Full-layer mucosal histology in achalasia: Histological epithelial wave is characteristic in "pinstripe pattern"-positive achalasia.

BACKGROUND: Previously, the mucosal histology in achalasia has only been investigated using superficial biopsy or surgically resected esophageal specimens in end-stage cases. We investigated the histology of the full-layer mucosa in early and advanced achalasia. METHODS: Endoscopy was performed for the pinstripe pattern (PSP) (an early achalasia indicator) and dilation and thickening of the mucosa (advanced achalasia indicators). A mucosal entry site for peroral endoscopic myotomy was created using cap-fitted endoscopic mucosal resection to access the full-layer mucosa and the submucosa. KEY RESULTS: Mucosal histology was compared between 32 patients with achalasia and 15 controls. Histological esophagitis with findings of inflammatory cell infiltration and dilated intercellular spaces was observed more in patients with achalasia than in controls (87.5% vs 13.3%, P<.001; 84.4% vs 46.7%, P=.049). Muscularis mucosae (MM) atrophy and epithelial wave were only observed in achalasia (40.6% vs 0%, P=.005; 28.1% vs 0%, P=.043). Fibrosis was more common in achalasia, but without statistical significance (31.3% vs 20.0%, P=.503). In achalasia with endoscopic dilation and thickening of the mucosa, MM atrophy was observed histologically, and in cases involving endoscopic PSP, the histological epithelial wave was observed. CONCLUSIONS & INFERENCES: Histological findings of esophagitis were observed endoscopically even in early achalasia. Pinstripe pattern corresponds to the epithelial wave observed histologically in achalasia, whereas endoscopic findings in advanced achalasia correspond to MM atrophy. Appropriate management is necessary during early achalasia to prevent progression to advanced achalasia with more severe histological changes.

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study.

The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 ± 0.5 and 1.0 ± 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of ΔDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r = -0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.

Impact of intra-arterial chemotherapy including internal carotid artery for advanced paranasal sinus cancers involving the skull base.

BACKGROUND: The most significant problem of intra-arterial chemotherapy for advanced paranasal sinus carcinomas and residual cancers supplied by internal carotid artery (ICA) and involving the skull base is the lack of salvage therapies. OBJECTIVE: The objective of the study was to evaluate the usefulness of intra-arterial chemotherapy including ICA infusion for treating advanced paranasal sinus carcinomas, which have invaded the skull base. METHODS: Forty-six patients with advanced paranasal sinus carcinomas supplied by ICA were treated by intra-arterial chemotherapy using CDDP and sodium thiosulphate (STS) as a neutraliser of CDDP toxicity. After evaluating CT angiography, 150 mg m(-2) of CDDP was superselectively administered weekly to each feeding artery including ICA four times. RESULTS: The 10-year overall survival rate and progression-free survival rate were 70.7 and 60.2%, respectively. Compared with control group without infusing ICA, recurrences at anterior skullbase or anterior ethomoid sinus were significantly diminished. Of 32 patients in which the orbital apex had been invaded, 29 patients were treated with successful preservation of orbital contents. The CT angiography could efficiently determine all feeding arteries supplying the cancers. Consequently, chemotherapy could be administered on schedule, and side effects were minimal and acceptable. CONCLUSIONS: This new method has promising applications in the treatment of advanced paranasal sinus carcinomas involving the skull base.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

[Giant mediastinal thyroid follicular carcinoma with tracheal stenosis].

A 76-year-old female was admitted to the hospital with dyspnea and hypertention. She had the giant thyroid tumor which had been awared but not treated for 40 years. On a computed tomography (CT) scan and magnetic resonance imaging (MRI), the tumor was 14 x 10 cm and the tracheal stenosis was completely intrathoracic, which was 5 x 7 mm. Tracheal incubation was performed safety by using percutaneous cardiopulmonary support. A subtotal thyroidectomy was performed by midsternotomy with cervical incision. The weight of the resected specimen was 340 g and the pathological diagnosis was follicular thyroid carcinoma. The postoperative course was uneventful and the patient suffered no hoarseness and dyspnea.

Effects of high-monounsaturated fatty acid enteral formula versus high-carbohydrate enteral formula on plasma glucose concentration and insulin secretion in healthy individuals and diabetic patients.

We investigated the effects of high-monounsaturated fatty acid (MUFA) versus high-carbohydrate enteral formula on post-prandial plasma glucose concentration and insulin response in Japanese patients with type 2 diabetes mellitus and healthy Japanese volunteers. Ten healthy volunteers aged 20.8 +/- 1.2 years and 12 diabetic patients with good glycaemic control (glycosylated haemoglobulin < 7%) aged 58.6 +/- 7.7 years were randomly assigned to take high-MUFA or high-carbohydrate formula after a 12-h overnight fast. The patients switched to the other formula after 7 days. Post-prandial plasma glucose and insulin response were significantly lower in all subjects after taking high-MUFA formula compared with high-carbohydrate formula. No differences were observed in free fatty acids, triglycerides and plasma glucagon between the two diet groups. In conclusion, a high-MUFA enteral formula suppresses post-prandial hyperglycaemia without exaggerated insulin secretion compared with a high-carbohydrate enteral diet in patients with type 2 diabetes and healthy subjects.

Phylogeny and biogeography of the genus Lycium (Solanaceae): inferences from chloroplast DNA sequences.

Lycium comprises approximately 70 species and is disjunctly distributed in temperate to subtropical regions in South America, North America, southern Africa, Eurasia, and Australia. Among them, only Lycium sandwicense A. Gray sporadically occurs widely on oceanic islands in the Pacific Ocean. To investigate phylogenetic and biogeographic relationships of the genus with emphasis on L. sandwicense, the coding region of matK, the two intergenic spacers trnT (UGU)-trnL (UAA) and trnL (UAA)-trnF (GAA), and the trnL (UAA) intron of chloroplast DNA (cpDNA) were sequenced. A strict consensus tree resulting from the phylogenetic analysis indicates the following: (1) New World species comprise a potentially paraphyletic assemblage; (2) southern African, Australian, and Eurasian species together are monophyletic; (3) southern African species are a paraphyletic assemblage; and (4) L. sandwicense is in a clade with certain New World species. The estimated biogeographic events based on the cpDNA analysis indicate that (1) Lycium originated in the New World, (2) all southern African, Australian, and Eurasian species have a common ancestor from the New World, (3) Australian and Eurasian species originated once from a southern African progenitor, and (4) L. sandwicense differentiated from the New World species.

Pollination mode in fig wasps: the predictive power of correlated traits.

The over 700 species of Ficus are thought to have co-speciated with their obligate pollinators (family Agaonidae). Some of these wasp species pollinate figs actively, while others are passive pollinators. Based on direct observations of mode of pollination in 88 species, we show that mode of pollination can confidently be predicted from fig traits only (anther-to-ovule ratio) or from wasp traits only (presence of coxal combs). The presence of pollen pockets is not a predictor of mode of pollination. Data, direct and indirect, on 142 species, demonstrate numerous cases of the loss of active pollination and suggest one or few origins of active pollination. Hence, active pollination, an impressive example of the sophisticated traits that may result from mutualistic coevolution, depends on selective forces that can be overcome in some species, allowing reversions. Despite frequent loss, active pollination remains the predominant mode of pollination in Ficus.

Improved survival with oral administration of enteric-coated tegafur/uracil for advanced stage IV-A hepatocellular carcinoma.

BACKGROUND AND AIMS: There is currently no proven chemotherapy regimen for hepatocellular carcinoma (HCC). The principal chemotherapeutic approach in most cases is infusion therapy into the hepatic arteries feeding the tumors. However, the clinical effects of chemotherapy are extremely poor. Therefore, in the present study, we conducted a prospective randomized trial of the efficacy of oral administration of enteric-coated tegafur/uracil for advanced HCC. METHODS: From 1994 to 1999, a total of 56 consecutive patients with unresectable stage IV-A HCC were studied prospectively to examine the efficacy of enteric-coated tegafur/uracil in HCC and to determine the significant prognostic factors. Twenty-eight patients were treated only with enteric-coated tegafur/uracil without other anticancer treatment. Another 20 patients were given conservative management only. The remaining eight patients withdrew from the study. RESULTS: In the group treated only with enteric-coated tegafur/uracil, the median survival time and 1 and 2 year survival rates were 12.13 months and 55.3 and 36.9%, respectively. In the control group, the median survival time and 1 year survival rate were 6.20 months and 5.5%, respectively. By both univariate analysis and multivariate analysis using Cox's proportional hazards model, treatment with enteric-coated tegafur/uracil was shown to be the factor most significantly favoring a better prognosis. CONCLUSIONS: Although the prognosis of most patients with stage IV-A HCC is poor, administration of enteric-coated tegafur/uracil induces long-term survival and is an effective treatment for stage IV-A HCC.

Troglitazone prevents the rise in visceral adiposity and improves fatty liver associated with sulfonylurea therapy--a randomized controlled trial.

Monotherapy with sulfonylurea may result in the exhaustion of pancreatic beta-cell function, fat accumulation, and dyslipidemia. We examined the possibility of dose reduction by administering sulfonylurea together with troglitazone, and investigated changes in insulin secretion and fat deposition. Seventy-eight patients with type 2 diabetes adequately controlled with glibenclamide were randomly allocated to a troglitazone (400 mg/d)-added group (n = 40) or a control group without placebo (n = 38) and monitored for 24 weeks. The daily dose of glibenclamide was adjusted to maintain stable HbA(1c) levels. Fat accumulation to the liver and thigh muscle were measured in mean Hounsfield units determined on computed tomography (CT) scan. Visceral fat accumulation (V), subcutaneous fat accumulation (S), and the V/S ratio were also determined by CT scan. The daily dose of glibenclamide and serum fasting insulin level in the troglitazone-added group significantly decreased (from 4.05 +/- 2.50 mg/d to 1.84 +/- 1.65 mg/d and from 8.47 +/- 4.62 microU/mL to 6.49 +/- 3.28 microU/mL, respectively) during the observation period compared with the control group (P < .01 and P < .01, respectively). Serum triglyceride and homeostasis model insulin resistance index (HOMA-R) in the troglitazone-added group decreased significantly in comparison to the control group (P < .05 and P < .01, respectively). The mean Hounsfield units of liver significantly decreased in the control group compared with the troglitazone-added group (P < .05). Visceral fat area and the V/S ratio significantly increased in the control group compared with the troglitazone-added group (P < .01 and P < .01, respectively). Glibenclamide monotherapy resulted in fat accumulation accompanied by dyslipidemia. An alternate conclusion is that troglitazone reversed type 2 diabetes (not sulfonylurea)-associated fat accumulation. The addition of troglitazone decreased daily doses of glibenclamide, preserved fasting insulin secretion, improved fat accumulation in liver, and prevented dyslipidemia.

Mutations of p53 in morphologically non-neoplastic mucosa of long-standing ulcerative colitis.

Two cases of ulcerative colitis (UC)-associated carcinoma or dysplasia and morphologically non-neoplastic mucosa with p53 protein overexpression (MNNM-p53OE) were selected. DNA was extracted from the paraffin blocks of these lesions and exons 5 - 8 of the p53 gene were analyzed by PCR and direct sequencing. In addition, mutations in K-ras codon 12 were analyzed by PCR-RFLP methods. MNNM-p53OE was located surrounding and adjoining a coexisting carcinoma and / or dysplasia. A p53 mutation was detected in 12 / 22 (54.5%) MNNM-p53OE samples, 4 / 8 (50%) dysplasia samples and 8 / 8 (100%) carcinoma samples. The p53 mutations detected in MNNM-p53OE were identical to those demonstrated in the adjoining carcinoma and / or dysplasia. No K-ras codon 12 mutation was detected in any of the samples. These results indicate that MNNM-p53OE may share an identical clonal linkage with a coexisting carcinoma and / or dysplasia, and may be an initial and submorphological form of UC-associated neoplasia. Recognition of MNNM-p53OE in biopsy specimens may help to identify patients with UC at risk of developing colorectal carcinoma.

Heterogeneity of p53 mutational status in intramucosal carcinoma of the colorectum.

The aim of this study was to elucidate whether or not p53 genetic heterogeneity would occur while colorectal carcinoma was limited to the mucosa. Eight cases of endoscopically resected colorectal intramucosal carcinomas were analyzed to determine the p53 gene sequence (exons 5 to 8). Six out of 8 cases showed p53 gene mutations, and in all of them, the mutational status was heterogeneous. In 4 cases, mutated codons were heterogeneous as well. These data indicate that p53 gene alterations in colorectal carcinomas occur and diverge at the stage of intramucosal carcinoma, supporting our previously proposed hypothesis that colorectal carcinomas can be composed of various subclones as regards p53 gene mutation, while the carcinoma is limited to the mucosa, and one of these subclones commences invasion to the submucosa after clonal selection, thus generating a monoclonal invasive carcinoma.

A clinical study of oral tongue cancer.

Thirty-nine previously untreated patients with squamous cell carcinoma of the oral tongue treated with curative intent in our hospital from 1993 through 1998 are reviewed. Of these patients, those in the early stage (stages I and II) constituted 64%. The over all 5-year survival rate of all the patients was 60%. The 5-year survival rate of the patients with early stage cancers was unsatisfactory (stage I: 73%; II: 56%). This was thought to be related to the absence of elective neck dissection and the administration of chemotherapy in the patients with early stage cancer. We concluded that elective neck dissection for levels I, II and III is the first choice of treatment strategy for patients with stage II cancer. Our data indicate that chemotherapy in patients with early stage cancer was not beneficial and might have increased the risk of late lymph node metastasis in the clinically NO patients without neck dissection. There were 9 patients younger than 40 years of age and their survival rate at 5 years was 80%, which was better than that of the older patients. The treatment strategy for patients younger than 40 years of age was similar to that of older patients.

Streptococcus anginosus in head and neck squamous cell carcinoma: implication in carcinogenesis.

It has been suggested that Helicobacter pylori (H. pylori) infection might be associated with not only gastric ulcers but also gastric malignancies. Recently, it was reported that the Streptococcus anginosus (S. anginosus) DNA sequence was found in DNA samples extracted from esophageal cancers. Because smoking and alcohol abuse are regarded as risk factors for both esophgeal cancer and head and neck cancer, infection of S. anginosus might be associated with carcinogenesis of head and neck cancer. To investgate the involvement of S. anginosus infection in head and neck cancer, we analyzed 217 DNA samples prepared from head and neck squamous cell carcinomas. We performed PCR analysis with S. anginosus-16S ribosomal DNA-specific primers, and Southern blot analysis. For detection of S. anginosus in the oral and pharyngeal cavities, we used oropharyngeal bacteriological culture and PCR analysis of gingival smears of the patients. By PCR analysis, the S. anginosus DNA sequence was found in 217 out of 217 (100%) DNA samples obtained from head and neck cancers. By Southern blot analysis, positive bands were detected in 41 out of 125 (33%) samples. We could find no S. anginosus colony in oropharyngeal bacteriological culture dishes of 53 patients with and without head and neck cancer. On the other hand, we found the S. anginosus DNA fragment in 8 out of 8 DNA samples obtained from gingival smears by PCR analysis. These data indicate that the upper aerodigestive environment of the patients permitting S. anginosus infection was implicated in the carcinogenesis of head and neck squamous cell carcinoma.

[Significance of interferon alpha therapy for advanced renal cell carcinoma. Fukushima Renal Cancer Study Group].

We ranked prognostic factors to retrospectively evaluate the clinical significance of interferon alpha (IFN-alpha) therapy in patients with Robson stage IVB renal cell carcinoma. A total of 44 Robson stage IVB renal cancer patients were divided into 2 groups, one with more than 6 months administration of IFN-alpha (3-7 times a week: group A) and another without any IFN-alpha administration. The distribution of these 2 groups was not randomized. In addition to IFN-alpha therapy, survival was analyzed with respect to performance status (PS), mass reductive nephrectomy, concomitant use of other cytotoxic therapies, the number of metastatic organs, growth type, site of metastasis and the period of diagnosis, using a multivariate method with Cox proportional hazards regression. The multivariate analysis showed administration of IFN-alpha to be the most significant factor influencing a good prognosis. Improved survival was also significantly correlated with slow growing type and good PS. Among group A, a significant favorable prognosis was obtained in patients with the responses of no change (NC), partial response (PR) and complete remission (CR) 6 months after initiating administration of IFN-alpha, as well as with good PS and a slow growing type carcinoma. We conclude that IFN-alpha therapy might improve the prognosis of patients with Robson stage IVB renal cell carcinoma, especially, in cases when a greater than NC response is obtained after 6 months administration of IFN-alpha.

Early colorectal cancer with special reference to the superficial nonpolypoid type from a histopathologic point of view.

The incidence and histopathologic characteristics of nonpolypoid (superficial type) early colorectal carcinomas were studied and compared with those of the polypoid type. The superficial type was subclassified as elevated (type IIa), type IIa with central depression (type IIa + IIc), plain (type IIb), depressed (type IIc), and IIc with marginal elevation (type IIc + IIa). The superficial type comprised 22% and 27% of intramucosal and submucosal carcinomas, respectively. Pure type IIb was not found, and there were only three pure type IIc lesions. Type IIa + IIc and IIc + IIa (and IIc) showed a significantly higher rate of submucosal invasion among the small tumors (59% and 71% less than 20 mm, respectively) compared to the polypoid type; type IIa showed no significant difference. The incidence of lymph node metastasis among submucosal carcinomas showed no significant difference between the superficial type and the polypoid type. About 64% and 52% of type IIa and IIa + IIc tumors accompanied residual adenoma, suggesting that they originated from small, flat adenomas through the adenoma-carcinoma sequence, whereas type IIc + IIa (and IIc) did not have an adenomatous component, implying that they arose de novo or originated through an adenoma-carcinoma sequence at a smaller size than the type IIa and IIa + IIc lesions. Superficial-type early colorectal carcinomas are not rare, and they are not uniform in nature. Rapid growth and invasion to the submucosa is characteristic of superficial-type lesions with a central depression, and only superficial depressed (type IIc + IIa, IIc) lesions can arise de novo. Although they grow rapidly to invade the submucosa, it cannot be said that they show more aggressive behavior than the polypoid type.

Pancreatoblastoma. Three original cases and review of the literature.

PURPOSE: To describe the characteristics of pancreatoblastoma. MATERIAL AND METHODS: We studied 3 cases of pancretoblastoma and reviewed another 59 cases. Parameters analyzed were tumor site, hemorrhage, capsule formation, necrosis, vascularity, production of alpha-fetoprotein (AFP), cystic changes and calcification. RESULTS: The diagnostic findings were as follows: pancreatic head origin (24/54, 44%), pancreatic body and tail origin (30/54, 56%), hemorrhage (16/17, 94%), capsule formation (24/26, 92%), necrosis (28/31, 90%), hypervascularity (10/14, 71%), production of AFP (19/28, 68%), cystic changes (11/16, 69%), and calcification (10/21, 48%). All neonatal cases demonstrated cystic changes. Three of them were patients with Beckwith-Wiedmann syndrome. The incidence of capsule formation and calcification was not related to the origin of the tumor. CONCLUSION: The most common features of pancreatoblastoma are hemorrhage, capsule formation and necrosis.

Molecular phylogeny of Coriaria, with special emphasis on the disjunct distribution.

Coriaria, which has the most conspicuously disjunct distribution of the flowering plants, is distributed in four separate areas of the world. The phylogenetic relationships of 12 Coriaria species collected from the representative disjunct areas were inferred by comparing 2416 bp of the combined data set of rbcL (a large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase) and matK (maturase K) genes. The phylogenetic tree shows that the Chile-Papua New Guinea-New Zealand-Pacific islands species and the Central America-northern South America species form a sister group, and the Eurasian clade is more basal to them. The divergence time between the Eurasian group and the other species was estimated as 63 or 59 million years ago using rbcL and matK molecular clocks, respectively. These results do not support previously proposed hypotheses which explain the disjunct distribution on the basis of continental drift but suggest that the distribution pattern was formed by several geographical migrations and separations in the Cenozoic.