Effects of an elemental diet to reduce adverse events in patients with esophageal cancer receiving docetaxel/cisplatin/5-fluorouracil: a phase III randomized controlled trial-EPOC 2 (JFMC49-1601-C5).

BACKGROUND: Oral mucositis (OM) is an unpleasant adverse event in patients receiving chemotherapy. A prospective feasibility study showed that elemental diet (ED), an oral supplement that does not require digestion, may prevent OM. Based on this, we established a central review system for oral cavity assessment by dental oncology specialists blinded to background data. We used this system to elucidate the preventive effect of an ED against OM in patients with esophageal cancer receiving docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy. PATIENTS AND METHODS: In this phase III, multicenter, parallel-group, controlled trial, patients consuming a normal diet orally were randomly assigned (1 : 1) to receive two cycles of DCF with (group A) or without (group B) an ED (Elental® 160 g/day). We assessed the incidence of grade ≥2 OM evaluated by two reviewers, changes in body weight, prealbumin, C-reactive protein, and DCF completion rate based on ED compliance. RESULTS: Of the 117 patients randomly assigned to treatment, four failed to start treatment and were excluded from the primary analysis; thus, groups A and B comprised 55 and 58 patients, respectively. There were no significant differences in background characteristics. Grade ≥2 OM was observed in eight (15%) and 20 (34%) patients in groups A and B, respectively (P = 0.0141). Changes in body weight and prealbumin during the two DCF cycles were significantly higher in group A than B (P = 0.0022 and 0.0203, respectively). During the first cycle, changes in C-reactive protein were significantly lower in group A than B (P = 0.0338). In group A (receiving ED), the DCF completion rate was 100% in patients with 100% ED compliance and 70% in patients failing ED completion (P = 0.0046). CONCLUSIONS: The study findings demonstrate that an ED can prevent OM in patients with esophageal cancer receiving chemotherapy.

Comparison of neoadjuvant chemotherapy versus upfront surgery with or without chemotherapy for patients with clinical stage III esophageal squamous cell carcinoma.

Neoadjuvant chemotherapy (NAC) and chemoradiotherapy have been shown to extend postoperative survival, and preoperative therapy followed by esophagectomy has become the standard treatment worldwide for patients with esophageal squamous cell carcinoma (ESCC). The Japan Clinical Oncology Group 9907 study showed that NAC significantly extended survival in advanced ESCC, but the survival benefit for patients with clinical stage III disease remains to be elucidated. We compared the survival rates of NAC and upfront surgery in patients with clinical stage III ESCC. Consecutive patients histologically diagnosed as clinical stage III (excluding cT4) ESCC were eligible for this retrospective study. Between September 2002 and April 2007, upfront transthoracic esophagectomy was performed initially and, for patients with positive lymph node (LN) metastasis in a resected specimen, adjuvant chemotherapy using cisplatin and 5-fluororouracil every 3 weeks for two cycles was administered (Upfront surgery group). Since May 2007, a NAC regimen used as adjuvant chemotherapy followed by transthoracic esophagectomy has been administered as the standard treatment in our institution (NAC group). Patient characteristics, clinicopathological factors, treatment outcomes, post-treatment recurrence, and overall survival (OS) were compared between the NAC and upfront surgery groups. Fifty-one and 55 patients were included in the NAC and upfront surgery groups, respectively. The R0 resection rate was significantly lower in the NAC group than in the upfront surgery group (upfront surgery, 98%; NAC, 76%; P = 0.003). In the upfront surgery group, of 49 patients who underwent R0 resection and pathologically positive for LN metastasis, 22 (45%) received adjuvant chemotherapy. In the NAC group, 49 (96%) of 51 patients completed two cycles of NAC. In survival analysis, no significant difference in OS was observed between the NAC and upfront surgery groups (NAC: 5-year OS, 43.8%; upfront surgery: 5-year overall surgery, 57.5%; P = 0.167). Patients who underwent R0 resection showed significantly longer OS than did those who underwent R1, R2, or no resection (P = 0.001). In multivariate analysis using age, perioperative chemotherapy, depth of invasion, LN metastasis, surgical radicality, postoperative pneumonia, and anastomotic leakage as covariates, LN metastasis [cN2: hazard ratio (HR), 1.389; P = 0.309; cN3: HR, 16.019; P = 0.012] and surgical radicality (R1: HR, 3.949; P = 0.009; R2 or no resection: HR, 2.912; P = 0.022) were shown to be significant independent prognostic factors. In clinical stage III ESCC patients, no significant difference in OS was observed between NAC and upfront surgery. Although potential patient selection bias might be a factor in this retrospective analysis, the noncurative resection rate was higher after NAC than after upfront surgery. The survival benefit of more intensive NAC needs to be further evaluated.

Variations in survival and perioperative complications between hospitals based on data from two phase III clinical trials for oesophageal cancer.

BACKGROUND: Variations in institutional practice may contribute to different outcomes of cancer treatment. The impact of interinstitutional heterogeneity on outcomes between hospitals after oesophagectomy has not been examined previously using data from surgical clinical trials. METHODS: The data from two phase III trials for oesophageal cancer were used. Japan Clinical Oncology Group (JCOG) 9204 involved oesophagectomy (92-OP) versus oesophagectomy plus postoperative chemotherapy (92-POST), with accrual from 1992 to 1997. JCOG9907 involved postoperative chemotherapy (99-POST) versus preoperative chemotherapy (99-PRE), with accrual from 2000 to 2006. Hospitals contributing fewer than three patients were excluded. The influence of time and preoperative chemotherapy on interinstitutional heterogeneity related to postoperative complications and 5-year overall survival were evaluated by comparisons within and between these trial groups. Heterogeneity was estimated by a mixed-effects model after adjusting for age, sex, performance status, location of the primary tumour and clinical stage. RESULTS: Twelve hospitals in 92-OP (114 patients), 13 in 92-POST (114), 19 in 99-POST (158) and 18 in 99-PRE (154) were eligible. There was considerable heterogeneity in predicted postoperative complications in both groups in JCOG9204 (median 31.3 (range 15.0-68.2) per cent), and in 99-PRE (35.2 (22.6-46.6) per cent) but not in 99-POST (27.7 (27.7-27.7) per cent) from JCOG9907. A similar pattern was seen for predicted overall survival (92-POST: 66.4 (range 64.1-68.9) per cent; 99-PRE: 55.9 (54.0-59.7) per cent; 99-POST: 44.4 (44.4-44.4) per cent). CONCLUSION: Interinstitutional heterogeneity regarding complications and survival after oesophagectomy is a problem that merits wider consideration.

Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer.

AIMS: The aim of this study was to evaluate the usefulness of neoadjuvant systemic chemotherapy using irinotecan, 5-FU, and leucovorin (LV) for the treatment of locally advanced rectal cancer, which was a powerful ploychemotherapy in those days in Japan. METHODS: Between 2001 and 2004, 26 patients with T3 or T4 and N0-2 non-metastatic resectable rectal cancer were selectively enrolled in this study. Neoadjuvant chemotherapy consisted of two cycles of irinotecan (80 mg/m²), 5-FU (500 mg/m²), and LV (250 mg/m²) on days 1, 8, and 15 for 4 weeks. Surgical resection was performed in all the patients 2-4 weeks after the completion of chemotherapy. RESULTS: Overall down-staging was observed in 15 patients. T level and N level down-staging were observed in 12 and 13 patients, respectively. A pathological complete response was observed in one patients. The median follow-up period was 75 months (range, 8-97 months). Recurrences occurred in 5 patients including pelvic relapses in 3 and distant metastases in 2. The 5-year relapse-free and overall survival rates were 74% and 84%, respectively. CONCLUSIONS: Neoadjuvant systemic chemotherapy comprised of a combination of multi-drugs as irinotecan, 5-FU, and LV may be beneficial to the prognoses of patients with locally advanced rectal cancer.

[Clinical application of sentinel node navigation surgery for esophageal cancer].

In esophageal cancer, sentinel nodes (SNs) are identified as multiple nodes and widely spread from cervical to abdominal areas. In more than 80% of the cases, at least one SN is located in the 2nd or 3rd compartment of regional lymph nodes which have been considered to be "skip metastases". This characteristic distribution of SNs is attributed to the multi-directional lymphatic drainage routes from the esophagus. Clinical application of SN navigation surgery will be expected to play a key role for intraoperative diagnosis for lymph node metastasis and individualized multimodal therapy in patients with cT1N0 esophageal cancer.

Improved hatching for in vitro quail embryo culture using surrogate eggshell and artificial vessel.

The establishment of avian embryonic culture is important both for the analysis of the developmental process and the establishment of transgenic chickens that produce useful biological materials in eggs. However, the hatchability of cultured embryos has been approximately 50%. We identified that the low rate of hatchability of cultured embryos was caused by limited oxygen and calcium availability. In quail embryo culture using chicken eggshell as a culture vessel, viability in the middle stage of culture was improved and 30% of embryos were hatched by oxygen enrichment. Furthermore, hatchability increased to 80% by supplementation with calcium lactate in addition to oxygen aeration. In the present study, a fully artificial vessel for quail embryo culture was designed using a gas-permeable Teflon membrane. By the addition of fine eggshell powder and calcium lactate, quail embryos grew and developed normally, and 43% of embryos hatched. Although the hatchability was lower than that of cultures using a surrogate eggshell, we achieved in hatching an avian embryo using a fully artificial vessel.

[Salvage surgery for the T4 esophageal cancer following downstaging by neoadjuvant chemoradiotherapy].

The standard modality of the treatment for the patients with T4 esophageal cancer, whose prognosis still remains quite poor, is not established yet. Salvage surgery for the T4 esophageal cancer following downstaging by neoadjuvant chemo-radiotherapy has become to be available. During the period from 1992 to 96, 30 patients with the suspected T4 esophageal cancer underwent chemoradiotherapy, which consisted of two courses of CDDP/5-FU with-sequential or concurrent 50-60Gy radiotherapy. Among them eleven patients became to be resectable by means of thoracotomy and laparotomy and pathological CRs were obtained in either primary lesions or lymph nodes. The longest survival term following surgery is 36 months. Three patients died of cancer recurrence including the organ metastasis and one died from pyothorax without cancer due to severe immunosuppression attributable to chemoradiation. Our results warrants further studies of neoadjuvant chemoradiotherapy for the patients with T4 esophageal cancer.

A large DNA-binding nuclear protein with RNA recognition motif and serine/arginine-rich domain.

cDNA species encoding a large DNA-binding protein (NP220) of 1978 amino acids was isolated from human cDNA libraries. Human NP220 binds to double-stranded DNA fragments by recognizing clusters of cytidines. Immunofluorescent microscopy with antiserum directed against NP220 revealed a punctate or "speckled" pattern and coiled body-like structures in the nucleoplasm of various human cell lines. These structures diffused in the cytoplasm during mitosis. Western blot analysis showed that NP220 is enriched in the lithium 3,5-diiodosalicylate-insoluble fraction of nuclei. The domain essential for DNA binding is localized in C-terminal half of NP220. Human NP220 shares three types of domains (MH1, MH2, and MH3) with the acidic nuclear protein, matrin 3 (Belgrader, P., Dey, R., and Berezney, R. (1991) J. Biol. Chem. 266, 9893-9899). MH1 is a 48-amino acid sequence near the N terminus of both human NP220 and rat matrin 3. MH2 is a 75-amino acid sequence homologous to the RNA recognition motifs of heterogeneous nuclear RNP I and L. It is repeated three times in NP220 and twice in matrin 3. MH3 is a 60-amino acid sequence at the C terminus of both NP220 and matrin 3. NP220 has an arginine/serine-rich domain commonly found in pre-mRNA splicing factors. Close to the domain essential for DNA binding, there are nine repeats of the sequence LVTVDEVIEEEDL. Thus, NP220 is a novel type of nucleoplasmic protein with multiple domains.

Morphological and anthropological aspects of human triangular deciduous lower first molar teeth.

The crown and root morphology, and bilateral occurrence of human deciduous lower first molars that exhibited a triangular occlusal outline, taken from excavated samples of Japanese, Jomonese and Iraqi origin, were investigated. The crowns of triangular teeth had smaller mesiodistal and larger buccolingual diameters than normally shaped deciduous lower first molars. An elongated buccolingual diameter was derived from the buccal projection of the distobuccal cusp and lingual projection of the portion between the metaconid and distolingual cusp. In this analysis, all triangular deciduous lower first molars in which root morphology could be observed were accompanied by additional distolingual roots. Correlation between the right- and left-hand sides of this trait was high.

Deciduous dental morphology of the prehistoric Jomon people of Japan: comparison of nonmetric characters.

Morphological variations of the deciduous dentition are as useful as those of the permanent dentition for determining the biological affinities of human populations. This paper provides material on morphological variations of deciduous teeth of the prehistoric Japanese population from the Late and the Latest Jomon Period (ca. 2000-ca. 300 B.C.). The expression of nonmetric traits of the deciduous teeth in the Jomon sample shows a closer affinity with modern Japanese and Native American samples than with American White, Asiatic Indian, and African samples. However, the frequency of shoveling in deciduous upper incisors in the Jomon sample is lower than those in modern Japanese and Native American samples. The Jomon sample also expresses a much higher frequency of cusp 6 in deciduous lower second molars than seen in modern Japanese, Ainu, and Native American samples. The frequency in the Jomon sample is equal to that in the Australian Aboriginal sample, which shows cusp 6 most frequently among the samples compared. A somewhat low incidence of incisor shoveling in the Jomon sample was also reported in the permanent dentition (Turner [1976] Science 193:911-913, [1979] Am. J. Phys. Anthropol. 51:619-635, [1987] Am. J. Phys. Anthropol. 73:305-321, [1990] Am. J. Phys. Anthropol. 82:295-317; T. Hanihara [1992] Am. J. Phys. Anthropol. 88:163-182, 88:183-196). However, the frequency of cusp 6 in the Jomon sample shows no significant difference from those of Northeast Asian or Native American samples in the permanent dentition (Turner [1987] Am. J. Phys. Anthropol. 73:305-321; T. Hanihara [1992] Am. J. Phys. Anthropol. 88:163-182, 88:183-196). Evidently, some nonmetric traits express an inter-group difference only in the deciduous dentition.

alpha-Tocopherol enhances the hypocholesterolemic action of sesamin in rats.

The effect of alpha-tocopherol on the hypocholesterolemic action of sesamin was examined in rats given a cholesterol-enriched diet. When different levels (0.05 and 0.2%) of sesamin were fed, the supplementation of 1% alpha-tocopherol significantly accentuated the hypocholesterolemic action of sesamin, particularly with the higher sesamin level, although alpha-tocopherol alone did not affect the concentration of serum cholesterol. The dose-dependent promoting effect of alpha-tocopherol on the hypocholesterolemic action of sesamin was confirmed by supplementing different levels (0.2 and 1%) of alpha-tocopherol to a fixed level of sesamin (0.2%). alpha-Tocopherol was still effective at the 0.2% level. The metabolism of sesamin in the liver S9 fraction appeared to be interfered with alpha-tocopherol in vitro, suggesting a possible role of alpha-tocopherol in maintenance of the availability of sesamin.

Pancreas-specific venular labeling by monastral blue B in the BB rat: modulation by prostaglandins and their inhibitors.

Leaky blood vessels in the microcirculation can be detected in vivo by injecting an animal with colloidal pigments like Monastral blue B (MbB). We have previously used this labeling method in the BB rat, an animal model of spontaneous autoimmune diabetes, and detected increased vascular permeability restricted to the venules of the pancreas. The earlier data suggested that pancreata of animals susceptible to labeling contain trapped intravascular monocytes that are activated to release vasoactive mediators after phagocytosis of MbB. To explore these observations further, we investigated the effects of prostaglandins on this system. Prostaglandins are known to be important mediators of inflammatory responses and to modulate the expression of disease in other animal models of autoimmunity. We now report that MbB-induced pancreatic labeling is modulated by misoprostol (an analogue of prostaglandin E1), prostaglandins of the E series, and inhibitors of prostaglandin synthesis. The nonsteroidal anti-inflammatory drugs ibuprofen and ketorolac both reduced the intensity of labeling in susceptible BB rats in a dose dependent manner. In contrast, both misoprostol and prostaglandin E2 given at low doses induced pancreatic permeability in the labeling-resistant Wistar Furth rat. To extend this finding, we also tested much higher drug doses, since at high concentrations, E series prostanoids exert anti-inflammatory effects. We observed that large doses of prostaglandin E1, prostaglandin E2, and misoprostol all suppressed labeling in the BB rat. We conclude that presence of MbB in the pancreatic circulation of the rat induces organ specific venular leakage by an inflammatory process involving prostaglandins.

[Pharmacokinetics of trace elements by noncompartmental analysis in rats (Part 1): Significance of the pharmacokinetic parameters].

Six-week-old male Wistar rats were administrated the radioisotopes of five trace elements (iron, zinc, copper, manganese and iodine) intravenously in order to elucidate the significance of their pharmacokinetics by noncompartmental analysis. The mean residence time (MRT) and variance of residence time (VRT) increased in the order Mn, Cu, I, Fe and Zn. Neither MRT nor VRT indicated any statistical significance between I and Fe. These results suggested that Mn and Cu were voided rapidly from the plasma, whereas Zn persisted in the plasma for the longest time among these elements. Though I and Fe showed quite different plasma disappearance curves, both were considered to diminish at almost the same speed. The volume of distribution at steady state (Vdss) increased in the order Cu (32 ml), Fe (62 ml), I (149 ml), Mn (185 ml) and Zn (1012 ml). The distribution coefficient (Kd) of these elements increased in the same order as Vdss did. For Cu and Fe, Vdss was intermediate between the plasma volume and total body fluid volume of the rat, while, for the others, Vdss was greater than the total body fluid volume. In particular, Vdss of Zn was the greatest among these elements. Hence, the present study suggested that the plasma concentrations of Cu and Fe may reflect their body contents fairy well, though those of I, Fe and Zn can hardly do so. Vdss and Kd are, therefore, considered to be useful as supplementary diagnostic indices to understand the plasma concentrations of trace elements. Systemic clearance (CLs) increased in the order Fe (0.02 ml/min), Zn (0.07 ml/min), I (0.21 ml/min), Cu (0.37 ml/min) and Mn (4.61 ml/min). The CLs of Mn was similar to the hepatic plasma flow rate of the rat in size, indicating that the Cls of Mn may be one of the greatest among trace elements. It appeared, therefore, that when administered intravenously, Mn may be transferred from the plasma to the tissues more easily than the other elements.

Identification of soybean protein components that modulate the action of insulin in vitro.

We have reported that a 37-kDa protein from a soybean isolate shows an affinity for bile acids and modulates insulin action on fat decomposition in vitro [Makino et al., Agric. Biol. Chem., 52, 803 (1988)]. In this study, the major components of the protein were identified as the acidic A1a and A2 subunits of glycinin, via amino-terminal sequence analyses of purified proteins and examination of their effects on fat decomposition in rat adipose cells. The most hydrophobic region of the subunits was found to be responsible for the bile acid-binding ability, and the binding region probably does not contribute to the insulin-modulating activity. These bile acid-binding and insulin-modulating properties were also noted in a 40-kDa protein from pea seeds, probably acidic subunits of legumin, suggesting that these characteristics may be common to legume proteins.

[The clinical course of nodular type hepatocellular carcinomas after transcatheter arterial embolization (TAE) therapy].

TAEs were performed for 14 cases of nodular type hepatocellular carcinomas. The tumor size in 10 of the 14 cases was less than 5.0 cm in diameter. After 2 to 3 TAEs for each of the cases, tumor regression was noted in 11 cases and a decrease in the serum AFP in every case. The 1-year survival rate (1 YSR) was 79%, the 2YSR was 42%, and 3YSR was 10%, Re-growth of the tumors was observed in 45% of the cases 1-year after, and in all cases 2-year after. In cases which had multiple nodules or an incomplete capsule or a poor accumulation of Lipiodol, re-growth occurred even earlier.

Xenon contrast CT-CBF measurements in parkinsonism and normal aging.

Local cerebral blood flow (LCBF) and local tissue:blood partition, coefficient (L lambda) values were measured during CT scanning while patients with different types of Parkinson's syndrome (N = 14) inhaled a contrast mixture of 35-37 per cent stable xenon gas in oxygen. Single-compartment analysis fitted to infinity was used to calculate L lambda and LCBF values. Results were compared with results from normal age-matched volunteers (N = 24). Mean hemispheric (p less than 0.05) and subcortical (p less than 0.05) gray matter LCBF values were reduced in idiopathic Parkinson's disease (N = 11), compared to values from age-matched normals. Regionally, LCBF reductions included frontal (p less than 0.001), parietal cortex (p less than 0.05), caudate (p less than 0.05), lentiform nuclei (p less than 0.001) and thalamus (p less than 0.05) reductions. L lambda values were normal. Unilateral tremor and/or rigidity correlated directly with reduced LCBF in contralateral lentiform (p less than 0.01) and caudate (p less than 0.01) nuclei. In postencephalitic Parkinsonism (N = 1) LCBF reductions were diffuse, with normal L lambda values. In the akinetic form of Parkinsonism (N = 1) associated with lacunar infarcts, LCBF and L lambda reductions were patchy. In Parkinsonism following carbon monoxide poisoning (N = 1), LCBF values of gray and white matter were diffusely reduced and L lambda values were reduced in both pallidal regions. When dementia was present together with Parkinsonism (N = 3), LCBF reductions were more diffuse and severe. Dopaminergic deficiency correlated directly with reduced LCBF values, reflecting the severity of Parkinsonism.

Perturbation of phospholipid metabolism by erucic acid in male Sprague-Dawley rat heart.

Erucic acid was incorporated into cardiac phosphatidylserine and hepatic and cardiac sphingomyelin of male Sprague-Dawley rat. The fatty acid compositions of mitochondrial and microsomal phospholipids were similar in both liver and heart. The effect of a low fat diet and a diet containing erucic acid on the fatty acid composition of mitochondrial and microsomal phospholipids was also similar, except for the effect on sphingomyelin. However, the diet containing erucic acid influenced the metabolism of phosphatidylcholine of the heart but not of the liver, indicating that the turnover of 1-stearoyl-2-arachidonoyl phosphatidylcholine in the heart was inhibited by the diet containing erucic acid. On the other hand, the proportion of erucic acid in the free fatty acid was higher in the heart than in the liver.