CED demonstrated significant survival prolongation in both intracranial U-251MG and U-87MG xenograft models. CONCLUSIONS: Convection-enhanced delivery of PLD achieved extensive tissue distribution and sustained drug release. Convection-enhanced delivery of PLD is a promising chemotherapy for the treatment of malignant gliomas.

Enhanced antitumor effect of combined-modality treatment using convection-enhanced delivery of hydrophilic nitrosourea with irradiation or systemic administration of temozolomide in intracranial brain tumor xenografts.

OBJECTIVE: Convection-enhanced delivery (CED) is a local infusion technique that delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. We previously reported the safety and efficacy of CED of ACNU (nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride), a hydrophilic nitrosourea, in rat brain tumor models. This study evaluated the efficacy of combined-modality treatments using CED of ACNU with irradiation or systemic administration of temozolomide. METHODS: Antitumor efficacy and toxicity of the treatment were evaluated using rat 9L intracranial brain tumor models. RESULTS: Combined treatment using CED of ACNU with irradiation produced significantly longer survival time than each treatment alone (versus CED: p<0.001, versus irradiation: p<0.05, log-rank test) or systemic administration of ACNU with irradiation (p<0.001). Long-term survival (120 days) and eradication of tumor occurred only in this combined-treatment group. We also showed that CED of ACNU plus systemic administration of temozolomide significantly enhanced survival rate compared with each treatment alone (versus CED: p<0.001, versus systemic temozolomide: p<0.05). DISCUSSION: Multimodality treatment using CED of ACNU, radiotherapy and systemic chemotherapy with temozolomide is a promising strategy for treatment of brain tumors.

Iatrogenic Extravasation and Extracranial ICA Dissection during Neurointervention Evaluated by Transoral Carotid Ultrasonography: Case Report.

We described an 88-year-old woman presented with large aneurysm on the carotid siphon of the right internal carotid artery (ICA). Digital subtraction angiography showed extravasation from the distal cervical segment of the right ICA due to positioning a guiding catheter for intra-aneurysmal coil embolization. Transoral carotid ultrasonography (TOCU) showed arrested bleeding and a pseudolumen in the distal cervical segment of the right ICA. We originally described that TOCU was useful for evaluating iatrogenic extravasation and extracranial ICA dissection during neurointervention.

End-to-side anastomosis for coarctation of the aorta and type A aortic arch interruption with hypoplastic aortic arch.

OBJECTIVE: We investigated the advantages of reconstructing the aortic arch in neonates and infants by end-to-side anastomosis (ESA) in aortic coarctation and type A aortic arch interruption. SUBJECTS AND METHODS: The patients were 28 neonates and infants who underwent median full sternotomy for correction of aortic coarctation (CoA) and type A interrupted aortic arch (IAA), at our institute, from October 1997 to September 2002. The cases were divided into two groups: ESA was performed in 16 cases (group A) and extended end to end anastomosis in 12 cases (group B). All repairs were made using simple clamping of the descending aorta under cardiac arrest. We compared groups A and B with regard to duration of simple clamping, postoperative blood pressure in the upper and lower extremities, echocardiographic pressure gradient, and the presence or absence of tracheal stenosis as diagnosed by postoperative clinical symptoms and chest radiography. RESULTS: No significant difference between the groups was found in age, gender, body weight, or the ratio of CoA to IAA. In addition, there was no difference between the two groups in the duration of simple clamping or the difference in blood pressure between the lower and upper extremities. However, the echocardiographic pressure gradient at the site of anastomosis in group A was significantly lower than that in group B. There were no cases with symptoms of bronchial stenosis in either group. CONCLUSION: ESA is a relatively simple method for treating CoA or IAA with hypoplastic aortic arch, and was found to be effective for the elimination of residual stenosis.

Pheochromocytoma presenting as recurrent hypotension and syncope.

We report a case with pheochromocytoma presenting as recurrent syncope due to hypotension. A 71-year-old man was admitted because of recurrent syncope and paroxysmal hypotension. He was diagnosed as having pheochromocytoma. In spite of a large volume of infusion and insulin therapy, syncope and paroxysmal hypotension continued. We speculated that hypotension was mainly due to vasodilatation caused by excess plasma epinephrine and prescribed a non-selective beta-adrenergic blocker. It stabilized blood pressure and syncope disappeared. The right adrenal tumor was excised and he was discharged in good condition. This case report provides some implications for the management of pheochromocytoma complicated with hypotension.

Mitral valve replacement in children under 3 years of age.

OBJECTIVE: This study was undertaken to review our experience of mitral valve replacement in children under 3 years of age. METHODS: Between January 1990 and May 2004, 18 patients under 3 years of age underwent a total of 20 mitral valve replacements using a bileaflet mechanical prosthetic valve. There were 9 males and 11 females. The age at surgery ranged from 3 months to 3 (mean=1.02 +/- 0.72) years and body weight varied between 3.4 and 13.2 (mean=7.08 +/- 2.74) kg. RESULTS: There were 4 early and 2 late deaths, and these occurred in severe cases aged less than 1 year of age. Re-replacement of mitral valve was required in 3 patients (valve thrombosis in 2 and pannus formation in 1). Orifice size of the implanted prosthesis (OS) as compared with the predicted normal size of the mitral valve (NS) was well correlated with maximum transprosthetic flow velocity estimated by Doppler echocardiography. In this study, the OS/NS>0.65 was maintained in all patients, and none required re-replacement because of prosthesis-patient mismatch. CONCLUSION: Patients less than 1 year of age had significant mortality and morbidity. The results were satisfactory in the remainder (1-3 years). During this follow-up period, none required re-replacement due to somatic growth, but it will be an unavoidable problem in the future. The OS/NS, which can be checked with a regular physical examination, may serve as a guide to determine the most appropriate timing for the second surgery.

Ross procedure in an infant weighing 4.5 kg: eight years follow-up.

A 6 month-old male infant (weight: 4.5 kg) with congenital aortic stenosis underwent aortic valve replacement with a pulmonary autograft (Ross procedure). The right ventricular outflow tract (RVOT) was reconstructed with a polytetrafluoroethylene (PTFE) -valved equine pericardial conduit. At the age of 5, re-RVOT reconstruction with an equine pericardial patch bearing a PTFE monocusp was required because of severe pulmonary stenosis resistant to 2 attempts of percutaneous transluminal pulmonary valvotomy. Currently, at the age of 8, the degree of aortic regurgitation is trivial and the pulmonary autograft is free of functional deterioration despite somatic growth.

Tetralogy of Fallot with subarterial ventricular septal defect.

BACKGROUND: Tetralogy of Fallot with subarterial ventricular septal defect is frequently seen among Asians. Compared with infracristal ventricular septal defect, postoperative right ventricular outflow obstruction is more likely because of subpulmonary extension of the defect. Moreover the incidence of aortic regurgitation is a concern because of the absence of a supporting infundibulum. METHODS: Four hundred cases of classic tetralogy were reviewed, 61 of which had subarterial ventricular septal defect. RESULTS: Aortic regurgitation (of more than mild degree) was identified in 7 cases with subarterial and 7 with infracristal ventricular septal defects. The mechanism of infracristal defect was predominantly an annular dilation before surgery. In contrast 5 cases with subarterial defect had progression of aortic regurgitation after operation yielding an actuarial incidence of 29.7% at 20 years. In 2 patients the cause seemed to be fixation or plication of the aortic valve annulus by the ventricular septal patch. Compared with infracristal defect, subarterial defect was associated with increased incidence of reoperation (12.0% versus 1.9% at 10 years, p = 0.01), frequent use of transannular patch (70.5% versus 45.7%, p = 0.0004), and worse New York Heart Association (NYHA) functional class (p = 0.007). Right ventricular outflow obstruction was the reason for reoperation in 3 patients with subarterial defect and was associated with worse NYHA classification in the long-term, on multivariate analysis (p = 0.0002). CONCLUSIONS: Tetralogy with subarterial ventricular septal defect was associated with worse functional outcome. To prevent adverse outcomes, precise suturing of the distal ventricular septal patch, extensive infundibulectomy, lower threshold for transannular incision, and smaller-sized ventricular septal patch placement are warranted.

Mitral valve replacement for children with a small annulus using ATS open pivot prosthesis.

OBJECTIVES: The present study was conducted to review our experience of mitral valve replacement (MVR) in small children with the ATS open pivot prosthesis. METHODS: Between January 1999 and March 2002, 14 patients (7 males and 7 females) underwent a total of 15 ATS MVRs; 16AP in 9, 18AP in 3, and 20AP in 3 occasions. The mean age and body weight at operation were 1.1 +/- 0.7 (range 0.2 to 2.7) years and 6.8 +/- 2.6 (range 2.8 to 12.5) kg, respectively. RESULTS: There were 2 early and 2 late deaths, each non-valve related. Excluding one patient, the orifice size of the prosthesis was larger than the predicted normal size of the mitral valve for the age. The postoperative Doppler echocardiogram demonstrated normal maximal flow velocity across the prosthesis. There was no morbidity among survivors except for the patient who developed a stuck and immobile valve disc 10.2 months after the operation and required re-replacement. CONCLUSIONS: Our experience shows that MVR with the ATS open pivot prosthesis is a promising surgical option for small children.

Single-stage repair of complete atrioventricular septal defect and coarctation of the aorta in neonate.

Controversy over patients with complete atrioventricular septal defect (CAVSD) and coarctation of the aorta (CoA) continues: whether they should be treated with a primary total correction or a staged approach utilizing initial pulmonary artery banding during neonatal period. A 17-day-old neonate with Down's syndrome underwent definitive repair of CAVSD and CoA. With the postoperative course uneventful, he was discharged from the hospital on 19th postoperative day. Single-stage repair of CAVSD and CoA appears to offer a good prognosis provided that valve morphology is amenable to repair.

The reliability and validity of the Japanese version of the Appraisal of Diabetes Scale for type 2 diabetes patients.

AIMS: An appropriate questionnaire for measurement of the psychological burden of self-management or behavior modification in type-2 diabetes patients has yet to be developed in Japan. This study was conducted to test the reliability and validity of the Japanese version of the Appraisal of Diabetes Scale (ADS). METHODS: the study enrolled 346 Japanese patients with type 2 diabetes: 200 men and 146 women who were 63.2 ± 10.1 and 62.2 ± 11.9 years of age and had HbA1c levels of 6.9 ± 1.2% and 7.3 ± 1.9%, respectively. RESULTS: the questionnaire was divided into three components: "Psychological impact of diabetes", "Sense of self-control", and "Efforts for symptom management". Cronbach's alpha was 0.746-0.628. Significant correlations were observed between "Sense of self-control" and self-managed dietary and exercise behaviors and HbA1c levels; between "Psychological impact of diabetes" and various treatments, symptoms causing anxiety, and HbA1c levels; and between "Efforts for symptom management" and dietary and nutritional behaviors. The questionnaire showed better evidence of internal consistency, test-retest reliability and validity. CONCLUSION: our results suggested that the Japanese version of ADS may be a useful tool for the quick assessment of common anxieties and motivation toward treatment in patients with type 2 diabetes.

Minimum apparent diffusion coefficient for the differential diagnosis of ganglioglioma.

OBJECTIVES: The utility of apparent diffusion coefficient (ADC) values was evaluated for the differential diagnosis of ganglioglioma. METHODS: Ten consecutive patients, five men and five women, aged from 14 to 67 years, with histologically proven supratentorial gangliogliomas, underwent diffusion-weighted magnetic resonance imaging with echo planar imaging technique. The minimum ADC (minADC) of each tumor was pre-operatively determined from several regions of interest. The minADC of ganglioglioma was compared with that of low- or high-grade astrocytomas (astrocytoma, anaplastic astrocytoma and glioblastoma). Tumor cellularity of gangliogliomas was compared with the minADC. RESULTS: The mean minADC of the gangliogliomas (1.45 +/- 0.20 x 10(-3) mm(2)/s) was significantly higher than that of the low- or high-grade astrocytomas. Tumor cellularity of ganglioglioma was inversely correlated with the minADC value. DISCUSSION: The minADC value reflects in the low tumor cellularity of gangliogliomas and may provide a method for the differential diagnosis of ganglioglioma.

Safety and efficacy of convection-enhanced delivery of ACNU, a hydrophilic nitrosourea, in intracranial brain tumor models.

Convection-enhanced delivery (CED) is a local infusion technique, which delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED distribution is significantly increased if the infusate is hydrophilic. This study evaluated the safety and efficacy of CED of nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl) methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), a hydrophilic nitrosourea, in rat 9 L: brain tumor models. The local neurotoxicity of ACNU delivered via CED was examined in normal rat brains, and the maximum tolerated dose (MTD) was estimated at 0.02 mg/rat. CED of ACNU at the MTD produced significantly longer survival time than systemic administration (P < 0.05, log-rank test). Long-term survival (80 days) and eradication of the tumor occurred only in the CED-treated rats. The tissue concentration of ACNU was measured by high-performance liquid chromatography, which revealed that CED of ACNU at the dose of 100-fold less total drug than intravenous injection carried almost equivalent concentrations of ACNU into rat brain tissue. CED of hydrophilic ACNU is a promising strategy for treating brain tumors.

Short operation time: an important element to reduce operative invasiveness in pediatric cardiac surgery.

BACKGROUND: The mini skin incision procedure is considered an important element of minimally invasive cardiac surgery because of its definitive cosmetic advantage. However, the operative hazard of limited exposure may be associated with prolonged operation time and increased surgical insult. METHODS: A total of 357 consecutive patients undergoing repair of an isolated atrial or ventricular septal defect, in whom the mini skin procedure was applied, were investigated. Patients were grouped by diagnosis and body weight. Univariate and multivariate risk analyses were conducted in the specific patient group undergoing ventricular septal defect repair weighing less than 5 kg. RESULTS: The operation time was reduced by 21.0% (93.4 to 73.8 minutes) during this time period. Univariate risk analysis revealed that the operation time had a significant correlation with time to extubation (p < 0.0001), catecholamine duration (p = 0.0003), intensive care unit stay (p < 0.0001), hospital stay (p = 0.016), arterio-alveolar oxygen tension difference at the time of extubation (p = 0.0253), and furosemide dose required in the first 24 hours (p = 0.0332). Multiple linear regression analysis revealed that the operation time had an impact on time to extubation, arterio-alveolar oxygen tension difference at the time of extubation, and intensive care unit stay. The length of skin incision was not correlated with any outcome measure. CONCLUSIONS: The mini skin incision, if associated with prolonged operation time, may increase the overall insult in pediatric cardiac surgery. In order to reduce operative invasiveness, simultaneous effort to reduce, or at least not to increase, the operation time are mandatory.

Behavior of caveolae and caveolin-3 during the development of myocyte hypertrophy.

Recent studies have indicated that caveolae are enriched in a variety of signaling molecules, some of which are associated with cardiomyocyte hypertrophy. Caveolin-3, a major constituent of cardiac caveolae, has been suggested to interact with several signaling molecules. We investigated the morphologic changes of caveolae and caveolin-3 expression in hypertrophied cardiomyocytes induced by an alpha1-adrenergic agonist. Cultured rat neonatal cardiomyocytes were used for the experiments. Phenylephrine induced cellular hypertrophy associated with an increase of the number of caveolae and an up-regulation of caveolin-3. Although PMA increased the number of caveolae and the caveolin-3 expression, the extent of these up-regulations was less than that by phenylephrine. Moreover, ionomycin increased the number of caveolae and up-regulated caveolin-3 as much as phenylephrine. Phenylephrine-induced up-regulations of caveolae and caveolin-3 expression were inhibited by BAPTA, suggesting that the intracellular Ca2+ is involved in those regulations. Inhibitors of calcineurin and Ca2+calmodulin-dependent kinase II attenuated the phenylephrine-induced up-regulation of caveolin-3. In pressure-overloaded rat hearts, caveolin-3 protein levels were increased compared with sham-operated rats. In conclusion, the number of caveolae and the expression of caveolin-3 were up-regulated in rat hypertrophied cardiomyocytes, possibly via the alterations of intracellular Ca2+ and protein kinase C.

Total anomalous pulmonary venous connection with dysmorphic pulmonary vein: a risk for postoperative pulmonary venous obstruction.

Pulmonary venous obstruction after repair of total anomalous pulmonary venous connection remains potential and understanding of its mechanisms is warranted. Morphology of the pulmonary vein was qualitatively analyzed in 48 consecutive patients undergoing repair of non-isomeric total anomalous pulmonary venous connection. Pulmonary venous drainage was supracardiac in 26, cardiac in 7, infracardiac in 13, and mixed in 2. Nine had dysmorphic pulmonary venous confluence or tributary veins (Group A). Four had excessive (>or=5) tributary veins with a hypoplastic confluence (Type 1 abnormality). In the other four cases, the vertical vein was atretic (Type 2 abnormality). In a case with cardiac type, pulmonary veins had stenosis at orifices (Type 3 abnormality). The rest (n=39; Group B) had normal pulmonary vein. Eight patients (7 in Group A and 1 in Group B) developed postoperative pulmonary venous obstruction. Overall actuarial survival was 90.0% after 2.3 months up to 10 years. Actuarial freedom from pulmonary venous obstruction was 79.5% after 5.0 months up to 10 years. It was 22.2% at 1 year among Group A compared with 96.7% at 10 years among Group B (P<0.001). Morphological analysis of the pulmonary vein best predicted the incidence of postoperative pulmonary venous obstruction.

Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy.

Caveolae are omega-shaped organelles of the cell surface. The protein caveolin-3, a structural component of cardiac caveolae, is associated with cellular signaling. To investigate the effect of adenovirus-mediated overexpression of caveolin-3 on hypertrophic responses in cardiomyocytes, we constructed an adenovirus that encoded human wild-type caveolin-3 (Ad.Cav-3), mutant caveolin-3 (Ad.Cav-3Delta), or bacterial beta-galactosidase (Ad.LacZ). This mutant has been reported to cause human limb-girdle muscular dystrophy. It lacks 9 nucleotides in the caveolin scaffolding domain and behaves in a dominant-negative fashion. Rat neonatal cardiomyocytes were infected with the virus and then harvested 36 hours after infection. In noninfected cells, phenylephrine (PE) and endothelin-1 (ET) increased cell size and [3H]leucine incorporation, along with the induction of sarcomeric reorganization and the reexpression of beta-myosin heavy chain, indicating myocyte hypertrophy. Infection with Ad.LacZ had no effect on those parameters. Ad.Cav-3 prevented the PE- and ET-induced increases in cell size, leucine incorporation, sarcomeric reorganization, and reexpression of beta-myosin heavy chain. Ad.Cav-3 also blocked the PE- and ET-induced phosphorylations of extracellular signal-regulated kinases (ERKs) but did not affect c-Jun amino-terminal kinase and p38 mitogen-activated protein kinase activities. In contrast, Ad.Cav-3Delta significantly augmented hypertrophic responses to ET, which were associated with increased ET-induced phosphorylation of ERK1/2. These results suggest that caveolin-3 behaves as a negative regulator of hypertrophic responses, probably through suppression of ERK1/2 activity.