Tumor local chemohyperthermia using docetaxel-embedded magnetoliposomes: Interaction of chemotherapy and hyperthermia.

BACKGROUND AND AIM: We have studied and reported the usefulness of tumor local chemohyperthermia at a low-grade temperature below 43°C with docetaxel-embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor. METHODS: Human MKN45 gastric cancer cells were implanted in the hind limbs of Balb-c/nu/nu mice. DML, magnetite-loaded liposome, and docetaxel were injected into the tumors with or without being exposed to an alternating current magnetic field. Docetaxel and tumor necrosis factor-α concentrations, the cell cycle, and cell death rates in the tumor were examined. RESULTS: Docetaxel concentrations were significantly higher in the DML-injected group than in the docetaxel-injected group 3 days after injection. A G2/M peak was observed 1 day after treatment in the DML-injected and exposed group and the docetaxel-injected group, while it was observed 3 days after treatment in the DML-injected without heating group and the magnetite-loaded liposome group. The tumor cell death rate gradually increased in the DML-injected group, with or without being exposed, while it gradually decreased after its peak in other groups. The tumor necrosis factor-α concentration in the tumor treated with DML with heating remained at a high level on the 7th day after treatment, while it decreased after its peak in other groups. CONCLUSION: The antitumor effect of this treatment derives from a combination of hyperthermia and chemotherapy locally in the tumor.

Paraovarian Cyst Torsion in a Patient with Rubinstein-Taybi Syndrome: A Case Report.

Rubinstein-Taybi syndrome is an extremely rare autosomal dominant genetic disorder that occurs in 1/125,000 and is characterized by distinctive facial appearance, short stature, mild to severe mental retardation, and higher risk for cancer. In addition, variable organ anomalies had been reported. Paraovarian cyst causing torsion of the ipsilateral fallopian tube is less common, with an estimated incidence of 1/1,500,000, but it can adversely affect tubal function. It occurs mainly in women in the reproductive age and is very rare in prepubescent girls. Here, we described the successful treatment of an extremely rare case of paraovarian cyst causing torsion of the ipsilateral fallopian tube in a patient with Rubinstein-Taybi syndrome. A 14-year-old girl with Rubinstein-Taybi syndrome was referred to our hospital for abdominal pain. Her medical history was unremarkable, except for moderate hirsutism and keloid scar. Physical examination revealed tenderness in the lower abdominal midline. The preoperative diagnosis was torsion of a left ovarian cyst. An exploratory laparoscopy was performed because of acute abdominal pain and revealed a left fallopian tube that was twisted twice due to an ipsilateral paraovarian cyst. The huge paraovarian cyst required laparotomy cystectomy, and the left ovary was preserved. Her postoperative course was uncomplicated. Preoperative diagnosis of paraovarian cysts can be difficult. The moderate hirsutism seen in our patient suggested the presence of a large paraovarian cyst due to androgen receptor-mediated effects. Therefore, Rubinstein-Taybi syndrome patients with hirsutism should be screened and assessed by pediatric surgeons for the presence of paraovarian cysts.

Hypertensive Cardiomyopathy with Congestive Heart Failure in an Infant with Unilateral Wilms Tumor: A Case Report.

Wilms tumor (WT) is the most common malignant kidney tumor in children. High blood pressure is seen in up to 55% of children with WT. However, hypertensive cardiomyopathy with congestive heart failure due to WT is remarkably rare, with only several cases reported worldwide. In this report, a pediatric case of WT with hypertension causing hypertensive cardiomyopathy and congestive heart failure is presented. An 8-month-old male child with abdominal distension was seen by his primary physician. He was referred to our hospital for further examination and treatment. Abdominal contrast-enhanced computed tomography demonstrated a weakly enhancing, large abdominal mass, which was larger than 12 cm. Two-dimensional transthoracic echocardiography showed a diffuse hypokinetic left ventricle. The patient was diagnosed with cardiomyopathy caused by hypertension. Open surgical resection of the mass was successfully performed. His postoperative course was uncomplicated, and the patient was successfully discharged. The plasma renin activity was maintained at a high level even after left nephrectomy, suggesting that the right kidney was likely the source of renin secretion. Mechanical compression of the right renal blood vessels by a greatly enlarged left kidney can cause right renal ischemia, which activates renin excretion. Nephrectomy can be an effective treatment for a WT patient with hypertension causing hypertensive cardiomyopathy, and then cardiac function will be improved within several weeks. We recommend routine echocardiography surveillance in patients with WT. This report can help pediatric surgeons become more familiar with cardiomyopathy caused by WT.

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer.

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Usefulness of the HyperEye Medical System in Obstructive Colitis Proximal to Colon Carcinoma.

Obstructive colitis (OC) is a nonspecific inflammatory condition that occurs at the proximal side of a completely or partially stenotic lesion typically caused by colorectal cancer. Impaired blood flow caused by these stenotic changes in the colon or rectum results in this condition. During surgery for sigmoid colon carcinoma with OC, complete surgical removal of the OC lesions is required. However, it is difficult to anticipate the range of OC before surgery. Diagnosing the potential ischemia during surgery would decrease the need for re-operation. This is the first report of HyperEye Medical System (HEMS) angiography for surgery of colon cancer with OC. We report a case of sigmoid colon carcinoma in which HEMS angiography was used and found to be useful for real-time detection of the OC lesion.

Efficacy of continuous versus intermittent subglottic secretion drainage in preventing ventilator-associated pneumonia in patients requiring mechanical ventilation: A single-center randomized controlled trial.

OBJECTIVE: Aspiration of subglottic secretion is a widely used intervention to prevent ventilator-associated pneumonia (VAP). This study aimed to compare the efficacy of continuous and intermittent subglottic secretion drainage (SSD) in preventing VAP. METHODS: A single-center randomized controlled trial was conducted on adult postoperative patients who were expected to undergo mechanical ventilation for more than 48 hours. Primary outcome measure was incidence of VAP and secondary outcome measures were length of mechanical ventilation and intensive-care unit (ICU) stay. RESULTS: Fifty-nine patients received continuous SSD, while 60 patients received intermittent SSD. Of these 119 patients, 88 (74%) were excluded and 15 and 16 patients were allocated to receive continuous and intermittent SSD, respectively. VAP was detected in 4 (26.7%) and 7 (43.8%) patients in the continuous and intermittent groups, respectively, (p=0.320). The length of mechanical ventilation was significantly shorter (p=0.034) in the continuous group (99.5±47.1 h) than in the intermittent group (159.9±94.5 h). The length of ICU stay was also shorter (p=0.0097) in the continuous group (6.3±2.1 days) than the intermittent group (9.8±4.8 days). CONCLUSIONS: Although continuous SSD did not reduce the incidence of VAP, it reduced the length of mechanical ventilation and ICU stay when compared to intermittent SSD.

Identification of paralogous genes of firefly luciferase in the Japanese firefly, Luciola cruciata.

Two homologous genes of firefly luciferase, LcLL1 and LcLL2, were cloned from the Japanese firefly Luciola cruciata, and were expressed and characterized. The gene product of LcLL1 had long-chain fatty acyl-CoA synthetic activity, but not luciferase activity. The other gene product of LcLL2 did not show enzymatic activities of acyl-CoA synthetase and luciferase. RT-PCR analysis showed that the transcript of LcLL1 was abundant in larva but very low in adult, while LcLL2 was expressed in both larva and adult. Phylogenetic analysis indicated that LcLL1 and LcLL2 are paralogous genes of firefly luciferase. Recently, we found that CG6178 in Drosophila melanogaster is an orthologue of firefly luciferase and shows fatty acyl-CoA synthetic activity, but not luciferase activity. These results suggest that firefly luciferase might be evolved from a fatty acyl-CoA synthetase by gene duplication in insects.

Feasibility of tailored, selective and effective anticancer chemotherapy by direct injection of docetaxel-loaded immunoliposomes into Her2/neu positive gastric tumor xenografts.

We assessed the effects of direct injection of docetaxel-loaded immuno-(trastuzumab)-liposomes (IDL) on a xenograft mouse tumor model to determine potential clinical applications of intratumoral tailored chemotherapy against Her2/neu-overexpressing gastric cancer. The NCI-N87 Her2/neu overexpressing gastric cancer cell line xenograft mouse model was treated with IDL or docetaxel-loaded liposomes (DL). The ratio of the tumor volume of the treatment:control was determined. In addition, docetaxel pharmacokinetics in tumors were measured using high-performance liquid chromatography, and the cell viability and cell cycle distribution of Her2/neu positive cells were determined by flow cytometric analysis. The IDL group showed a significantly higher distribution of docetaxel in the N87 xenograft tumor tissues and superior antitumor efficacy compared to crude administration of docetaxel and/or trastuzumab and DL. The number of viable Her2/neu positive cells decreased following treatment with either free trastuzumab or IDL. On day 7 after treatment, a decrease in the G0/G1 phase of the cell cycle was observed in the DL and IDL groups compared to the control group. No local adverse effects were observed. These results suggest that intratumoral administration of IDL maintains a high concentration of docetaxel within the tumor leading to a safe and effective regional cancer therapeutic strategy. In addition to the inherent cytotoxic effect of trastuzumab, conjugation of trastuzumab to a liposome further enhanced the retention of docetaxel within the tumors. These data suggest that immuno-liposome mediated delivery of drugs is a promising new therapeutic option for patients with advanced gastric cancer that overexpress Her2/neu.

Enzymatic and genetic characterization of firefly luciferase and Drosophila CG6178 as a fatty acyl-CoA synthetase.

Recently we found that firefly luciferase is a bifunctional enzyme, catalyzing not only the luminescence reaction but also long-chain fatty acyl-CoA synthesis. Further, the gene product of CG6178 (CG6178), an ortholog of firefly luciferase in Drosophila melanogaster, was found to be a long-chain fatty acyl-CoA synthetase and dose not function as a luciferase. We investigated the substrate specificities of firefly luciferase and CG6178 as an acyl-CoA synthetase utilizing a series of carboxylic acids. The results indicate that these enzymes synthesize acyl-CoA efficiently from various saturated medium-chain fatty acids. Lauric acid is the most suitable substrate for these enzymes, and the product of lauroyl CoA was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Phylogenetic analysis indicated that firefly luciferase and CG6178 genes belong to the group of plant 4-coumarate:CoA ligases, and not to the group of medium- and long-chain fatty acyl-CoA synthetases in mammals. These results suggest that insects have a novel type of fatty acyl-CoA synthetase.