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Background/aim Several studies have reported that DM is closely associated with an increased incidence of hepatocellular carcinoma (HCC). To clarify the effects of diabetes mellitus (DM) and antidiabetic medications on the prognosis of patients with non-B non-C (NBNC) HCC following curative initial hepatectomy. Patients and methods HCC patients (n=156) were divided into three groups according to the presence or absence of chronic viral hepatitis: hepatitis B virus (HBV) group, hepatitis C virus (HCV) group, and NBNC group. The clinical characteristics and survival outcomes were compared. In the NBNC group, univariate and multivariate analyses were conducted to determine prognostic factors. Results The NBNC group had a higher incidence of DM, ethanol intake, and large nodules than the other groups. Disease-free survival (DFS) was significantly worse in the NBNC group than in the HBV group. In the NBNC group, insulin treatment was an independent prognostic factor for DFS and overall survival (OS). Conclusion Medications for DM that affect insulin resistance might be appropriate prognostic factors for NBNC-HCC.

Background/aims Although adhesion formation is a frequent adverse event following intraperitoneal surgery, efficient prophylactic interventions have not yet been established. We recently reported that blockade of interleukin (IL)-6 prevented postoperative adhesion after cecum cauterization. Intriguingly, this intervention dampened tumor necrosis factor (TNF) induction in the injured serosa. Herein, we addressed whether TNF might be a key target and, if so, how TNF blockade rescued adhesion formation. Methods Mice were administered an anti-TNF biologic (etanercept) on days -2 and -1 before and upon cecal cauterization. The adhesion scores were evaluated at day 7 postoperatively. Histological alterations were examined by immunochemistry/immunofluorescence studies. We incubated human neutrophils and mesothelial cell line cells with recombinant TNF in the presence of etanercept and measured transcript levels of cytokines and chemokines by quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Results Etanercept rescued mice from adhesion formation, accompanied by a robust reduction of neutrophilia in the injured serosa. Immunofluorescence revealed a substantial formation of neutrophil extracellular traps (NETs) with the potential to induce tissue damage and profibrotic responses. In contrast, the etanercept-treated mice lacked NET formation. In addition, etanercept inhibited TNF-induced IL-6, TNF, and neutrophil-recruiting chemokines in neutrophils and mesothelial cells, a major cellular source of myofibroblasts in the adhesion band. Conclusion Prophylactic administration of etanercept might be a potential strategy for preventing postoperative adhesion formation.

BACKGROUND/AIM Elevated neutrophil-lymphocyte ratio (NLR) has been reported to be a poor prognostic factor in patients with colorectal cancer (CRC). However, no studies have focused on the dynamic change of preoperative NLR (pre-NLR) in CRC patients. We investigated the prognostic value of the change in NLR (ΔNLR) in CRC patients before and after surgery. PATIENTS AND METHODS We retrospectively analyzed the data from 307 patients with stage II or III CRC. We compared the clinicopathological factors, OS, and DFS among the various NLR factors. RESULTS The 5-year OS rate of the high ΔNLR group was significantly lower than that of the low ΔNLR group (p

Background/aim The high rate of recurrence and repetitive features of hepatocellular carcinoma (HCC) require specific treatment strategies. This study aimed to evaluate the long-term outcomes of recurrent HCC focusing on clinicopathological factors. Patients and methods A total of 104 patients who were treated with re-hepatectomy, radiofrequency ablation (RFA) or transcatheter arterial chemoembolization for recurrent HCC were analyzed. Post-recurrent prognoses were compared between each treatment group based on the presence of adverse prognostic factors (APFs) identified. Results In the hepatectomy group, the prognosis of patients with APFs was significantly worse compared to those without APFs. By contrast, the survival rate of patients who underwent RFA was not significantly different from those with and without APFs. Conclusion Our results demonstrate the heterogeneity that exists in terms of the long-term survival of patients with recurrent HCC. The treatment strategy for recurrent HCC should be based on the assessment of presence of APFs to improve long-term prognosis.

Background/aim The platelet-to-lymphocyte ratio (PLR) has recently been suggested as a new predictor of the prognosis in several carcinoma types. However, the clinical impact remains controversial in patients with ampullary carcinoma. Thus, the aim of this study was to investigate other useful biomarkers for identifying poor prognosis in patients with ampullary carcinoma. Patients and methods Forty-one patients with ampullary carcinoma underwent pancreaticoduodenectomy (PD) with curative resection between April 2000 and April 2017. Various clinicopathological findings of the patients and their tumors were evaluated as potential prognostic factors which might enable better stratification of prognosis. Results Platelet-to-lymphocyte ratio, as well as other markers, was found to be a prognostic factor in patients with ampullary carcinoma. The 2-year disease-free survival percentage was significantly higher in the group with low PLR than in the high PLR group (70.2% vs. 28.6%; p=0.005). Combinational analysis of the PLR and conventional TMs enabled us to stratify prognosis of the patients more clearly than by each marker alone. Conclusion PLR was a useful prognostic factor for patients with ampullary cancer. The combination of preoperative PLR and conventional TMs markers may be powerful predictive factors for postoperative prognosis in patients with ampullary carcinoma following PD.

Objectives The aim was to evaluate the relationship between cytoglobin (Cygb) expression and both clinicopathologic factors and prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Methods Seventy-five patients with PDAC who underwent pancreatectomy between 2009 and 2014 at our department were included. Diagnosis was based on World Health Organization standards, with staging by TNM classification of Union for International Cancer Control. Expressions of Cygb, phosphoinositide-3 kinase, phosphorylated protein kinase B, interleukin-6, and vascular endothelial growth factor were evaluated by immunohistochemical staining of resected surgical specimens and densitometrical analysis. Results Elevated expression of Cygb was found mainly in carcinoma cells of PDAC. Patients with low expression of Cygb showed significantly shorter disease-free survival and disease-specific survival than those with high expression. There was also a significant negative correlation between Cygb expression and the expressions of phosphoinositide 3-kinase, phosphorylated protein kinase B, interleukin-6, and vascular endothelial growth factor. In univariate analysis, Cygb expression, clinical stage, histologic tumor grade, lymphatic invasion, and vascular invasion were prognostic factors. In multivariate analysis, Cygb expression and the clinical stage were independent prognostic factors. Conclusions Loss of Cygb may contribute to tumor recurrence and poor prognosis of PDAC by increases in angiogenic factor.

NADPH oxidases (NOXs) are a family of transmembrane proteins that generate reactive oxygen species. It was previously reported that patients with colon cancer who had high NOX5 expression had poor prognosis. However, no studies have investigated the cellular functions of NOX5 in colon cancer. The present study aimed to clarify the relationship between NOX5 and cancer development using an in vitro model. Reverse transcription‑quantitative PCR was performed to determine the NOX5 expression levels of colon cancer cell lines. NOX5‑knockdown experiments were conducted, and the effect on cell proliferation, migration, and invasion were analyzed. In addition, mRNA microarray was conducted to assess changes in gene profile. NOX5 mRNA expression was high in HCT116 cells and moderate in SW48 cells. NOX5 knockdown significantly inhibited cell migration and invasion in both HCT116 and SW48 cells; however, NOX5 knockdown reduced cell proliferation in only HCT116 cells. mRNA microarrays revealed a strong relationship between NOX5 expression levels and integrin‑linked kinase signaling pathways. The NOX5 expression in colon cancer cells affected cancer progression, especially cell motility. NOX5 may be a novel therapeutic target for the future development of treatments for colon cancer.

Gastric cancers located within the upper-third of the stomach (UGC), especially the esophagogastric junction GC (EGJGC), have distinct clinicopathological features due to their potential for multidirectional lymphatic spread. In this study, we investigated the clinical significance of hiatal hernias (HH) in patients with UGC, including EGJGC. In this retrospective study, we assessed status of HH in 147 patients with UGC who underwent curative resection at our hospital and examined the correlation between the presence of HH (+) and multiple clinicopathological factors. Thirty-four patients (23%) were HH (+). However, we found no significant correlation between HH (+) and clinicopathological factors. HH (+) patients frequently developed lymph node recurrences. Prognosis was significantly better in patients with UGC and HH (−), compared to those with UGC and HH (+). Similarly, EGJGC patients who were HH (−) showed superior survival compared to HH (+) patients. Multivariate analysis found that the HH (+) (p = 0.004), histological type (p = 0.029), and nodal stage (p = 0.034) were independent prognostic factors. The presence of HH might affect lymphatic spread of tumor cells, and consequently prognosis of patients with UGC. Therefore, special attention is needed in developing surgical and postoperative strategies for such patients with UGC who are HH (+).

Background The low accuracy of preoperative diagnosis of lymph node metastasis in gastric cancer (GC) complicates decisions on patient indication for neoadjuvant chemotherapy. Methods We investigated the use of preoperative clinical diagnosis of lymph node involvement (cN) in GC patients compared with postoperative pathological diagnosis. Results In a series of 265 patients enrolled at the University of Yamanashi Hospital, the overall sensitivity was 44.4% and specificity was 93.4% of CT for detecting lymph node metastasis. The positive and negative predictive values were 80.0% and 73.8%, respectively. The negative predictive value was lower for undifferentiated adenocarcinoma than that for differentiated adenocarcinoma (64.9% vs. 78.7%, p = 0.034). In cT2 ≤ and cN2 ≤ GC, overdiagnosis of lymph node metastasis was significantly more frequent in patients with differentiated (50.0%) than in undifferentiated (13.3%) adenocarcinoma (p = 0.046). Conclusions Diagnostic accuracy of lymph node involvement depended on histological type and cT-stage. Thus, considering preoperative histological type in GC, it may be useful to decide treatment plan.

Background/aim Recent studies have reported the involvement of NADPH oxidases (NOXs) in tumor progression. However, the role of NOX5 in colon cancer is unclear. We examined the clinical significance of NOX5 expression in colon cancer. Patients and methods NOX5 expression was evaluated by immunohistochemistry in 119 patients with stage II or III colon cancer, and the relationship between NOX5 expression and clinicopathological data was analyzed. Results Of all tissues, 39.5% were negative and 60.5% were positive for NOX5 expression. Positive expression was significantly associated with undifferentiated histology (p=0.037) and lymph node metastasis (p=0.023). The 5-year progression-free survival rate of NOX5-positive patients was significantly worse than that of NOX5-negative patients (p=0.046). The rates of local recurrence observed in NOX5-positive patients were higher than that in NOX5-negative patients. Conclusion NOX5 expression may be related to poor prognostic factors and could be useful as a prognostic biomarker.

BACKGROUND/AIM Treatment algorithms for primary and recurrent hepatocellular carcinoma (HCC) are described in the current Japanese Clinical Practice Guidelines; however, primary and recurrent tumors exhibit several differences in oncological characteristics such as clinicopathological features and prognostic factors. This study aimed to investigate the prognostic factors for recurrent HCC including time of recurrence after primary hepatectomy, to elucidate appropriate treatment strategies in these patients. PATIENTS AND METHODS One hundred and nine patients who had undergone radical resection of primary HCC at our Hospital and had experienced intrahepatic recurrence were included in this study. Patients were categorized into the early-recurrence (ER

Background/aim The extent of lymph node (LN) dissection is defined according to the type of gastrectomy regardless of tumor location in recent Japanese gastric cancer treatment guidelines. However, lymphatic flow from lower-third stomach mainly drain to supra- and infra-pyloric nodes, as well as to partially lesser curvature nodes along the descending limb of the left gastric artery. In this study, we evaluated the prognostic impact of LN dissection of right paracardial (No. 1) and left greater curvature (No. 4sb) nodes in gastric cancer of lower-third stomach (LGC). Patients and methods A total of 239 patients with LGC who underwent distal gastrectomy at our hospital were retrospectively analyzed. The therapeutic value index (TVI) of each node was calculated by multiplying the incidence of LN metastasis by the 5-year survival rate of patients with metastasis to each nodal station. Results The incidence of No. 1 LN metastasis was 4.5% (positive/negative; 5/110 cases, unknown or no description; 129 cases). The 5-year survival rate of patients with metastasis to the node was 0%, and consequently the TVI of No. 1 LN station was "0". Similarly, the TVI of No. 4sb was found to be "0". Conclusion Survival benefit of dissection of No. 1 and No. 4sb LNs was presumed to be extremely low, suggesting that dissection of these two LNs could be omitted in LGC patients when undergoing distal gastrectomy.

Background/aim Basaloid squamous cell carcinoma of the oesophagus (BSCCE) is a variant of oesophageal squamous cell carcinoma (ESCC), that has a more aggressive biological behaviour than that of typical ESCC. miR-3687 has been previously identified to be highly expressed in BSCCE. This study aimed to evaluate the prognostic impact of miR-3687 in ESCC and determine the role of miR-3687 in ESCC motility. Materials and methods miR-3687 expression in human ESCC cell lines and in primary tumour samples obtained from patients with ESCC who underwent esophagectomy were analyzed via real-time polymerase chain reaction (PCR). Knockdown and over-expression experiments were conducted with miR-3687 siRNA and miRNA mimic, and the effect on cell proliferation, migration, and invasion was analyzed. Results A total of 92 samples were analyzed. High miR-3687 expression was correlated with poor prognosis. miR-3687 upregulation promoted cell migration and invasion. Conclusion miR-3687 expression negatively impacts the prognosis of patients with ESCC.

Background/aim Although perioperative management and operative techniques for pancreatic surgery have improved, postoperative pancreatic fistula (POPF) remains the major cause of morbidity and mortality following distal pancreatectomy (DP). The purpose of this study was to evaluate the superiority of the reinforced stapler compared to the bare triple row stapler. Patients and methods A total of 93 patients who underwent DP at the First Department of Surgery at Yamanashi University were examined. The patients were divided into two groups according to the closure method for the pancreatic stump; the bare triple-row stapler (BTRS) group and the reinforced triple-row stapler (RTRS) group. The postoperative outcomes were then compared in terms of several clinicopathological factors between the two groups. Results Seven patients were diagnosed with Grade B/C POPF in this series. The incidence of POPF in the RTRS group was lower than that in the BTRS group (3.6% vs. 13.5%), although there was no significant difference (p=0.077). Further detailed analysis demonstrated that RTRS significantly reduced POPF compared to BTRS in obese patients with a BMI >25.0 kg/m2 (p=0.038). Conclusion Reinforced triple-row staplers may reduce the incidence of severe POPF, especially in obese patients with a BMI >25 kg/m2.

Background/aim Nab-paclitaxel plus gemcitabine (nab-P+Gem) is one of most reliable and effective regimens for borderline or unresectable pancreatic cancer (PC). However, the feasibility and clinical benefits of this regimen have never been evaluated for patients with recurrent PC after pancreatectomy. The aim of this study was to investigate the feasibility of combination therapy with nab-paclitaxel plus gemcitabine (nab-P+Gem) for patients with recurrent PC. Patients and methods Twenty-two patients with recurrent PC received an intravenous infusion of nab-P (125 mg/m2) and Gem (1,000 mg/m2) on days 1, 8, and 15 of a 4-week cycle. The primary end-point of this study was completion of the 4 cycles. The secondary end-points were the safety, efficacy, and disease control rate. Results The treatment completion rate of the 4 cycles was 90.9%. The objective response rate was 13.6% and the disease control rate was 63.6%. The median progression-free survival was 7.2 months. The most common grade 3 or higher hematological toxicity was neutropenia (72.7%). There was no treatment-related death. Furthermore, the chemotherapeutic effects varied with the time of recurrence. Conclusion Combination nab-P+Gem therapy was well-tolerated and effective in patients with recurrent PC.

Background Disseminated intravascular coagulation (DIC) is associated with high mortality in patients with severe sepsis. The purpose of this study was to investigate the effects of recombinant human thrombomodulin (rhTM) in septic patients undergoing continuous hemodiafiltration (CHDF). Furthermore, effects of rhTM in acute lung injury, the first target organ in sepsis, was investigated using a sepsis model in rats. Methods Clinical laboratory data, and the DIC, Sequential Organ Failure Assessment (SOFA), and Acute Physiologic and Chronic Health Evaluation (APACHE) II scores were compared between patients undergoing CHDF alone (rhTM- group; n = 23 cases) and patients undergoing CHDF treated with rhTM (rhTM+ group; n = 21 cases). Rats underwent cecal ligation and puncture (CLP) treated with or without rhTM, and acute lung injury (ALI) was analyzed. Production of TNF-α by isolated tissue macrophages (Mfs) was assessed. Results The numbers of leukocytes, and C-reactive protein and D-dimer levels were significantly suppressed, and platelet counts recovered significantly faster in the rhTM+ group compared with the rhTM- group. The DIC score was reduced in both groups. The SOFA and APACHE II scores gradually reduced in the rhTM+ group. The CHDF treatment and ICU admission periods were shortened in the rhTM+ group compared with the rhTM- group. Treatment of rhTM was an independent factor for CHDF treatment period by multivariate analyses. CLP-induced ALI was significantly improved by rhTM. Increased TNF-α production by tissue Mfs was significantly suppressed by rhTM in vivo and in vitro. Conclusion Additive effects of rhTM treatment were observed in septic patients undergoing CHDF.

The clinical significance of lymph node micrometastasis (LNMM) remains controversial in gastric cancer (GC). In this study, we investigated the prognostic impact of LNMM in patients with GC. A total of 624 patients with pathologically lymph node metastasis-negative (pN0) and N1 status (pN1) who underwent gastrectomy between 2004 and 2018 were enrolled in this retrospective study. The diameter of tumor cell clusters in metastatic lymph nodes was measured in 120 patients with pN1 GC. Patients with lymph node tumors

50's man who have performed anterior pelvic exenteration with lateral lymph node dissection for rectal cancer with pT4bN0M0, pStage Ⅱc about 2 years ago, was admitted to our hospital for the treatment of intrapelvic recurrence of rectal cancer. No distant metastasis was found in the computed tomography examination but the tumor invaded the dorsal side of the pubis. Because radical excision was impossible with these findings, he received chemoradiotherapy(CRT). Post-CRT imaging showed that the tumor of intrapelvic recurrence region reduced the size, and invasion of pubis had disappeared and been markedly reduced. Thus, radical excision seemed possible at this point, and we decided to attempt operation after total 6 weeks of S-1(120 mg/day)regimen and radiation(40 Gy/20 Fr). We performed Miles' operation. The final pathological examination demonstrated that no viable tumor cells remained in the resected rectum specimen, confirming that a pathological complete response(pCR)had been achieved.

BACKGROUND/AIM We aimed to evaluate the correlation between stroke volume variation (SVV) and intraoperative blood loss (IBL) in hepatocellular carcinoma (HCC) resection and examine the perioperative utility of SVV-based management. PATIENTS AND METHODS Ninety-five patients who underwent partial or sub-segmental hepatectomy for HCC between 2013 and 2019 at the University of Yamanashi Hospital were retrospectively analyzed. A correlation analysis between IBL and SVV was performed, and then all cases were divided into three groups: high, middle, and low-SVV groups. Perioperative short-term outcomes based on SVV groups were analyzed. RESULTS There was a weak but significant negative correlation between SVV and IBL (ρ=-0.372, p

Among several noninvasive evaluation methods of portal hypertension (PH), the measurement of spleen stiffness is a reliable method for predicting esophageal variceal bleeding; however, the underlying mechanisms for increased stiffness remain unclear. We attempted to elucidate the pathological changes to the spleen and the underlying mechanisms in patients with PH.Histological examination was performed using splenic tissues from 42 patients with PH who underwent laparoscopic splenectomy, and the results were compared with those from patients without PH.In addition to splenic sinus congestion, diffuse fibrosis was detected in the splenic cords in the red pulp of patients with PH. The degree of the fibrosis was well correlated with severity in thrombocytopenia and splenomegaly. Cells expressing α-smooth muscle actin dramatically increased in the splenic cord. Cytoglobin (Cygb) expression was detected in human splenic cords as reported in animal reticular cells, and fluorescent double immunostaining revealed that these cells expressed α-smooth muscle actin in patients with PH, suggesting transformation of Cygb-expressing cells to myofibroblastic cells. Expression levels of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 2, nitrotyrosine, and transforming growth factor-β were markedly upregulated in the red pulp of patients with PH, implying a significant role of oxidative stress in the mechanism for splenic fibrosis.Splenic fibrosis progresses along with advancement of PH. Cygb-expressing cells in the splenic cord possibly participate in this process through mechanisms including oxidative stress.

A man in his 70s was admitted to our hospital for the treatment of gastric cancer type 3 located in the antrum of the stomach. Computed tomography revealed tumor invasion of the liver and metastatic lymph node invasion of the pancreatic head and splenic artery. The patient was diagnosed with unresectable T4bN3M0, Stage ⅢC advanced gastric cancer. As radical excision was impossible, the patient underwent chemotherapy with S-1 and oxaliplatin(SOX). After 13 courses of SOX, imaging showed reduction in the size of the primary tumor and disappearance or marked reduction in the size of the metastatic lymph nodes. Therefore, conversion surgery was attempted after 14 courses of SOX. Distal gastrectomy with D2 lymphadenectomy including station 14v was performed. Pathological examination demonstrated no viable tumor cells in the resected stomach specimen or dissected lymph nodes, confirming that a pathologic complete response(pCR)had been achieved.

BackgroundThe indications for extrahepatic bile duct (EHBD) resection remain a major controversy in the surgical management of patients with gallbladder cancer. On the other hand, perineural invasion (PNI) was reported as an important factor in patients with gallbladder cancer because gallbladder cancer cells frequently spread to the tissues surrounding the EHBD via perineural routes. We assessed the correlation of PNI with clinicopathological factors in patients with gallbladder cancer to elucidate EHBD resection indications specifically in patients with PNI.MethodsThis retrospective study assessed the PNI status of 50 patients with gallbladder cancer who underwent curative resection and examined the correlation between the presence of PNI and clinicopathological factors.ResultsThirteen patients (26%) were PNI positive. PNI was significantly correlated with male sex, proximal-type tumor, lymphatic and vascular invasion, and advanced T stage. Multivariate analysis found that PNI positivity (p< 0.001), lymphatic invasion (p= 0.007), and nodal stage (p< 0.001) were independent prognostic factors. PNI was never observed in patients with stage T1 cancer. Conversely, PNI was detected rarely in distal-type tumors, all of whom developed various types of recurrences.ConclusionsThese results clearly demonstrated the prognostic impact of PNI in patients with gallbladder cancer. We suggest that EHBD resection in combination with cholecystectomy may not be useful for distal-type tumors from a perspective of PNI.

Objectives Nutritional status significantly influences postoperative prognosis in gastrointestinal cancers. It has been evaluated using sarcopenia before treatments such as surgery and chemotherapy, despite constant changes in nutritional status. We consider that nutritional status at cancer recurrence is one of the important factors that affect treatment choice and intensity. This study evaluated the prognostic effects of improved postoperative nutritional status for people with colorectal cancer recurrence. Methods We enrolled 209 participants with pathologically confirmed stage II or III colorectal cancer who underwent radical resection. Sarcopenia was diagnosed using the psoas muscle index obtained from analysis of three-dimensional computed tomographic images. We adopted the cutoff value that was proposed by Hamaguchi et al. (psoas muscle index Results Among the 209 participants, 81 (38.8%) had preoperative sarcopenia; this group had significantly lower overall survival than those without sarcopenia (P = 0.028). Colorectal cancer recurred in 48 participants. Of those 46, sarcopenia was evaluated at the time of recurrence; 19 of those 46 had preoperative sarcopenia. Preoperative sarcopenia did not affect the cancer recurrence ratio (sarcopenia, 23.5%; non-sarcopenia, 21.3%; P = 0.893). The sarcopenia-improvement group had higher overall survival than the sarcopenia-continuation group (P = 0.042). Conclusions Among participants with preoperative sarcopenia, the prognosis at the time of recurrence improved for the sarcopenia-improvement group compared to the sarcopenia-continuation group. In people with colorectal cancer and sarcopenia, nutritional management is important not only before but also after surgery.

Some studies reported that the decrease in skeletal muscle mass worsens the immune and nutritional status and related to the poor prognosis in colorectal cancer. We examined the relationship of skeletal muscle mass, immune and nutritional index, and outcome in patients with colorectal cancer at our hospital.We retrospectively analyzed 196 patients of cStageⅡ andⅢ colorectal cancer who underwent curative surgery in our institution between 2007 and 2013. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on preoperative computed tomography was assessed to calculate the psoas muscle index(PMI). Patients are divided into high PMIgroup(H-group)and low PMIgroup (L-group)with cut off value(6.36 cm / / 2/m2 for males and 3.92 cm2/m2 for females). Patient background, tumor factor, overall survival(OS), recurrence free survival(RFS)were examined retrospectively.There were 119 cases in H-group and 77 cases in L-group. Significant differences were recognized in gender, age, Alb value, BMI, and adjuvant chemotherapy between 2 groups. The 5-year survival rate was significantly different from 82.8% in H-group and 70.3% in L-group(p0.01). The 5-year recurrence-free survival rate was 74.0%in the H-group, and 68.3%in the L-group (p=0.46). Univariate and multivariate analysis showed that age(OR: 1.90, p0.01), high CEA(OR: 0.012, p0.05), depth of invasion(OR: 2.19, p0.05), lymph node metastasis(OR: 2.21, p0.01), and preoperative low PMI(OR: 2.05, p0.01), were significantly related to decrease of OS.Preoperative PMIsuggested to become prognostic factors in Stage Ⅱ and Ⅲ colorectal cancer.

Basaloid squamous cell carcinoma of the oesophagus (BSCCE) has poorer prognosis than conventional oesophageal squamous cell carcinoma (ESCC). This study is the first report on highly expressed miRNAs in BSCCE and their target genes.BSCCE and ESCC patients who underwent esophagectomy were selected for this study. Total RNA was extracted from formalin-fixed paraffin-embedded blocks to examine expression of miRNAs and target genes. miRNA mimic or inhibitor transfected cells were used in validation experiments. miRNA and mRNA quantification were performed by quantitative reverse transcription polymerase chain reaction (qRT-PCR).miRNA microarray analysis revealed four candidate miRNAs. Further investigations including cell line experiments demonstrated that miR-3687 was a candidate miRNA and progesterone receptor membrane component2 (PGRMC2) was its target gene. PGRMC2 was found to be related to cell proliferation and local progression.miR-3687 may be a candidate miRNA conferring BSCCE aggressiveness, and PGRMC2 is one of its target genes.

Cholestatic liver injury leads to liver dysfunction. The available evidence suggests that platelets can either promote or reduce liver injury and fibrosis. This study focused on the functions of the C-type lectin-like receptor 2 (CLEC-2), a new special platelet receptor that binds with podoplanin-activating platelets. The role of CLEC-2 and podoplanin in cholestatic liver injury was investigated. Mice were injected intraperitoneally with weekly doses of anti-CLEC-2 antibody (2A2B10) to achieve effective CLEC-2 inhibition in their platelets. Next, left and middle hepatic bile duct ligation (BDL) procedures were performed, and mice were euthanized 1 week later (2A2B10-BDL group). In addition, mice were prepared for control groups, and relevant histological and laboratory variables were compared among these groups. The inhibition of CLEC-2 resulted in increasing hepatocellular necrosis, hepatic inflammation, and liver fibrosis. In addition, podoplanin was strongly expressed in hepatic sinusoidal endothelial cells in BDL-treated mice. Moreover, in 2A2B10-BDL mice, total plasma bile acid levels were significantly increased. In summary, podoplanin is expressed on hepatic sinusoidal endothelial cells upon BDL. Platelets bind with podoplanin via CLEC-2 and become activated. As a result, the total bile acid pool is decreased. Therefore, the CLEC-2-podoplanin interaction promotes liver protection and inhibits liver fibrosis after cholestatic liver injury.

Background and purpose Approximately 20% of all patients with colorectal cancer (CRC) are diagnosed at more advanced stages with synchronous distant metastasis, and the prognosis in these patients is usually poor. The aim of this study was to determine the factors that can identify subgroup(s) of patients with stage IV CRC who could benefit from curative (R0) resection of both primary and metastatic lesions. Patients and methods A total of 126 patients with stage IV CRC who underwent surgical resection of primary tumor were retrospectively analyzed. Among these patients, 26 cases of R0 resection were further examined subsequently. Information on various clinicopathological factors of the patients were obtained from hospital records. Overall survival was estimated using the Kaplan-Meier method, and log-rank tests were used to compare survival distribution. All the factors with P

α‑Fetoprotein (AFP)‑producing gastric cancer (AFPGC) is recognized as one of the most aggressive tumors with subsequent poor prognosis compared with common gastric cancer (GC) subtypes. However, the molecular mechanism remains to be elucidated. We previously identified that miR‑122‑5p could be a useful biomarker in AFPGC patients. We examined herein the biological function of miR‑122‑5p and the molecular mechanism underlying tumor progression in AFPGC. We used the AFPGC cell line (FU97) and miR‑122‑5p inhibitor to examine the function of miR‑122‑5p. Moreover, we investigated the possible targets of miR‑122‑5p. The expression level of miR‑122‑5p was significantly increased in the FU97 cell line than in common GC cell lines. Also, suppression of miR‑122‑5p significantly reduced AFP levels and proliferation in AFPGC through an induction of apoptosis. Western blotting revealed that the expression of anti‑apoptotic protein (Bcl‑2) was decreased and that of pro‑apoptotic protein (caspase‑3) was increased in miR‑122‑5p suppression of FU97. Moreover, we revealed that FOXO3 was an important target of miR‑122‑5p in AFPGC, which inhibited apoptosis and subsequently manifested aggressiveness. In conclusion, miR‑122‑5p inhibited apoptosis and facilitated tumor progression by targeting FOXO3 in AFPGC, which indicates the possibility of miR‑122‑5p as a potential therapeutic target in AFPGC.

Sialylation in Fc portion of IgG plays a crucial role in the pathogenesis of autoimmune diseases and the working mechanism of intravenous immunoglobulin (IVIG). We aim to test whether IgG-Fc sialylation is a biomarker of disease activity for chronic inflammatory demyelinating polyneuropathy (CIDP).By using specific lectins for sialylation, galactosylation and agalactosylation, lectin-enzyme assay and lectin blotting with pretreatment of IgG degradating enzyme of Streptococcus pyogenes were performed to compare the glycosylation levels of serum IgG-Fc (1) between patients of untreated CIDP (n=107) and normal control subjects (n=27), (2) among patients with untreated CIDP of different clinical severities and (3) before and after IVIG treatment of patients with CIDP (n=12).Sialylation and galactosylation of IgG-Fc were significantly reduced in patients with CIDP than normal control subjects (p=0.003 and 0.033, respectively), whereas agalactosylation was increased in CIDP (p=0.21). Ratios of sialylated/agalactosylated IgG-Fc levels were significantly reduced in CIDP (p0.001) and inversely related to disease severity (p=0.044). After IVIG treatment, levels of sialylated IgG-Fc significantly increased (p=0.003).Sialylation of IgG-Fc is reduced in CIDP. Its level correlated with clinical severity and increased after IVIG treatment. Sialylated as well as ratio of sialylated/agalactosylated IgG-Fc could be new measures to monitor the disease severity and treatment status in CIDP.

Polymorphisms of interleukin-1 (IL-1) genes have been reported to modify the risk of gastric carcinoma (GC) in Caucasians. The significance of IL-1β gene polymorphisms was evaluated in Japanese GC patients with or without infection of Helicobacter pylori and Epstein Barr virus (EBV) with special reference to the topographic features of GC. IL-1β gene polymorphisms at positions -511 and +3953 were evaluated by PCR-RFLP and a penta-allelic polymorphism of IL-1RA by PCR in healthy controls (n = 103) and GC (n =140; corpus 95, antrum 45). EBV-infection was determined in the neoplastic tissues by EBER1 in situ hybridization, and H. pylori infection in nonneoplastic gastric mucosa by PCR targeting of the H. pylori urease A gene. GC consisted of EBV-associated (n = 24) and EBV-negative (n = 116) patients, whereas H. pylori infection was positive in 130 cases. Among IL-1β gene polymorphisms, genotype IL-1β+3953 C/T was more frequent in the EBV-negative (21%) and corpus GC (23%) patients, compared to the controls (10%), respectively, although there was no genotype IL-1β+3953 T/T in either group. Thus, the effect of IL-1β+3953 T was statistically significant in logistic regression models adjusted for age in EBV negativity (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.02–5.05) and in the corpus GC (2.70, 1.19–6.12) with highest OR 3.55 (1.54–8.23) in EBV-negative corpus GC. There was no significant influence of IL-1 gene polymorphism in EBV-associated GC, but it occurred predominantly in the corpus (24/24) compared to EBV-negative GC (71/116) (p = 0.00002). There was no correlation between H. pylori infection and IL-1 gene polymorphism in GC. The cancer risk of the gastric corpus in Japanese is influenced by IL-1β+3953 polymorphisms. On the other hand, the risk of EBV-associated GC, which occurs predominantly in the corpus, is not influenced by this pro-inflammatory polymorphism. © 2005 Wiley-Liss, Inc.

Topical application of mustard oil (allyl isothiocyanate) to the skin or injection into joints induces hyperalgesia, allodynia, and neuroinflammation. However, when applied to the oral or nasal mucosa, mustard oil evokes a desensitizing pattern of irritation. Presently we investigated the responses of neurons in superficial laminae of trigeminal subnucleus caudalis (Vc) to noxious thermal (53 degrees C) and chemical (pentanoic acid; 200 mM) stimuli prior to and following lingual mustard oil application. A low concentration of mustard oil (0.125%) applied by constant flow (0.5 ml/min; 15 min), initially excited Vc neurons followed by partial desensitization. Responses to noxious heat were unchanged following mustard oil. A high concentration of mustard oil (1.25%) initially excited Vc neurons followed quickly (within 20 s) by nearly complete desensitization. The desensitization was transient since reapplication of mustard oil approximately 20 min later elicited a comparable response that also rapidly desensitized. Mustard oil also transiently cross-desensitized Vc responses to pentanoic acid (to 52%), in striking contrast to noxious heat-evoked responses which were significantly sensitized to approximately 160% of pre-mustard oil levels. The data suggest that the effect of mustard oil on subsequent lingual nociceptive responses is concentration dependent, transient, and modality specific.

Promoter hypermethylation of various tumor-related genes is extremely frequent in gastric carcinoma (GC) associated with Epstein-Barr virus (EBV). To investigate the significance of the promoter methylation in this type of GC, we examined the methylation densities of the promoter regions of p14ARF and p16INK4A in EBV-associated (n=7) and EBV-negative (n=14) GC. Bisulfite sequencing demonstrated a high frequency of concurrent methylation of p14ARF and p16INK4A promoter regions in EBVaGC. Methylation was observed in all 29 CpG sites of p14ARF and all 16 sites of p16INK4A with equally high densities. In EBV-negative GC, the methylation profiles differed between the 2 genes. Promoter methylation was sporadic and variable in p14ARF, and only the last position of CpG in p14ARF was methylated at high frequency. High-density methylation in p16INK4A was observed in a subset of GC, but the first position of CpG was never methylated in EBV-negative GC. These findings suggest the presence of mechanisms of de novo and maintenance methylation specific to EBVaGC that might be associated with EBV infection.

We investigated the possible role of amiloride-sensitive ion channels of the ENaC/DEGenerin superfamily in the activation of trigeminal nociceptive neurons elicited by noxious chemical stimulation of the oral mucosa using two methodologies, single-unit recording and c-fos immunohistochemistry. In pentobarbital-anesthetized rats, single-unit recordings were made from neurons in superficial laminae of dorsomedial trigeminal subnucleus caudalis (Vc) that responded to noxious thermal and chemical stimuli applied to the dorsal tongue. Successive application of each of three chemicals (250 mM pentanoic acid, n=6 units; 250 mM citric acid, n=8; 5 M NaCl, n=6) evoked responses that were not affected following topical application of amiloride (1 mM). In separate experiments, pentobarbital-anesthetized rats received one of the following stimuli delivered to the dorsal tongue: 250 mM pentanoic acid (n=6); 1 mM amiloride followed by 250 mM pentanoic (N=6); 5 M NaCl (n=5); or 1 mM amiloride followed by 5 M NaCl (n=5). Two hours later they were perfused with 4% paraformaldehyde and the brain stems processed for c-fos immunoreactivity. Both pentanoic acid and 5 M NaCl evoked similar numbers and patterns of fos-like immunoreactivity (FLI) in dorsomedial Vc and other brain stem regions, with no significant difference in counts of FLI in animals pretreated with amiloride. These results suggest that amiloride-sensitive Na(+) channels are not essential in mediating the activation of intraoral trigeminal nociceptors.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinoma (GC), which is considered to develop in a different pathway from EBV-negative GC. To evaluate a possible role of p16, an inhibitor of G1/S transition of the cell cycle, in the carcinogenesis of EBVaGC, p16-immunohistochemistry and methylation-specific PCR analysis (MSP) were applied to surgically resected gastric carcinomas. When the percentage of p16-positive cells in more than 1000 carcinoma cells was expressed as p16 labeling index (p16-LI), it ranged from 2.5 to 88.1 (mean 42.9+/-24.4) in 70 gastric carcinomas. EBVaGC showed significantly lower values (n=15, 26.1+/ -22.1) than EBV-negative GC (n=55, 47.5+/-23.2) (P=0.0036). Fresh frozen tissues of 55 gastric carcinomas (16 EBVaGC and 39 EBV-negative GC) were further subjected to MSP, to evaluate abnormal methylation of the promoter region of the p16 gene. The frequency of methylation was significantly higher in EBVaGC (14/16) than in EBV-negative GC (9/39) (

In human studies, repeated intraoral application of strong acidic or salt stimuli induces irritation that progressively increases across trials (sensitization), whereas irritation elicited by nicotine progressively decreases (desensitization). We investigated whether nociceptive neurons in trigeminal subnucleus caudalis (Vc) exhibit increasing or decreasing patterns of firing to the intraoral application of these irritants. In rats anesthetized with halothane and thiopental, single-unit recordings were made from nociceptive neurons in superficial layers of dorsomedial Vc that responded to mechanical and noxious thermal and chemical stimulation of the tongue. NaCl (5M), citric acid (300 mM), pentanoic acid (300 mM) or nicotine (600 mM) were separately delivered to the tongue by constant flow (0.32 ml/min) for 15 or 25 min. NaCl, citric acid and pentanoic acid each elicited a progressive, significant increase in Vc neuronal firing over the initial 10 min to a plateau level that was maintained for the stimulus duration. Nicotine induced a significant increase in firing rate of Vc neurons within 6 min, followed by a decline back to the baseline level over the ensuing 10 min. Following a rest period, reapplication of nicotine no longer activated Vc neurons, indicative of self-desensitization. We additionally tested for nicotine cross-desensitization to acid. After recording the responses of Vc neurons to pentanoic acid and noxious heat, nicotine was then applied for 15 min. Post-nicotine responses to pentanoic acid were markedly reduced (to 13% of control), indicative of cross-desensitization; responses to noxious heat were also reduced to a lesser degree (to 71% of control). The progressive increase in Vc neuronal firing elicited by NaCl and acid, and the decline in firing after initial nicotinic excitation, resemble psychophysical patterns of sensitization and desensitization, respectively, and support the involvement of Vc neurons in the signaling of oral irritant sensations.

A patient, who developed an amyotrophic lateral sclerosis-like disorder subsequent to ganglioside treatment, had IgM antibodies to GM2 as well as to minor gangliosides X1 and X2 containing GM2 epitope. These gangliosides as well as GM1 were tested in 655 sera obtained from patients who were suspected of having amyotrophic lateral sclerosis or motor neuron disease to find a treatable condition. Three patients had high titers of IgG anti-GM1 antibodies, but no IgM anti-GM1 antibodies. One of the patients also had IgG anti-X2 antibodies. The patients, being diagnosed with having lower motor neuron syndrome, had neither upper motor neuron signs nor multifocal conduction block. Both IgM and IgG anti-GM1 antibodies should be tested in patients who have lower motor neuron syndrome.

Background: We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Methods: The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed. Results: KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation. Conclusions: Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

A one-year-and-ten-months-old male infant with Arima syndrome, a very rare genetic disorder, underwent urgent insertion of a catheter for continuous ambulatory peritoneal dialysis (CAPD) under general anaesthesia. During the procedure he showed QRS-interval changes caused by hyperkalaemia which was successfully treated with calcium gluconate. The management and intraoperative complications of this syndrome are reported and available literature reviewed.

To clarify the significance of p73 in Epstein-Barr virus (EBV)-associated gastric carcinoma (GC), the immunohistochemical expression and CpG-island methylation of p73 were evaluated in cancer tissues and adjacent nonneoplastic tissues of GC with and without EBV infection. Loss of p73 expression by immunohistochemistry was specific to EBV-associated GC (11/13) compared to EBV-negative GC (3/38), which was independent of abnormal p53 expression. With methylation-specific polymerase chain reaction (MSP), the aberrant methylation of p73 exon 1 was similarly specific to EBV-associated GC (12/13), and also rare in EBV-negative GC (2/38). Bisulfite sequencing for p73 exon 1 and its 5' region confirmed the MSP results, showing uniform and high-density methylation in EBV-associated GC. Comparative MSP analysis of p14, p16 and p73 methylation, using 20 cases each of formalin-fixed and paraffin-embedded tissues of early GC with and without EBV infection, confirmed 2 types of methylation: global methylation with increased rates (p14 and p16) and specific methylation of p73 in EBV-associated GC. In nonneoplastic mucosa, p14, p16 and p73 methylation occurred in both EBV-associated (8/33, 6/34 and 3/38, respectively) and EBV-negative GC (6/23, 4/35, and 1/35). p73 methylation was observed in the mucosa without H. pylori infection in all 4 samples. Loss of p73 expression through aberrant methylation of the p73 promoter occurs specifically in EBV-associated GC, together with the global methylation of p14 and p16. A specific type of gastritis, prone to a higher grade of atrophy and p73 methylation, may facilitate the development of EBV-associated GC.

Epstein-Barr-virus-associated gastric carcinoma (EBVaGC) is a distinct subset of gastric carcinoma (GC). The expressions of cytokeratins (CK)7, 8, 18, 19 and 20 and truncated basic hair keratin 1 (hHb1-deltaN) were investigated in GC to clarify the characteristics of EBVaGC.For immunohistochemical evaluation, 173 GC tissues were examined and 31 GC tissues and 5 GC cell lines were used for quantitative real-time RT-PCR (qrt-RT-PCR) and RT-PCR.EBVaGC showed significantly lower immunohistochemical positivity of CK7 (-/(+/-)/+/+ +/+ + +; 27/15/4/1/1) compared to EBV-negative GC (12/29/27/44/13), even after stratification by histological types. The qrt-RT-PCR test demonstrated decreased amounts of CK7, 18 and 19 mRNAs in EBVaGC. Two among 5 GC cell lines showed a decrease of CK7 mRNA level after recombinant EBV infection. hHb1-deltaN expression was not specific to EBVaGC.Abnormalities of CK7, 18 and 19 expressions, especially a decreased amount of CK7 expression, are characteristics of EBV-associated epithelial malignancies and might be important in carcinogenesis.

Promoter hypermethylation of various tumor-related genes is extremely frequent in Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To investigate the significance of the promoter methylation in EBVaGC, we focused on one of the important proteins in the carcinogenesis of the stomach, E-cadherin. Methylation-specific PCR analysis (MSP) was applied to surgically resected gastric carcinomas, together with immunohistochemistry, PCR-based analysis of mutations and allelic loss, and site-specific MSP of E-cadherin gene. By MSP, nearly all of the carcinomas showed aberrant methylation of E-cadherin promoter in EBVaGC (21/22), and the frequency of this aberration was significantly higher than that in EBV-negative gastric carcinoma (GC; 45/81; p = 0.0003). According to immunohistochemistry of E-cadherin, the frequency of abnormal staining pattern in EBVaGC (87%) was comparable to that in the diffuse type (80%), but higher than that in the intestinal type of EBV-negative GC (47%). Promoter methylation was well correlated with abnormal staining pattern in EBVaGC, but not in EBV-negative GC. Neither mutation nor allelic loss of E-cadherin was observed in EBVaGC. Methylation status of E-cadherin within each carcinoma was heterogeneous as far as examined. Thus, in addition to the known association involving p16, we determined that promoter methylation-mediated silencing of E-cadherin gene was also closely associated with the development of EBVaGC, although it becomes heterogeneous within a given tumor along its progression.

A 49-year-old man developed severe headache after spinal anesthesia. We found diffuse meningeal enhancement on gadolinium enhanced MRI and diffuse meningeal thickening on plain MRI. These MRI findings and postural headache suggest intracranial hypotension. Injection of autologous blood 10 ml into his epidural space was effective to ameliorate the headache. MRI findings were useful for the diagnosis of postspinal headache.

DNA hypermethylation may play a primary role in the genesis of Epstein-Barr virus (EBV)-associated gastric carcinoma (GC) (EBVaGC). Methylation-specific PCR targeting CpG-islands demonstrated markedly increased methylation of specific genes, such as p14, p15 and p16 genes, in EBVaGC in vivo. A high frequency of methylation was observed in an EBVaGC strain of severe combined immunodeficiency mice, and the expression of methylated genes in the strain was apparently lower than the expression of the unmethylated genes in EBV-negative GC strains. Although over-expression of DNA methyltransferases (DNMTs) is known to be associated with some human cancers, real-time PCR demonstrated that DNMTs expression was suppressed in EBVaGC. The DNA methylation of specific genes, independently of DNMTs expression, may be important in the development of EBVaGC.

UNLABELLED Electroconvulsive therapy provokes abrupt changes in both systemic and cerebral hemodynamics. An anesthetic that has a minor effect on cerebral hemodynamics might be more suitable for patients with intracranial complications, such as cerebral aneurysm. The purpose of our present study was to compare the effects of thiopental and propofol on cerebral blood flow velocity. We continuously compared cerebral blood flow velocity at the middle cerebral artery (MCA) during electroconvulsive therapy, using propofol (1 mg/kg, n = 20) versus thiopental (2 mg/kg, n = 20) anesthesia. Systemic hemodynamic variables and flow velocity at the MCA were measured until 10 min after the electrical shock. Heart rate and arterial blood pressure increased in the thiopental group until 5 min after the electrical shock. In the propofol group, an increase in mean blood pressure was observed to 1 min after the electrical shock. Mean flow velocity at the MCA decreased after anesthesia in both groups, and increased at 0.5-3 min after the electrical shock in the thiopental group and at 0.5 and 1 min after the shock in the propofol group. The flow velocities at 0.5-5 min after the electrical shock were significantly more rapid in the thiopental group compared with the propofol group. ?abs? IMPLICATIONS Cerebral blood flow velocity change, measured by transcranial Doppler sonography during electroconvulsive therapy, was minor using propofol anesthesia compared with barbiturate anesthesia. Propofol anesthesia may be suitable for patients who cannot tolerate abrupt cerebral hemodynamic change.

Anesthetics such as isoflurane act in the spinal cord to suppress movement in response to noxious stimulation. Spinal anesthesia decreases hypnotic/sedative requirements, possibly by decreasing afferent transmission of stimuli. We hypothesized that isoflurane action in the spinal cord would similarly depress the ascending transmission of noxious input to the thalamus and cerebral cortex. In six isoflurane-anesthetized goats, we measured electroencephalographic (EEG) and thalamic single-unit responses to a clamp applied to the forelimb. Cranial bypass permitted differential isoflurane delivery to the torso and cranial circulations. When the cranial-torso isoflurane combination was 1.3% +/- 0.2%-1.0% +/- 0.4% the noxious stimulus did not evoke significant changes in the EEG or thalamic activity: 389 (153-544) to 581 (172-726) impulses/min, (median, 25th-75th percentile range, P:0.05). When the cranial-torso isoflurane combination was 1.3% +/- 0.2%-0.3% +/- 0.2%, noxious stimulation increased thalamic activity: 804 (366-1162) to 1124 (766-1865) impulses/min (P:0.05), and the EEG "desynchronized": total EEG power decreased from 25 +/- 20 microV(2) to 12 +/- 8 microV(2) (P:0.05). When the cranial-torso isoflurane was 1.7% +/- 0.1%-0.3% +/- 0.2%, the noxious stimulus did not significantly affect thalamic: 576 (187-738) to 1031 (340-1442) impulses/min (P:0.05), or EEG activity. The indirect torso effect of isoflurane on evoked EEG total power (12.6 +/- 2.7 microV(2)/vol%, mean +/- SE) was quantitatively similar to the direct cranial effect (17.7 +/- 3.0 microV(2)/vol%; P:0.05). These data suggest that isoflurane acts in the spinal cord to blunt the transmission of noxious inputs to the thalamus and cerebral cortex, and thus might indirectly contribute to anesthetic endpoints such as amnesia and unconsciousness.Isoflurane action in the spinal cord diminished the transmission of noxious input to the brain. Because memory and consciousness are likely dependent on the "arousal" state of the brain, this indirect action of isoflurane could contribute to anesthetic-induced amnesia and unconsciousness.

Repeated application of capsaicin at a 1-min interstimulus interval (ISI) to the tongue induces a progressively increasing irritant sensation (sensitization), followed after a rest period by reduced sensitivity to further capsaicin (desensitization). Sequential reapplication of capsaicin induces irritation that eventually increases to initial levels: stimulus-induced recovery (SIR). In contrast, repeated application of nicotine elicits a declining irritant sensation across trials. To investigate possible neural correlates of these phenomena, we recorded from single units in superficial laminae of the dorsomedial trigeminal subnucleus caudalis (Vc) that responded to noxious thermal (54°C) and chemical (1 M pentanoic acid) stimulation of the tongue of anesthetized rats. We then recorded responses to either capsaicin (330 μM) or nicotine (0.6 M), delivered either once, repeatedly at 1-min ISI, or continually by constant flow. After the initial capsaicin application and a rest period, the capsaicin was reapplied in the identical manner to test for SIR. The mean response of 14 Vc units to sequential application of pentanoic acid did not vary significantly across trials, indicating lack of tachyphylaxis or sensitization. The averaged response of 11 Vc units to repeated capsaicin increased significantly across the first eight trials and then plateaued. Following the rest period, spontaneous firing had returned to the precapsaicin level. With capsaicin reapplication, the averaged response increased again after a significant delay (due to desensitization), but did not reattain the peak firing rate achieved in the initial series (partial SIR). Constant-flow application of capsaicin induced an identical sensitization followed by nearly complete SIR. A single application of capsaicin induced a significant rise in firing in eight other units, but the rate of rise and maximal firing rate were both much lower compared with repetitive or constant-flow capsaicin. When capsaicin was reapplied once after the rest period, there was no change in firing rate indicating absence of SIR. These results indicate that maintenance of the capsaicin concentration induces a progressive increase in neuronal response that parallels sensitization. With recurrent capsaicin application, desensitization can be overcome to result in a delayed recovery of Vc responses similar to SIR. In contrast, the averaged response of 17 Vc units to repeated or constant-flow application of nicotine increased only over the first 3 min, and then decreased to spontaneous levels even as nicotine was still being applied. These results are consistent with the decrease in the perceived irritation elicited by sequential application of nicotine in humans.