Clinical Significance of Glioma-associated Oncogene 1 Expression in Patients With Locally Advanced Gastric Cancer Administered Adjuvant Chemotherapy With S-1 After Curative Surgery.

BACKGROUND/AIM: Glioma-associated oncogene 1 (GLI1) is an important transcription factor in the hedgehog signalling pathway and tumour formation. We evaluated the clinical significance of GLI1 expression as a prognostic factor in patients with locally advanced gastric cancer (GC). PATIENTS AND METHODS: GLI1 expression levels were measured by quantitative real-time polymerase chain reaction analysis of cancerous and adjacent normal mucosa specimens obtained from 142 patients with Stage II/III GC administered adjuvant chemotherapy with S-1 after curative resection. The associations of GLI1 expression with clinicopathological features and survival were evaluated. RESULTS: Clinicopathological features and GLI1 expression showed no association. Overall survival was significantly poorer in the high compared to the low GLI1 expression group (p=0.04). Multivariate analysis revealed that GLI1 expression was a significant independent prognostic factor [p=0.019, hazard ratio (HR)=1.94, 95% confidence interval (CI)=1.70-3.38]. CONCLUSION: GLI1 expression may be a useful prognostic marker in patients with locally advanced GC.

Randomized phase II study of TJ-54 (Yokukansan) for postoperative delirium in gastrointestinal and lung malignancy patients.

The present study evaluated the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies. Patients ≥70 years of age who underwent surgery for gastrointestinal or lung malignancy were eligible for participation in the study. The 186 eligible patients were randomly assigned at a 1:1 ratio to receive TJ-54 or control during their peri-operative care (between 7 days prior to surgery and 4 days following surgery, except for the operation day). The signs and symptoms of delirium were assessed using the Diagnostic and Statistical Manual of Mental Disorders-IV by the investigator during the peri-operative period. A total of 186 eligible gastrointestinal or lung malignancy patients were analyzed (93, TJ-54; 93, control). There were no marked differences between the two randomized groups. The incidence of delirium was 6.5% (6 patients) in the TJ-54 group and 9.7% (9 patients) in the control group, with no significant difference (P=0.419). However, of the patients categorized with a mini-mental state examination (MMSE) score of ≤26, the incidence of postoperative delirium was 9.1% in the TJ-54 group and 26.9% in the control group [risk ratio, 0.338; 95% confidence interval (0.078-1.462), P=0.115]. Treatment with TJ-54 reduced the incidence of postoperative delirium compared with the control group. Although TJ-54 did not demonstrate any contribution to preventing or treating postoperative delirium in patients following surgery for gastrointestinal or lung malignancy, TJ-54 reduced the risk of postoperative delirium in the patients who were classified as MMSE ≤26. Further phase III studies with a larger sample size are required in order to clarify the effects of TJ-54 against postoperative delirium.

Lysophosphatidylcholine Acyltransferase-3 Expression Is Associated with Atherosclerosis Progression.

Free arachidonic acid (AA) is an important precursor of lipid mediators such as leukotrienes and prostaglandins that induces inflammation and is associated with atherosclerosis progression. Recent studies have shown that lysophosphatidylcholine acyltransferase-3 (LPCAT3) converts lysophosphatidylcholine (LPC) and free AA into phosphatidylcholine (PC)-containing AA (arachidonyl-PC) and thereby can regulate intracellular free-AA levels. However, the association between LPCAT3 and atherosclerosis remains to be established. In this study, we analyzed human and mouse atherosclerotic tissues to gain insight into the arachidonyl-PC metabolism involving LPCAT3 using imaging mass spectrometry. The data revealed a complementary distribution of arachidonyl-PC and LPC in human atherosclerotic tissues with arachidonyl-PC decreasing and LPC increasing as atherosclerosis progressed. Furthermore, we found a homologous distribution of LPCAT3 expression and arachidonyl-PC based on atherosclerotic progression. In contrast, in ApoE-deficient mice, atherosclerosis increased both arachidonyl-PC accumulation and LPCAT3 expression. Taken together, these findings suggest that the regulation of LPCAT3 expression might be associated with atherosclerotic progression in humans.

Inhalation of a racemic mixture (R,S)-linalool by rats experiencing restraint stress alters neuropeptide and MHC class I gene expression in the hypothalamus.

Some odorants have physiological and psychological effects on organisms. However, little is known about the effects of inhaling them, particularly on the central nervous system. Using DNA microarray analysis, we obtained gene expression profiles of the hypothalamus from restraint stressed rats exposed to racemic (R,S)-linalool. Hierarchical clustering across all probe sets showed that this inhalation of (R,S)-linalool influenced the expression levels of a wide range of genes in the hypothalamus. A comparison of transcription levels revealed that the inhalation of (R,S)-linalool restored the expression of 560 stress-induced probe sets to a normal status. Gene Ontology (GO) analysis showed that these genes were associated with synaptic transmission via neurotransmitters including anxiolytic neuropeptides such as oxytocin and neuropeptide Y. These genes also included several major histocompatibility complex (MHC) class I molecules necessary for neural development and plasticity. Moreover, Upstream Regulator Analysis predicted that the hormone prolactin would be activated by the inhalation of (R,S)-linalool under stress. Our results reveal some of the molecular mechanisms associated with odor inhalation in the hypothalamus in organisms under stress.

Utility of a preloaded fenestrated graft in thoracoabdominal aneurysm repair.

An 84-year-old man with a thoracoabdominal aortic aneurysm was treated using a fenestrated stent graft with a preloaded guidewire system under local anesthesia. He suffered from severe chronic obstructive pulmonary disease. We successfully placed 4 bridging stent grafts for perfusion of the celiac artery, superior mesenteric artery, and bilateral renal arteries via the 4 fenestrations. A preloaded wire system was used to insert a catheter into the celiac artery from the left brachial artery. Our findings indicate that a fenestrated stent graft with a preloaded wire system may expand the indication for treating thoracoabdominal aortic aneurysms in high-risk patients.

Does herbal medicine reduce the risk of hepatocellular carcinoma?

Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials.

Effects of inhaled (S)-linalool on hypothalamic gene expression in rats under restraint stress.

Linalool has two enantiomers, (R)-linalool and (S)-linalool. Both are known to possess several biological activities in stressed animals. Our previous work revealed that inhalation of (R)-linalool altered hypothalamic gene expression in rats under stress. In the present study, we monitored hypothalamic gene expression in restrained rats with and without (S)-linalool inhalation by DNA microarray. The entire gene expression profile showed that inhalation of (S)-linalool significantly changed the expression levels of 316 hypothalamic genes in the restrained rats. The differentially expressed genes (e.g., App, Avp, Igf2, Igfbp2, Sst and Syt5) were found to relate to cell-to-cell signaling and nervous system development. These results indicate that (S)-linalool influences hypothalamic gene expression in restrained rats, and that inhalation of (S)-linalool under the stressed condition has some effects on stress-related biological responses.

The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease.

BACKGROUND: The guidelines established by the National Comprehensive Cancer Network do not describe mucinous histology as a clinical factor that should influence the therapeutic algorithm. However, previous studies show conflicting results regarding the prognosis of colorectal mucinous adenocarcinoma. In this study, we described the clinicopathological features of mucinous adenocarcinoma in Japan, to identify optimal therapeutic strategies. METHODS: 144 patients with mucinous and 2673 with non-mucinous adenocarcinomas who underwent primary resection in two major centers in Yokohama, Japan were retrospectively evaluated for clinicopathological features and treatment factors. A multivariate analysis for overall survival followed by the comparison of overall survival using Cox proportional hazard model were performed. RESULTS: Patients with mucinous adenocarcinoma had larger primary lesions, higher preoperative CEA levels, a deeper depth of invasion, higher rates of nodal and distant metastasis, and more metastatic sites. A multivariate analysis for overall survival revealed a mucinous histology to be an independent prognostic factor. In the subgroup analysis stratified by stage, Patients diagnosed as stageIII and IV disease had a worse survival in mucinous adenocarcinoma than non-mucinous, while survival did not differ significantly in patients diagnosed as Stage0-II disease. In stageIII, local recurrence in rectal cases and peritoneal dissemination were more frequently observed in patients with a mucinous histology. CONCLUSIONS: Our study indentified that mucinous adenocarcinoma was associated with a worse survival compared with non-mucinous in patients with stageIII and IV disease. In rectal StageIII disease with mucinous histology, additional therapy to control local recurrence followed by surgical resection may be a strategical alternative. Further molecular investigations considering genetic features of mucinous histology will lead to drug development and better management of peritoneal metastasis.

[Modified FOLFIRI (l-LV, 5-fluorouracil and irinotecan) therapy for Japanese patients with metastatic colorectal cancer].

PURPOSE: As a project of the Kanagawa Colorectal Cancer Study Group, we performed this study to analyze the efficacy and the safety of modified FOLFIRI (irinotecan: 150 mg/m2) therapy for Japanese patients with metastatic colorectal cancer. PATIENTS AND METHODS: We treated PS 0-1 Japanese patients with measurable or assessable colorectal cancer who either had not received preliminary treatment, or were postoperative with metastasis and had undergone radiation therapy or adjuvant chemotherapy before more than four weeks, and further had provided written acceptance of our proposed procedures. Twenty patients received modified FOLFIRI therapy as a 2-hour infusion of CPT-11 150 mg/m/2 and l-LV 200 mg/m2 followed by a bolus 5-FU 400 mg/m/2 and 46-hour infusion 5-FU 2, 400 mg/m2. Tumor response was assessed by RECIST and toxicity by NCI-CTC. RESULTS: Thirty males and seven females underwent an average 10 courses of treatment. This therapy achieved a 50% response rate, 80%disease-control rate, and 316+/-40 days PHS. Regarding hematological toxicity, 11 patients (55%) experienced leukemia, which developed to grade 3/4 in 5 (25%) of them. Twelve patients (65%) experienced neutropenia, which developed to grade 3/4 in 10 (50%) of them. Digestive toxicity was observed in 16 patients (80%), which developed to grade 3/4 in only one patient (5%) with gastric ulcer. Six patients (30%) experienced alopecia, which was grade 1/2 only. CONCLUSION: This clinical study was safely carried out. The efficacy was as good as in previous reports using a regular dose of CPT-11.

Intraperitoneal administration of hyperbarically oxygenated perfluorochemical enhances preservation of intestinal mucosa against ischemia/reperfusion injury.

Perfluorochemicals (PFCs) have a high solubility for oxygen. We have previously demonstrated the effect of peritoneal lavage with oxygenated PFC (O2-PFC) on ameliorating ischemia/reperfusion (I/R)-induced intestinal ischemic damage in an animal model. In this study, we applied hyperbarically O2-PFC (HBO-PFC) to investigate whether a larger amount of oxygen carried by PFC could enhance the protective effect of O2-PFC during intestinal malperfusion. Rats were subjected to ischemia by clamping the superior mesenteric artery (SMA) for 90 min. The SMA was then declamped. Rats were divided into four groups. In group A, only anesthesia and abdominal incision were performed. In group B, SMA was clamped without O2-PFC. In group C, during the SMA clamp, 1 atm O2-PFC was injected into the abdominal cavity. In group D, 5 atm O2-PFC (HBO-PFC) was prepared using a custom-made hyperbaric oxygen tank and administered to the abdominal cavity during the SMA clamp. Ileal tissue adenosine triphosphate (ATP) levels 90 min after SMA declamping were determined using luciferase assay. To assess intestinal mucosal barrier function at 90 min after release of the SMA clip, everted gut sacs were prepared to measure the mucosal-to-serosal passage of fluorescein-conjugated dextran (FD4, molecular weight = 4 kDa). Thirty minutes after i.p. administration, partial pressure of oxygen in HBO-PFC remained around 1000 mmHg, whereas partial pressure of oxygen in 1 atm O2-PFC decreased to around 400 mmHg. The intestinal tissue ATP was significantly preserved in group D. Moreover, the mucosal hyperpermeability of the gut sac after I/R was significantly ameliorated in group D. Hyperbarically oxygenated perfluorochemical might supply a larger amount of oxygen to ischemic tissue during SMA clamp, which protected the small intestine from I/R injury, possibly caused by the maintenance of tissue ATP levels during ischemia.