A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

ITPKC and CASP3 polymorphisms and risks for IVIG unresponsiveness and coronary artery lesion formation in Kawasaki disease.

Functional single-nucleotide polymorphisms (SNPs) in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) (rs28493229) and caspase-3 (CASP3) (rs113420705; formerly rs72689236) are associated with susceptibility to Kawasaki's disease (KD). To evaluate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG) unresponsiveness, we investigated 204 Japanese KD patients who received a single IVIG dose of 2 g kg(-1) (n=70) or 1 g kg(-1) daily for 2 days (n=134). The susceptibility allele of both SNPs showed a trend of overrepresentation in IVIG non-responders and, in combined analysis of these SNPs, patients with at least 1 susceptible allele at both loci had a higher risk for IVIG unresponsiveness (P=0.0014). In 335 prospectively collected KD patients who were treated with IVIG (2 g kg(-1)), this 2-locus model showed a more significant association with resistance to initial and additional IVIG (P=0.011) compared with individual SNPs. We observed a significant association when all KD patients with coronary artery lesions were analyzed with the 2-locus model (P=0.0031). Our findings strongly suggest the existence of genetic factors affecting patients' responses to treatment and the risk for cardiac complications, and provide clues toward understanding the pathophysiology of KD inflammation.

Modified Bielschowsky and immunocytochemical studies on cerebellar plaques in Alzheimer's disease.

Senile plaques (SP) in the cerebellum of 23 cases of Alzheimer's disease (AD), three with widespread amyloid angiopathy, were studied with a modified Bielschowsky stain and immunocytochemical methods using antibodies to a beta-amyloid synthetic peptide (beta ASP), phosphorylated neurofilament proteins, ubiquitin, tau protein, and glial fibrillary acidic protein (GFAP). The four subtypes of SP (diffuse plaques, compact plaques, perivascular plaques, and subpial fibrillar deposits) that were observed with the modified Bielschowsky stain were also stained with antibodies to beta ASP. Many cerebellar SP contained ubiquitin-positive granular elements resembling dystrophic neurites. In contrast to neuritic elements in cerebral SP in AD, ubiquitin-positive elements in cerebellar SP were not labeled with antibodies to phosphorylated neurofilament or tau proteins. Various degrees of glial reaction were observed in all subtypes of SP except diffuse plaques. The absence of phosphorylated neurofilament and tau epitopes in neuritic elements in cerebellar SP is not surprising since paired helical filaments have not been seen in the cerebellum. Nevertheless, our results suggest that cerebellar SP are frequently associated with dystrophic neurites.

Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissues.

The distribution of nitric oxide synthase was investigated in human cerebral blood vessels and brain tissues. NADPH-diaphorase histochemistry, which is a marker for nitric oxide synthase in neurons and endothelial cells, revealed periadventitial nerve fibers in the arteries of the circle of Willis and their cortical branches, as well as the common carotid and subclavian arteries. The fibers were mostly nonvaricose in the periadventitial nerve trunk and were varicose within the adventitia. Patchy reaction products were distributed in the perinuclear region of each endothelial cell. Smooth muscle cells in the tunica media were weakly stained. Staining was particularly intense in regions with atherosclerotic changes, which consist of macrophage infiltration and proliferation of fibroblasts. In the neural parenchyma, two types of NADPH-diaphorase reactive neurons were differentiated. Type I neurons were intensely stained, medium-sized, and bipolar or multipolar. They were distributed in the cerebral cortex and white matter, mostly in the subcortical white matter. Type II neurons were lightly stained, small oval neurons with fine processes and were distributed in the cerebral cortex. Endothelial cells were intensely reactive for NADPH-diaphorase in the arteries, arterioles, and capillaries but weakly in veins. Immunohistochemistry for neural nitric oxide synthase labeled perivascular nerves in the larger arteries and those in the neural parenchyma. Both type I and type II neurons were labeled. Nitric oxide synthase in endothelial cells and the nerve encircling blood vessels further suggests a dual control of cerebral circulation by nitric oxide in human brain.

Large neurons in the tuberomammillary nucleus in patients with Parkinson's disease and multiple system atrophy.

To investigate whether the histaminergic neurons degenerate in Parkinson's disease (PD) and multiple system atrophy (MSA), we studied the number of large-sized neurons in the tuberomammillary nucleus in patients with PD, patients with MSA, and age-matched controls. The number of large-sized neurons in the tuberomammillary nucleus in PD patients was not altered compared with controls, and Lewy bodies were rarely present in the tuberomammillary nucleus. In contrast, the number of large-sized neurons in the tuberomammillary nucleus in MSA patients was significantly decreased compared with controls. Thus, the central histaminergic neurons are affected in MSA and preserved in PD.

Reduction in levels of amphiphysin 1 mRNA in the hippocampus of aged rats subjected to repeated variable stress.

Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.

Aberrant phosphoinositide metabolism in Alzheimer's disease.

Since phosphoinositide-specific phospholipase C (PLC) is one of the key molecules in signal transduction, its involvement was assessed in Alzheimer's disease (AD). The phosphatidyl-inositol (PI)-specific PLC activity in the Alzheimer cytosolic and particulate fractions was not significantly different from that in the control fractions. The PI-specific PLC activity as a function of the free Ca2+ concentration was also similar between control and Alzheimer brains. These results suggest that the PI-specific PLC activity is not altered in AD. Immunostaining of a specific antibody against the PLC isozyme, PLC-delta, demonstrated that this enzyme was abnormally accumulated in neurofibrillary tangles (NFT), the neurites surrounding senile plaque (SP) cores, and neuropil threads in AD brains. Western blot analysis confirmed that PLC-delta was concentrated in the paired helical filament (PHF)-rich fraction of AD brains. PLC-delta marked the same neurons containing tau immunoreactivity and yet tau and PLC-delta often marked different structures within the same neuron, with tau more clearly on NFT and PLC-delta covering it superficially. The double stain with PLC-delta and basic fibroblast growth factor (bFGF) binding suggest that PLC-delta is an intracellular marker, showing little overlap with bFGF binding, an extracellular marker. All of this was consistent with the electron microscopy, with PLC-delta being NFT associated. Antibodies to other PLC isozymes did not produce positive immunostaining of these pathologic structures. Moreover, diffuse and amorphous deposits of PLC-delta were found to precede the accumulation of fibrillary deposits. These results suggest that PLC-delta accumulation plays a possible role in the formation of intraneuronal inclusions in AD.

Presence of calpain II immunoreactivity in senile plaques in Alzheimer's disease.

Calpains are calcium-dependent neutral cysteine proteinases. We utilized a specific anti-calpain II antibody to examine immunohistochemically whether calpain II is associated with pathological changes in Alzheimer's disease (AD). Calpain II was mainly expressed in the neurons in control human brains. In AD brains, intense immunoreactivity was present in the dystrophic neurites of senile plaques. These results suggest that calpain II is involved in the pathogenesis of AD.

Synaptophysin and chromogranin A immunoreactivities of Lewy bodies in Parkinson's disease brains.

Lewy bodies commonly observed in brains with Parkinson's disease (PD) histochemically contain both protein and lipid as chemical components. Ultrastructurally, they are composed of filamentous, vesicular and granular structures. We investigated PD brains with light and electron microscopic immunohistochemistry using antibodies against two marker proteins for neuronal secretory vesicles, synaptophysin and chromogranin A. Both antibodies immunolabeled the peripheral zones and occasionally central cores of Lewy bodies of the classical and intraneuritic types. In addition, the diffuse immunolabeling was observed in Lewy bodies of the cortical type. Furthermore, the ultrastructural immuno-decoration was found mainly in the vesicular structures, and also in the filamentous and granular structures of Lewy bodies. Immuno-blot analysis of each antibody showed no difference between PD and normal control brains. The present observations suggest that vesicular profiles of Lewy bodies represent presynaptic and dense core secretory vesicles, and therefore that the lipid elements of Lewy bodies are derived from membrane lipids of these vesicles.

Bifurcation of P9 far-field potentials induced by changes in the shoulder position.

Somatosensory evoked potentials to stimulation of the left median nerve were recorded from normal adults with reference to the right knee in the usual shoulder position and in an elevated shoulder position. A single peak of the P9 potentials in the former position bifurcated into two peaks in the latter position without changing the onset latency. This waveform change can be accounted for by changes in the resistance of the volume conductor around the nerve trunk.

Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer's disease.

We studied the number of large-sized neurons and neurofibrillary tangles (NFT) in the tuberomammillary nucleus (TM) of the hypothalamus from cases with Alzheimer's disease (AD) and age-matched controls. Numerous NFT were found in TM of AD. However, NFT was never observed in this nucleus of age-matched controls. The number of large-sized neurons was significantly reduced in AD compared with that in controls. Since the majority of large neurons in TM appear to correspond to histamine neurons, the loss of large neurons observed in TM may, at least partly, cause the histaminergic dysfunction in AD brain.

Abnormal accumulation of phospholipase C-delta in filamentous inclusions of human neurodegenerative diseases.

We have previously demonstrated that an antibody to phosphoinositide-specific phospholipase C (PLC) isozyme, PLC-delta, intensely stained neurofibrillary tangles (NFT) in the brain tissue of Alzheimer's disease (AD). This study was performed to determine if abnormal PLC-delta accumulation might be present in the filamentous inclusions of other neurodegenerative diseases. We found that the anti-PLC-delta antibody stained neuronal inclusions of Pick's disease, progressive supranuclear palsy and diffuse Lewy body disease while the inclusions of idiopathic Parkinson's disease lacked PLC-delta accumulation. These results suggest a possible role for PLC-delta interaction in the formation of intraneuronal filamentous inclusions in human neurodegenerative diseases.

Transient myoclonic state with asterixis in elderly patients: a new syndrome?

We report 7 patients who developed acute co-occurrences of fragmentary generalized myoclonus and asterixis. All patients were elderly and had other chronic diseases. This condition appeared acutely, progressed over several hours and then disappeared in 2-3 days with diazepam administration. No sequelae were noted, although most cases developed recurrences. The myoclonus occurred spontaneously and was slightly enhanced by action. The myoclonus was widely distributed but predominated in the neck, shoulder girdle, and upper extremities. Opsoclonus was not noted. Clinically apparent myoclonus was not evoked by sensory stimuli. Asterixis was observed in the upper extremities in all cases. Asterixis-like movements of the protruded tongue were also observed. Neurological findings other than the myoclonus and asterixis were unremarkable. Neither metabolic nor organic abnormalities clearly responsible for this condition were identified. Cerebral potentials preceding the myoclonic jerks recorded in one case suggested that the myoclonus may have been a spontaneous cortical myoclonus. We named this condition a transient myoclonic state with asterixis (TMA). Awareness of this syndrome is clinically important because of its benign nature, although it can recur.

Experimental Sendai virus-induced labyrinthitis in guinea pigs. An ultrastructural study of cochlear lesions.

Guinea pigs were inoculated with a Sendai virus into the scala tympani and subsequent pathological changes of the cochleas were investigated by electron microscopy. Replication of the virus was indicated by buddings at the endolymphatic surface and by the intracytoplasmic occurrence of filamentous substances, ie, nucleocapsids. Budding viruses or free virus particles observed in a series of our experiments were identified as Sendai viruses by means of the immunological labeling with ferritin. Viral lesions, which were defined as the pathological changes of the cells associated with virus multiplication, were found in eight cochleas out of 20. This study revealed that the early lesions of the cochleas infected by Sendai viruses were primarily confined to Reissner's membrane and the stria vascularis, but the sensory cells were not affected.

Clinical and biological features of t1 ductal adenocarcinoma of the pancreas.

BACKGROUND/AIMS: The impact of tumor size on tumor development and long-term prognosis is still controversial for patients with ductal adenocarcinoma of the pancreas. We investigated the clinicopathological and biological features of ductal adenocarcinoma limited to the pancreas without direct histological extrapancreatic invasion (t1 tumor). METHODOLOGY: The clinical records of 86 patients who underwent surgery for ductal adenocarcinoma of the pancreas were reviewed to determine clinical features, histopathological findings, operative management and outcomes. Immunohistochemical staining of the p53 tumor suppressor gene (p53) was performed for the resected specimens. RESULTS: Only 10 (12%) of the 86 resected ductal adenocarcinomas of the pancreas were t1 tumors. Six of the 10 patients with t1 tumors survived for more than 5 years. The rates of nodal metastasis (10%) and neural plexus invasion (0%) in t1 tumors were significantly lower than those in non-t1 tumors, although the rates of blood-borne metastasis (30%) and p53 expression (50%) in t1 tumors were the same as those in non-t1 tumors. CONCLUSIONS: Curative resection contributes to a satisfactory long-term prognosis of patients with t1 tumor of the pancreas as a result of the low rates of both nodal metastasis and neural plexus invasion associated with this procedure. In patients with t1 tumor of the pancreas, a satisfactory long-term prognosis can be assured as a result of the low rates of both nodal metastasis and neural plexus invasion associated with curative resection.

Eosinophilic granuloma of the stomach mimicking gastric cancer, report of a case.

We report a rare case of eosinophilic granuloma of the stomach mimicking gastric cancer. A 49-year-old man was admitted to our hospital to undergo surgery for gastric tumor. Radiologic and endoscopic examination showed a protruding tumor with a deep ulcer at the anterior wall of the pylorus. Although malignant cells were not histologically confirmed in the biopsy specimens, subtotal gastrectomy with lymphadenectomy was performed because gastric cancer was strongly suspected. The gross appearance of the tumor seemed to be that of a gastric cancer, but the histological diagnosis was eosinophilic granuloma. If submucosal tumor of the stomach is suspected, eosinophilic granuloma should be considered as one of the differential diagnoses. Endoscopic removal of the tumor may be useful to make a precise diagnosis before surgery.

Electron microscopic study on the esophageal mucosa in human fetuses.

Morphogenetic studies of the esophageal mucosa in human fetuses have been few and there is only one report at the ultrastructural level. We thus studied the esophageal mucosa in human fetuses (at the gestational ages from the 7th to 21st week) by scanning (SEM) as well as transmission electron microscopy (TEM). Our results and the review of the literature lead to the following conclusions: 1) Primary cilia were seen in the 7th and 8th week of gestation. 2) Ciliated cells appeared around the 8th week of gestation. They increased in number according to the fetal ages, but gradually decreased after the 14th week of gestation. Their degenerative process at the ultrastructural level was similar to that reported previously. 3) The stratified squamous epithelia appeared at the 14th week of gestation, but the squamous cells remained immature even at the 21st week. 4) Glycogen granules in non-ciliated cells decreased as the differentiation of the cells proceeded, suggesting that they provide an energy source necessary for the cell differentiation.

Benign schwannoma of the pterygopalatine fossa with intracranial extension: a case report.

The authors present a rare case of benign schwannoma arising in the pterygopalatine fossa. The patient, an 18-year-old female, initially noticed blurring of her left eye but later, sudden loss of her left vision occurred. Radiological and computed tomographic studies outlined a mass occupying the left pterygopalatine fossa, which extended into the middle cranial fossa, the maxillary, ethmoid and sphenoid sinuses and the orbit. The histology of a transantral biopsy was reported as a benign schwannoma. The tumor was successfully removed by a transmaxillary approach. The eye symptoms disappeared four weeks following surgery. The nerve of origin of the tumor was not identified. The authors posturate that erosion of the skull base with mild to moderate extension into the middle cranial fossa, does not appear to be a contraindication for excising a schwannoma by the transmaxillary approach in this area.

Electron microscopic study on the epiglottic mucosa in human fetuses.

The differentiation of the epiglottic mucosa in human fetuses has so far been studied only by light microscopy. So, we studied the epiglottic mucosa in human fetuses (at gestational ages from the 7th to 21st week) by scanning (SEM) and transmission electron microscopies (TEM), and could disclose more detailed features of cellular differentiation of this mucosa. These results and the review of the literatures lead to the following conclusions: 1. Primary cilia appeared in the epiglottic mucosa around the 7th week of gestation. 2. Ciliated cells and the stratified squamous epithelium of the lingual surface appeared at the similar period as reported by others, but our study revealed that the squamous cells are immature even at the 21st week. 3. Glycogen granules in non-ciliated cells decreased paralleling the differentiation of the cells, suggesting that they provide a source of energy necessary for the cell differentiation.

[A patient with myopathy due to preclinical Cushing syndrome].

A 57 year-old man with a history of diabetes mellitus was admitted to our hospital for the complaint of slowly progressive muscle weakness involving proximal limbs and head dropping. His serum CK level was within normal range, and muscle biopsy showed no inflammatory changes. To rule out myasthenia gravis, computerized tomography was done for the detection of thymoma, and detected an adrenal tumor in stead. He was not over-weighted, and his morning plasma levels of ACTH and cortisol were within normal ranges. Additional hormonal examinations revealed daily autonomous hypersecretion of cortisol. He received diagnosis of preclinical Cushing syndrome. After resection of the tumor, muscle weakness improved and his diabetes mellitus was controlled better. The muscle symptoms seem to be related with steroid myopathy. Preclinical Cushing syndrome should be included as a differential diagnosis for myopathy of unknown etiology.