Kouzou Fukuyama

Detection of human papillomavirus genome and analysis of expression of c-myc and Ha-ras oncogenes in invasive cervical carcinomas

Invasive carcinomas of the uterine cervix of 38 patients were examined for the presence of human papillomavirus (HPV) genomes and for the state of the c-myc and Ha-ras oncogenes. A combination of Southern blot hybridization and polymerase chain reaction revealed the presence of the genome of HPV type 16 in 17 tumors (45%), that of HPV type 18 in 3 tumors (8%), and that of unknown types in 16 others (42%), while no viral DNA sequences were detected in 2 tumors. Of the 38 tumors, c-myc amplification was found in only 1 tumor, while there was no Ha-ras amplification. Overexpression of the c-myc gene was observed in 15 (44%) of the 34 tumors analyzed, while there was no overexpression of Ha-ras. Of the 23 squamous cell carcinomas analyzed, relapse-free rates at 24 months were 55% in tumors with c-myc overexpression and 100% in case of tumors with no c-myc overexpression, respectively. The results suggest the possibility that activation of the c-myc oncogene is involved in tumor progression.

Combination of Flow Reversal and Distal Filter for Cerebral Protection during Carotid Artery Stenting

BACKGROUND Carotid artery stenting (CAS) with distal filter protection allows continuous cerebral perfusion, although it is associated with a greater risk of cerebral ischemic complications than other protection systems. To reduce cerebral ischemic complications, CAS was performed under combined cerebral protection using both flow reversal (FR) and a distal filter. METHODS Fifty-six stenoses of 52 patients were treated with CAS using the combined protection of FR and a distal filter, with intermittent occlusion of both the common carotid artery (CCA) and the external carotid artery. The blood flow was reversed into the guiding catheter to the central venous system via an external filter, which collected the debris. Clinical outcomes, the rates of capturing visible debris, and new ischemic signals on diffusion-weighted magnetic resonance imaging (DWI-MRI) were evaluated. RESULTS The overall technical success rate was 92.9% (52/56). Successful stent deployment was achieved in 100% (56/56) of the cases. No procedural-related emboli causing a neurologic deficit were observed. In 38.5% (20/52) of the cases, visible debris were captured by only the external filter, and in 17.3% (9/52), visible debris were captured by both external and distal filters. In no case was visible debris noted in only the distal filter. New ischemic signals on DWI-MRI were detected in 9.6% (5/52). The 30-day myocardial infarction, stroke, and death rates were 0%. CONCLUSIONS The additional use of a distal filter captures emboli in 17.3% of cases, and because the occlusion is only intermittent, the procedure is potentially applicable even in those who cannot tolerate prolonged balloon occlusion of the CCA.

Ret expression in the central nervous system

The ret proto‐oncogene product (Ret) has been shown to be one of the glial cell line‐derived neurotrophic factor (GDNF) receptors in dopaminergic, norepinephric and motor neurons. We immunohistochemically examined the expression of Ret in the human central nervous system (CNS). The distribution of Ret was generally identical to that of myclin as stained using the Klüver‐Barrera method. We further investigated the expression of Ret in human fetal brains (19, 29 and 39 weeks gestation) and various brain tumors. The Ret positivity was observed to be associated with the myelin sheath of the cerebral white matter in 29‐and 39‐week‐old fetal brains. Ret is known to be expressed in neural crest‐derived cells. We could immunohistochemically confirm the Ret expression in the pheochromocytomas and neuroblastomas of retroperitoneal space. As for the brain tumors, no Ret expression was observed in glioblastomas, oligodendrogliomas, and schwannomas examined, although the glial cells surrounding the tumor and the pre‐existing myelin sheath revealed positivity for Ret. In the CNS, Ret expression appears to be closely associated with the myelin sheath; therefore, Ret immunostaining may be useful in ascertaining the demyelinating lesions in the CNS.

Near-infrared spectroscopy cerebral oximetry as a predictor of neurological intolerance during carotid artery stenting with proximal protection

Carotid artery stenting (CAS) with proximal protection can expose occlusion intolerance (OI) due to ipsilateral cerebral hemisphere hypoperfusion. Near-infrared spectroscopy (NIRS) cerebral oximetry can monitor regional cerebral oxygenation (rSO2) in the frontal lobes, and is used during CAS to predict cerebral blood flow insufficiency. The aim of this study was to evaluate rSO2 as a predictor of OI during CAS. We retrospectively examined 146 patients who underwent CAS with proximal protection. An INVOS® NIRS oximeter was used for rSO2 measurement, which was compared with stump pressure (SP) measured by a guiding catheter during occlusion of the common carotid artery (CCA) and external carotid artery. For the lesion with OI, distal filter protection was combined with proximal protection if possible, and CCA was intermittently occluded during the procedure. Twenty-seven patients (18%) developed OI. The relative decrease in NIRS oximeter saturation (ΔrSO2) on the ipsilateral side was significantly lower in the OI group than in the tolerance group (14 ± 5.1% vs. 3.4 ± 3.5, p < 0.001). Using ΔrSO2 of 8% as the cutoff value for predicting OI, sensitivity was 92% and specificity was 89%. SP was significantly lower in the OI group than in the tolerance group (22 ± 13 mmHg vs. 40 ± 22 mmHg, p < 0.001). Using SP ≤25 mmHg as the cutoff value for predicting OI, sensitivity was 78% and specificity was 77%. ΔrSO2 was more reliable than SP for predicting OI. Distal filter protection should be combined with proximal protection to prevent prolonged neurological symptoms due to OI.

An Analysis of Genetic Alterations of the p53 Gene in Human Glioma

Restriction fragment length polymorphisms (RFLPs) analysis of human glioma tissue has revealed frequent loss of heterozygosity on the long arm of the chromosome 10 [1] as well as the short arm of the chromosome 17 [2,3]. It has recently been thought that certain tumor suppressor genes are located on chromosomes 10 and 17. The p53 gene is located on 17pl3.1, which is often deleted in various human tumors such as those of colorectal cancer, breast cancer, lung cancer, and osteosarcoma [4]. Detailed study of the p53 gene revealed that the remaining allele contained mutations particularly in the region conserved throughout the species [4]. It is reported that the product of a mutant-type p53 gene has a prolonged half-life and contains a cellular transforming activity. The p53 gene product acts in a dimer and the mutant-type p53 gene product inactivates the wild-type p53 gene product by binding to it [5]. While the mutant-type p53 gene causes cell immortalization in combination with the activated ras gene, the wild-type p53 gene product supresses normal somatic cell transformation. Thus, the genetic alterations of the p53 gene are thought to contribute to the tumorigenetic process in various type of cells, with the p53 gene being a putative tumor suppressor gene. Recent studies revealed that the p53 gene product may be acting as a transcriptional activator for some other genes [6,7]. This fact may well explain the diversity of tumor types which result from mutations in the p53 gene.

The Expression and Structure of p53 Gene Products in Cultured Glioma Cells

Previous studies have demonstrated that the allelic deletions of the short arm of chromosome 17 (17p) and the long arm of 10 (10q) are closely associated with tumorigenesis of human malignant gliomas [1,2]. While the allelic deletion in chromosome 10q appears to occur in a relatively late phase associated with the transition from a less malignant to a more malignant state [3], the deletion in chromosome 17p seems to be an early event associated with the occurrence of neoplastic glial cells, suggesting that anti-oncogenes or tumor suppressor genes are important in the development of human gliomas. However, the role of anti-oncogenes in human gliomas has not been studied in detail. Recent studies have demonstrated that the cellular protein p53, which is encoded on chromosome 17p13.1, may function as a suppressor of neoplastic growth and may play an important role in the pathogenesis of human malignant tumors. The p53 protein was first identified through its interaction with the large T antigen of simian virus 40 (SV 40) [4], and had been thought to be a dominant oncogene enabling full transformation of vertebrate somatic cells in combination with an activated ras gene [5]. However, it has recently been shown that the p53 protein observed in the neoplastic cells is entirely mutant and that the wild type p53 suppresses normal cells from transforming [6], which means that the p53 protein may act as a tumor suppressor, like the product of the retinoblastoma susceptibility gene.