Neonatal isoflurane exposure disturbs granule cell migration in the rat dentate gyrus.

It has been reported that neonatal isoflurane exposure causes behavioral abnormalities following neurodegeneration in animals and gamma-aminobutyric acid type A (GABAA) receptor activation during the synaptogenesis is considered to be one possible trigger. Additionally, the inhibitory effect of excitatory GABAA receptor signaling on the granule cell (GC) migration in the neonatal rat dentate gyrus (DG) was reported in a febrile seizure model. Then, we hypothesized that neonatal isoflurane exposure, which activates GABAA receptor, causes GC migration disturbances in the neonatal rat. Rat pups were injected with 5-bromo-2'-deoxyuridine (BrdU) and divided into five treatment groups, and double immunofluorescent staining targeting BrdU and homeobox prospero-like protein 1 (Prox1) was performed to examine the localization of BrdU/Prox1 colabeled cells, and then the GC migration was assessed. As a result, we found that the ectopic migration of GC after 2% isoflurane exposure on postnatal day 7 significantly increased after P21. The number of hilar ectopic GCs was influenced by the concentration of isoflurane and the exposure day but not by carbon dioxide exposure. Our main finding is that neonatal isoflurane anesthesia disturbs the migration of GCs in the rat DG, which may be one possible mechanism underlying the neurotoxicity following neonatal isoflurane anesthesia.

Interleukin-1ß Modulates Synaptic Transmission and Synaptic Plasticity During the Acute Phase of Sepsis in the Senescence-Accelerated Mouse Hippocampus.

BACKGROUND: Aging and pre-existing cognitive impairment are considered to be independent risk factors for sepsis-associated encephalopathy. This study aimed to investigate the manner in which aging and pre-existing cognitive dysfunction modified neuroinflammation, synaptic plasticity, and basal synaptic transmission during the acute phase of sepsis using Senescence-Accelerated Mice Prone 8 (SAMP8) and Senescence-Accelerated Resistant Mice 1 (SAMR1). METHODS: We used 6-month-old SAMP8 and SAMR1. Sepsis was induced using cecal ligation and puncture (CLP). The animal's hippocampi and blood were collected for subsequent investigations 24 h after surgery. RESULTS: Long-term potentiation (LTP) was impaired in the Shaffer-collateral (SC)-CA1 pathway of the hippocampus in SAMP8 without surgery compared to the age-matched SAMR1, which was reflective of cognitive dysfunction in SAMP8. CLP impaired the SC-CA1 LTP in SAMR1 compared to the sham-operated controls, but not in SAMP8. Moreover, CLP decreased the input-output curve and increased the paired-pulse ratio in SAMP8, suggesting the reduced probability of basal synaptic transmission due to sepsis. Immunohistochemical analysis revealed that CLP elevated IL-1ß levels, especially in the hippocampi of SAMP8 with microglial activation. In vivo peripheral IL-1 receptor antagonist (IL-1ra) administration in the septic SAMP8 revealed that the neuroinflammation was not correlated with the peripheral elevation of IL-1ß. Ex vivo IL-1ra administration to the hippocampus ameliorated LTP impairment in SAMR1 and the reduction in basal transmission in SAMP8 after sepsis. CONCLUSIONS: The mechanism of the modulation of synaptic transmission and synaptic plasticity by the acute stage of sepsis differed between SAMR1 and SAMP8. These changes were related to centrally derived IL-1 receptor-mediated signaling and were accompanied by microglial activation, especially in SAMP8.

Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice.

BACKGROUND: Postoperative cognitive decline (PCD) requires microglial activation. Voltage-gated Kv1.3 potassium channels are involved in microglial activation. We determined the role of Kv1.3 in PCD and the efficacy and safety of inhibiting Kv1.3 with phenoxyalkoxypsoralen-1 (PAP-1) in preventing PCD in a mouse model. METHODS: After institutional approval, we assessed whether Kv1.3-deficient mice (Kv1.3-/-) exhibited PCD, evidenced by tibial-fracture surgery-induced decline in aversive freezing behaviour, and whether PAP-1 could prevent PCD and postoperative neuroinflammation in PCD-vulnerable diet-induced obese (DIO) mice. We also evaluated whether PAP-1 altered either postoperative peripheral inflammation or tibial-fracture healing. RESULTS: Freezing behaviour was unaltered in postoperative Kv1.3-/- mice. In DIO mice, PAP-1 prevented postoperative (i) attenuation of freezing behaviour (54 [17.3]% vs 33.4 [12.7]%; P=0.03), (ii) hippocampal microglial activation by size (130 [31] pixels vs 249 [49]; P<0.001) and fluorescence intensity (12 000 [2260] vs 20 800 [5080] absorbance units; P<0.001), and (iii) hippocampal upregulation of interleukin-6 (IL-6) (14.9 [5.7] vs 25.6 [10.4] pg mg-1; P=0.011). Phenoxyalkoxypsoralen-1 neither affected surgery-induced upregulation of plasma IL-6 nor cartilage and bone components of the surgical fracture callus. CONCLUSIONS: Microglial-mediated PCD requires Kv1.3 activity, determined by genetic and pharmacological targeting approaches. Phenoxyalkoxypsoralen-1 blockade of Kv1.3 prevented surgery-induced hippocampal microglial activation and neuroinflammation in mice known to be vulnerable to PCD. Regarding perioperative safety, these beneficial effects of PAP-1 treatment occurred without impacting fracture healing. Kv1.3 blockers, currently undergoing clinical trials for other conditions, may represent an effective and safe intervention to prevent PCD.

Isoflurane induces c-Fos expression in the area postrema of the rat.

INTRODUCTION: Volatile anesthetics are speculated to cause postoperative nausea and vomiting via stimulation of the chemoreceptor trigger zone (CTZ). However, the precise mechanism underlying the emetic action of these drugs is not well understood. In this study, we assessed whether isoflurane induced the expression of c-Fos, a neuronal activation marker, in the area postrema (AP), the locus of the CTZ, in rats, which do not have vomiting action. MATERIALS AND METHODS: Male rats were exposed to 1.3% isoflurane for 0-240 min, or to various concentrations of isoflurane (0, 1.3%, or 2.6%) for 120 min. Finally, the rats were exposed to 1.3% isoflurane for 120 min after ondansetron administration. After the treatments, immunohistochemistry of the rat AP was performed using c-Fos antibody staining. RESULTS: One-way analysis of variance showed that isoflurane exposure significantly increased c-Fos expression in the AP; however, the rats pretreated with 4 mg/kg ondansetron showed significantly decreased c-Fos expression. Moreover, we evaluated the effect of the anesthetic on inducing pica in the rats, and found that kaolin intake was not influenced by isoflurane exposure. CONCLUSION: Overall, these results suggest that isoflurane activates AP neurons and may be involved in the emetic mechanism of isoflurane. This study further suggests the feasibility of using rats as a model for studying emetic mechanisms of drugs, despite their lack of vomit action.

Changes of Cerebral Blood Volume During Robot-Assisted Laparoscopic Radical Prostatectomy: Observational Prospective Study Using Near-Infrared Time-Resolved Spectroscopy.

Purpose: Robot-assisted laparoscopic radical prostatectomy (RARP) requires a steep head-down tilt and pneumoperitoneum, which may cause an increase in cerebral blood volume (CBV). With a new near-infrared time-resolved spectroscopy device, the tNIRS-1, we can measure the absolute value of the cerebral hemoglobin concentration and hence calculate CBV and cerebral oxygen saturation (rSO2). Using this device, we evaluated the time course of CBV during surgery and also evaluated the changes in rSO2 simultaneously. Materials and Methods: We performed a prospective observational study of 21 patients scheduled for RARP. We evaluated CBV and rSO2 by using the tNIRS-1 at 10 time points during surgery. Results: The CBV was 2.92 ± 0.38 mL ·100 g-1 after the end of anesthetic preparation. It significantly increased to 3.05 ± 0.44 mL ·100 g-1 after the head-down tilt and was around 3.1 mL ·100 g-1 until 120 minutes after the head-down tilt. However, just before the return to the horizontal position, it decreased to 2.93 ± 0.46 mL ·100 g-1 and then decreased more after the return to the horizontal position. Changes in rSO2 over time were within only 3%, and no significant differences from the control value were observed. Conclusions: The increase in CBV was <10% despite the steep head-down tilt and pneumoperitoneum, and it was compensated for at around the end of surgery. Clinically significant changes in rSO2 were not observed during the surgery.

Influence of nitrous oxide on granule cell migration in the dentate gyrus of the neonatal rat.

For several decades, the neurotoxicities of anesthetics to the developing brain have been reported by many researchers focusing on various phenomena such as apoptosis, neurodegeneration, electrophysiological aberrations, and behavioral abnormalities. According to these reports, signals via N-methyl-D-aspartate receptors (NMDA-r) and/or γ-aminobutyric acid type A receptors (GABAA-r) are implicated in the anesthetic neurotoxicity. On the other hand, during brain development, NMDA-r and GABAA-r are also recognized to play primary roles in neural cell migration. Therefore, anesthetics exposed in this period may influence the neural cell migration of neonates, and increase the number of hilar ectopic granule cells, which are reported to be a cause of continuous neurological deficits. To examine this hypothesis, we investigated immunohistochemically granule cell distribution in the hippocampal dentate gyrus of Wistar/ST rats after nitrous oxide (N2O) exposure. At postnatal day (P) 6, 5-bromo-2'-deoxyuridine (BrdU) was administered to label newly generated cells. Then, rats were divided into groups (n = 6 each group), exposed to 50% N2O at P7, and evaluated at P21. As a result, we found that ectopic ratios (ratio of hilar/total granule cells generated at P6) were decreased in rats at P21 compared with those at P7, and increased in N2O exposed rats for over 120 min compared with the other groups. These results suggest that 50% N2O exposure for over 120 min increases the ratios of ectopic granule cells in the rat dentate gyrus.

Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice.

BACKGROUND: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern-induced cognitive decline. METHODS: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage-associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. RESULTS: Damage-associated molecular pattern-induced cognitive decline and inflammation (mean ± SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 ± 8.69% vs. 41.45 ± 7.64%, P < 0.0001; plasma interleukin [IL]-1ß: 7.0 ± 2.2 pg/ml vs. 49.8 ± 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 ± 1.6 pg/ml vs. 19.5 ± 1.7 pg/ml, P < 0.0001; hippocampal IL-1ß: 4.1 ± 3.0 pg/mg vs. 41.6 ± 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 ± 1.3 pg/mg vs. 16.2 ± 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and α7 nicotinic acetylcholine receptors but not by α2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 ± 0.1 vs. 0.7 ± 0.1, P < 0.0001; spleen: 1.5 ± 0.2 vs. 0.6 ± 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 ± 0.2 vs. 0.9 ± 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 ± 0.2 vs. 3.0 ± 0.3, P < 0.0001) humoral mediators that was prevented by α7 nicotinic acetylcholine receptor blockade. CONCLUSIONS: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline.

Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice.

Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2+ leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.

Exercise Prevents Enhanced Postoperative Neuroinflammation and Cognitive Decline and Rectifies the Gut Microbiome in a Rat Model of Metabolic Syndrome.

INTRODUCTION: Postoperative cognitive decline (PCD) can affect in excess of 10% of surgical patients and can be considerably higher with risk factors including advanced age, perioperative infection, and metabolic conditions such as obesity and insulin resistance. To define underlying pathophysiologic processes, we used animal models including a rat model of metabolic syndrome generated by breeding for a trait of low aerobic exercise tolerance. After 35 generations, the low capacity runner (LCR) rats differ 10-fold in their aerobic exercise capacity from high capacity runner (HCR) rats. The LCR rats respond to surgical procedure with an abnormal phenotype consisting of exaggerated and persistent PCD and failure to resolve neuroinflammation. We determined whether preoperative exercise can rectify the abnormal surgical phenotype. MATERIALS AND METHODS: Following institutional approval of the protocol each of male LCR and male HCR rats were randomly assigned to four groups and subjected to isoflurane anesthesia and tibia fracture with internal fixation (surgery) or anesthesia alone (sham surgery) and to a preoperative exercise regimen that involved walking for 10 km on a treadmill over 6 weeks (exercise) or being placed on a stationary treadmill (no exercise). Feces were collected before and after exercise for assessment of gut microbiome. Three days following surgery or sham surgery the rats were tested for ability to recall a contextual aversive stimulus in a trace fear conditioning paradigm. Thereafter some rats were euthanized and the hippocampus harvested for analysis of inflammatory mediators. At 3 months, the remainder of the rats were tested for memory recall by the probe test in a Morris Water Maze. RESULTS: Postoperatively, LCR rats exhibited exaggerated cognitive decline both at 3 days and at 3 months that was prevented by preoperative exercise. Similarly, LCR rats had excessive postoperative neuroinflammation that was normalized by preoperative exercise. Diversity of the gut microbiome in the LCR rats improved after exercise. DISCUSSION: Preoperative exercise eliminated the metabolic syndrome risk for the abnormal surgical phenotype and was associated with a more diverse gut microbiome. Prehabilitation with exercise should be considered as a possible intervention to prevent exaggerated and persistent PCD in high-risk settings.

Synthesis and Photophysical Properties of a 13,13'-Bibenzo[b]perylenyl Derivative as a π-Extended 1,1'-Binaphthyl Analog.

A 13,13'-bibenzo[b]perylenyl derivative-an axially chiral π-extended compound in which two perylene subunits fused to 1,1'-binaphthyl scaffold-has been synthesized from 1,8-dibromophenanthrene using an anionic cyclodehydrogenation reaction in the presence of potassium metal as the key step. The pair of enantiomers can be separated by chiral high-performance liquid chromatography (HPLC), which showed a strong circular dichroism (CD) (Δε = 330 M(-1) cm(-1) at 449 nm, |gCD| = 5.8 × 10(-3) at 453 nm), high fluorescence quantum yield (Φf = 64%), and strong circular polarized luminescence (CPL) (|gCPL| = 5 × 10(-3) at 454 nm) in solution phase.

Co-existing liver disease increases the risk of postoperative thrombocytopenia in patients undergoing hepatic resection: implications for the risk of epidural hematoma associated with the removal of an epidural catheter.

PURPOSE: A common surgical diagnosis for hepatic resection in Japan is hepatocellular carcinoma secondary to chronic viral hepatitis. It is known that chronic liver disease causes a decrease in blood platelet count. We retrospectively reviewed the perioperative changes in blood platelet count associated with hepatic resection at a Japanese institution and evaluated the incidence and risk factors for postoperative thrombocytopenia, which may increase the potential risk of epidural hematoma. METHODS: We analyzed the data of 165 patients who underwent hepatic resection between 1 March 2010 and 30 June 2012 at Hokkaido University Hospital. The criterion of the platelet count for the unsafe removal of epidural catheter was <100,000/µL. Logistic regression was used to model the association between postoperative thrombocytopenia and co-existing liver disease, estimated blood loss and type of hepatic resection. RESULTS: After hepatic resection, 42.4 % of patients without preoperative thrombocytopenia experienced thrombocytopenia. The presence of co-existing liver disease was identified as a risk factor for postoperative thrombocytopenia [odds ratio 3.17 (95 % confidence interval 1.63-6.18)]. There was no epidural hematoma in the 149 patients who had epidural anesthesia. CONCLUSION: Hepatic resection can cause postoperative thrombocytopenia that may increase the potential risk of epidural hematoma associated with catheter removal, and the presence of co-existing liver disease heightens concerns for postoperative crucial thrombocytopenia.

Neonatal exposure to sevoflurane causes significant suppression of hippocampal long-term potentiation in postgrowth rats.

BACKGROUND: The inhaled anesthetic sevoflurane is commonly used for neonates in the clinical setting. Recent studies have indicated that exposure of neonatal rodents to sevoflurane causes acute widespread neurodegeneration and long-lasting neurocognitive dysfunction. Although acute toxic effects of sevoflurane on cellular viability in the hippocampus have been reported in some studies, little is known about the effects of neonatal sevoflurane exposure on long-term hippocampal synaptic plasticity, which has been implicated in the processes of learning and memory formation. Our study is the first to examine the long-term electrophysiological impact of neonatal exposure to a clinically relevant concentration of sevoflurane. METHODS: On postnatal day 7, rats were exposed to sevoflurane (1% or 2% for 2 hours) with oxygen. To eliminate the influence of blood gas abnormalities caused by sevoflurane-induced respiratory suppression, a group of rats were exposed to a high concentration of carbon dioxide (8% for 2 hours) to duplicate respiratory disturbances caused by 2% sevoflurane exposure. RESULTS: Exposure of neonatal rats to 2% sevoflurane for 2 hours caused significant suppression of long-term potentiation (LTP) induction in the postgrowth period. There was no significant difference between the control group and the CO2-exposed group in LTP induction, indicating that sevoflurane-induced LTP suppression was not caused by blood gas abnormalities. CONCLUSION: Our present findings indicate that neonatal exposure to sevoflurane at a higher concentration can cause alterations in the hippocampal synaptic plasticity that persists into adulthood.

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood.

BACKGROUND AND OBJECTIVE: The use of dexmedetomidine (DEX), a selective alpha-2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long-term neurological consequences of neonatal administration of DEX, we investigated the long-term effects of neonatal administration of DEX on hippocampal synaptic activity. METHODS: The rat pups received a bolus intraperitoneal injection of either 5 or 10 µg·kg(-1) DEX, or an equivalent volume of vehicle on postnatal day 7 (P7). Nine weeks after administration, evoked potentials (population spike, PS) and long-term potentiation (LTP) in the hippocampal CA1 region of rats were studied in vivo. RESULTS: Dexmedetomidine had a considerable sedative effect at these doses with little respiratory depression on P7. Nine weeks after administration of DEX, the amplitude of PS in the two treated groups was similar to that in the control group. DEX-treated rats showed no impairment in the induction of LTP. Furthermore, the response in PS to the paired stimuli was not impaired by neonatal administration of DEX. CONCLUSION: These findings demonstrate that a single administration of DEX to rats on P7 preserves hippocampal synaptic plasticity as well as synaptic transmission later in life. In view of the some evidence that have demonstrated the permanent detrimental impact of commonly used anesthetics on neurological outcomes after neonatal exposure, our findings may suggest the relative safety of DEX administered as a sedative agent to neonatal animals with regard to the development of hippocampal synaptic functions.

[Case of lung torsion after esophagectomy].

A 77-year-old man underwent esophagectomy for esophageal cancer. Chest radiograph just after the operation showed opacification of the right lung. Although chest radiograph still showed a marked opacification of almost whole right lung in the ICU in spite of multiple bronchoscopy examination and suctioning of pulmonary secretions, he showed no dyspnea. On the second postoperative day, his respiratory symptoms deteriorated unexpectedly. Computed tomography showed torsion of the right upper and middle lobes, and urgent surgery was scheduled. Following double-lumen endotracheal intubation, thoracotomy was performed under one lung ventilation. The lung was found rotated. The surgeons tried to reduce the torsion to preserve the viable lung, but failed. Bleeding from infarcted lung was observed (approximately 150 ml). Accordingly, stapled lobectomy was performed. After the second surgery, he fortunately recovered without any complications. Although lung torsion is a rare complication, not only thoracic surgeons, but also we, anesthesiologists, should be aware of this disease.

Unusual presentation of intraparenchymal renal artery aneurysm mimicking cystic renal cell carcinoma: a case report.

We describe a case of intraparenchymal renal artery aneurysm in a 58-year-old normotensive man with a history of distal ureterectomy. Imaging studies of the pre-existing right renal mass had been interpreted as being consistent with a simple renal cyst. Three years after ureterectomy, a small parietal nodule with contrast enhancement developed within the cyst. Partial nephrectomy was carried out based on a preoperative diagnosis of cystic kidney cancer. Surprisingly, pathological diagnosis was an aneurysm with a revascularized thrombus. Even though the present case represents an extremely rare clinical manifestation of intraparenchymal renal artery aneurysm, clinicians should be aware that imaging studies cannot distinguish all instances of renal vascular disease.

Evaluation of bispectral index (BIS) as an indicator of central nervous system depression in horses anesthetized with propofol.

The bispectral index (BIS) was evaluated as an indicator of central nervous system (CNS) depression in horses anesthetized with propofol. Five non-premedicated horses were anesthetized with 7 mg/kg, IV propofol and the minimum infusion rate (MIR) of propofol required to maintain anesthesia was determined during intermittent positive pressure ventilation in each horse. The BIS was determined 20 min later and after stabilization at 2.0 MIR, 1.5 MIR, and 1.0 MIR. The BIS was also recorded after the cessation of propofol infusion when the horses regained spontaneous breathing and swallowing reflex. The MIR and plasma concentration (Cp) of propofol were 0.20 +/- 0.03 mg/kg/min and 17.5 +/- 4.0 microg/ml, respectively. The BIS value and Cp were 59 +/- 13 and 26.7 +/- 8.6 microg/ml at 2.0 MIR, 63 +/- 9 and 22.9 +/- 9.7 microg/ml at 1.5 MIR, 64 +/- 13 and 20.1 +/- 5.9 microg/ml at 1.0 MIR, 64 +/- 24 and 13.0 +/- 2.8 microg/ml at return of spontaneous breathing, and 91 +/- 4 and 11.0 +/- 3.4 microg/ml when the swallowing reflex returned, respectively. The BIS value was significantly less in anesthetized horses compared to horses once swallowing returned (p=0.025). The BIS value was significantly correlated with the propofol Cp (r=-0.625, p=0.001). There was not a significant difference in the BIS values during the MIR multiples of propofol. The BIS was a useful indicator of awakening but did not indicate the degree of CNS depression during propofol-anesthesia in horses.

Gallbladder reefing for cholelithiasis as a complication of colon cancer.

In an 83-year-old woman presenting with gallstones and a cancer in the sigmoid colon, resection was performed through a median incision, after which the wound was extended, the stones were crushed, and the gallbladder was infolded and sutured (reefed). Even in elderly patients, some treatment for bile stones should be done at abdominal section to avoid future cholecystitis or complications. Reefing is a useful technique that can be done easily from a comparatively narrow field of view.

[Controversies in esophageal cancer surgery].

In esophageal cancer treatment, the choice of treatment modality and the indications and extent of lymph node dissection surgery are controversial. In terms of the biological characteristics, esophageal cancer is more virulent than any other gastrointestinal malignancy. The distribution of lymph node metastases is very wide, extending from the neck to abdominal regions, and the sizes of lymph node metastases are very small. Almost two-thirds of all metastatic lymph nodes showed minute metastases less than 5 mm in diameter. In patients with superficial cancer with only submucosal invasion, lymph nodes metastases were found in both the upper mediastinal and paracardial areas in up to 27% cases. Furthermore, the accuracy of preoperative diagnosis of lymph node metastasis in esophageal cancer is still unsatisfactory. False negative rates in preoperative diagnosis of lymph node metastases are 14% in the neck area, 36% in the mediastinal area, and 34% in the abdominal area. Therefore, in order to cure esophageal cancer by surgery, wide, precise and complete removal of possible metastatic lymph nodes is essential. It is at this time that the quality assurance of surgery is indispensable in reducing morbidity and mortality, and in improving the patient survival. Because both surgery and chemoradiotherapy are local treatments, we must recognize the limitation of these therapeutic modalities. To improve overall survival of esophageal cancer patients, we have to make a more concentrated effort toward the systemic control of this disease.

[Surgery for benign submucosal tumors of the esophagus (leiomyoma and hemangioma)].

Among the submucosal tumors of the esophagus, leiomyoma is the most frequently found. Esophageal leiomyoma usually originates from the muscle layer of the esophageal wall and grows spirally around the esophageal axis. In the surgical treatment of leiomyoma, we enucleate the tumor through video-assisted thoracic surgery. When we enucleate leiomyoma, we must be very careful to aviod perforation of the esophageal mucosa. Esophageal hemangioma is a relatively rare disease. The location of this disease is mainly within the submucosal layer, without invading the muscle layer proper. After confirming the localization within the mucosa or submucosa with endoscopic ultrasonography, esophageal hemangioma can be resected safely using the endoscopic mucosal resection technique. In the treatment of benign esophageal submucosal tumors, "informed consent" is as essential as in esophageal cancer surgery. We have no absolute criteria concerning the indications for surgery for benign esophageal submucosal tumors. We must give reasons why the operation is necessary and indicated to the patients. Surgical treatment of esophageal submucosal tumors should be as minimally invasive as possible.