Evaluation of Biocompatibility, Anti-Inflammatory, and Antinociceptive Activities of Pequi Oil-Based Nanoemulsions in In Vitro and In Vivo Models.

Pequi oil (Caryocar brasiliense) contains bioactive compounds capable of modulating the inflammatory process; however, its hydrophobic characteristic limits its therapeutic use. The encapsulation of pequi oil in nanoemulsions can improve its biodistribution and promote its immunomodulatory effects. Thus, the objective of the present study was to formulate pequi oil-based nanoemulsions (PeNE) to evaluate their biocompatibility, anti-inflammatory, and antinociceptive effects in in vitro (macrophages­J774.16) and in vivo (Rattus novergicus) models. PeNE were biocompatible, showed no cytotoxic and genotoxic effects and no changes in body weight, biochemistry, or histology of treated animals at all concentrations tested (90−360 µg/mL for 24 h, in vitro; 100−400 mg/kg p.o. 15 days, in vivo). It was possible to observe antinociceptive effects in a dose-dependent manner in the animals treated with PeNE, with a reduction of 27 and 40% in the doses of 100 and 400 mg/kg of PeNE, respectively (p < 0.05); however, the treatment with PeNE did not induce edema reduction in animals with carrageenan-induced edema. Thus, the promising results of this study point to the use of free and nanostructured pequi oil as a possible future approach to a preventive/therapeutic complementary treatment alongside existing conventional therapies for analgesia.

Rhinacanthin-C but Not -D Extracted from Rhinacanthus nasutus (L.) Kurz Offers Neuroprotection via ERK, CHOP, and LC3B Pathways.

Neurodegenerative diseases present an increasing problem as the world's population ages; thus, the discovery of new drugs that prevent diseases such as Alzheimer's, and Parkinson's diseases are vital. In this study, Rhinacanthin-C and -D were isolated from Rhinacanthus nasustus, using ethyl acetate, followed by chromatography to isolate Rhinacanthin-C and -D. Both compounds were confirmed using NMR and ultra-performance-LCMS. Using glutamate toxicity in HT-22 cells, we measured cell viability and apoptosis, ROS build-up, and investigated signaling pathways. We show that Rhinacanthin-C and 2-hydroxy-1,4-naphthoquinone have neuroprotective effects against glutamate-induced apoptosis in HT-22 cells. Furthermore, we see that Rhinacanthin-C resulted in autophagy inhibition and increased ER stress. In contrast, low concentrations of Rhinacanthin-C and 2-hydroxy-1,4-naphthoquinone prevented ER stress and CHOP expression. All concentrations of Rhinacanthin-C prevented ROS production and ERK1/2 phosphorylation. We conclude that, while autophagy is present in HT-22 cells subjected to glutamate toxicity, its inhibition is not necessary for cryoprotection.

Dosimetric advantages of volumetric modulated arc therapy (VMAT) with deep inspiration breath hold (DIBH) technique in Halcyon Linac for left breast cancer treatment.

To evaluate the dosimetric advantages of incorporating the deep inspiration breath hold (DIBH) technique into left breast cancer volumetric modulated arc therapy (VMAT) treatment under Halcyon Linac and to investigate the correlation between mean heart dose (MHD) and distance from the heart to target volumes in left breast cancer VMAT treatment. Fifteen Post-lumpectomy, left-sided breast patients treated between January 2017 and October 2020 were selected. Two plans were generated for each patient using Eclipse treatment planning system (TPS) with the prescription of 50.4 Gy to planning target volume (PTV) breast and 58.8 Gy to PTV boost in 28 fractions. For each patient, DIBH and free breathing (FB) VMAT treatment plans under Halcyon Linac were generated. Dosimetric parameters, monitor unit and beam-on time of both DIBH and FB groups were compared. Three-dimensional distances from heart surface to each target volume were measured on computed tomography images using the TPS contouring tool and their correlation with MHD was evaluated by Pearson's correlation coefficient (r). Comparable target coverage was shown in both groups. Mean dose to heart, left anterior descending artery, and left ventricle in Halcyon-DIBH-VMAT group were significantly reduced by 0.49 Gy, 1.19 Gy, and 0.57 Gy, respectively, compared to Halcyon-FB-VMAT (p < 0.001). A significant lung dose reduction was also achieved in Halcyon-DIBH-VMAT group. There was also a strong negative correlation between MHD and distance from heart surface to PTV boost in both FB and DIBH group (r = -0.741, p < 0.001), but not observed for distance from heart surface to PTV breast. Incorporating DIBH into left breast cancer VMAT treatment under Halcyon Linac demonstrated significant cardiac and lung dose reduction. It was also demonstrated that MHD had a strong negative correlation with distance from heart surface to PTV boost but relatively independent of distance from heart surface to PTV breast. Recognizing the distance from the heart surface to PTV boost as the main factor in affecting MHD could potentially facilitate clinical treatment planning workflow and decision.

Laparoscopic anatomical liver resection using indocyanine green fluorescence imaging.

BACKGROUND: Anatomical liver resections guided by a demarcation line after portal staining or inflow clamping of the target area have been established as essential methods for curative treatment of hepatocellular carcinoma (HCC) and have subsequently been applied to other malignancies. However, laparoscopic anatomical liver resection (LALR) procedures are very difficult to reproduce, and the confirmation of demarcation of the hepatic segment on a monitor is also challenging. Recently, indocyanine green (ICG) fluorescence imaging has been used to identify hepatic tumors and segmental boundaries during hepatectomy. Herein, we describe LALR using ICG fluorescence imaging. METHODS: Three patients underwent pure LALR using ICG fluorescence imaging at our institute. One patient underwent anatomical partial liver resection for HCC, another underwent segmentectomy 3 for metastatic liver cancer, and the third underwent right anterior sectionectomy for HCC. To visualize hepatic perfusion and the demarcation line by negative staining using an optical imaging system, 2.5 mg ICG was injected intravenously during surgery following clamping or closure of the proximal Glissonean pedicles. RESULTS: For all three cases, ICG fluorescent imaging clearly delineated the demarcation lines and allowed identification of intersegmental planes to some extent because the tumor-bearing hepatic region became non-fluorescing parenchyma during parenchymal transection. This allowed surgeons to recognize the direction and guide the transection of the liver parenchyma when performing LALR. CONCLUSION: LALR using ICG fluorescence imaging is a feasible procedure for resection of the tumor-bearing hepatic region and facilitates visualization of the demarcation line and identification of the boundaries of the hepatic sections.

Laparoscopic transabdominal preperitoneal approach for giant inguinal hernias.

BACKGROUND: Many surgical techniques have been developed to treat inguinal hernia. In recent years, the laparoscopic transabdominal preperitoneal (TAPP) approach has been widely performed to repair inguinal hernia. Giant inguinal hernia (GIH) is an extremely rare disease that is a challenge for general surgeons. GIH appears when patients neglect the treatment for many years and it is defined as an inguinal hernia that extends below the midpoint of inner thigh in standing position. According to previous publications, the Lichtenstein tension-free hernioplasty is recommended to repair GIH. In this article, we describe consecutive four cases of GIH repaired via the TAPP approach. METHODS: From April 2015 to March 2017, 200 patients underwent hernioplasty against inguinal hernia at our hospital. Inguinal hernias were treated via the TAPP approach in principle. We performed hernioplasty via the TAPP approach in all 4 patients (2%) who met the definition of Type 1 GIH. Demographic information, maximum diameter of hernia sac, hernia orifice size, and surgical data were obtained. RESULTS: The mean operative time was 135 min. No intraoperative complications were encountered. All patients could walk from postoperative day 1 and were discharged home early, but they all had scrotal seromas. Three patients did not need puncture or drainage, but one of them required puncture. All seromas disappeared within 6 months. There was no recurrence in the 8- to 24-month follow-up. CONCLUSION: The TAPP approach is a feasible, safe therapeutic option that may reduce wound size and pain following surgical treatment of Type 1 GIH.

A resected case of gallbladder metastasis with symptoms of acute cholecystitis in multiple metastatic ductal carcinoma of the breast.

Gallbladder metastasis from breast cancer, especially from ductal carcinoma, is rare. Herein, we report a rare case of gallbladder metastasis from ductal carcinoma of the breast that was diagnosed after laparoscopic cholecystectomy (LC) for acute cholecystitis. A 78-year-old woman presented with right upper abdominal tenderness and positive Murphy's sign during chemotherapy for advanced multiple metastases of the breast cancer. Abdominal ultrasonography and computed tomography showed a slightly thickened gallbladder wall and two calculi. After a diagnosis of acute calculous cholecystitis was established, LC was performed. Pathological examination revealed poorly differentiated adenocarcinoma infiltrating the submucosal and subserosal layer over the entire gallbladder, and a lymph node metastasis in the gallbladder neck. Immunohistochemical examination revealed that the tumor cells tested positive for estrogen receptor and negative for progesterone receptor, which was consistent with primary breast cancer. The patient was uneventfully discharged without abdominal pain 7 days later. Although she subsequently underwent several chemotherapies, she died 16 months later. In conclusion, gallbladder metastasis should be considered in patients with multiple metastatic breast cancer who present with signs or symptoms of cholecystitis. Moreover, LC should be considered to relieve the symptoms of cholecystitis for improved prognosis, even in a patient with multiple metastases.

Intestinal colonization with resistant bacteria: a prognostic marker of mortality in decompensated cirrhosis.

Infections due to drug-resistant (DR) bacteria are increasingly recognized as an emerging problem worldwide. Asymptomatically colonized patients may contribute to the reservoir in the hospital setting, causing both horizontal transmission and endogenous infections. We aimed to evaluate the prevalence of intestinal colonization with DR bacteria on subsequent clinical infection development and prognosis in patients with decompensated cirrhosis. One hundred seven patients without infection at baseline were screened and prospectively followed-up for 3 months. Among the patients screened, DR bacteria were isolated in 47 (43.9%), 14 colonized with multidrug- (MDR) and 33 with extensively drug (XDR)-resistant bacteria or a mixture of MDR/XDR bacteria. Severity of liver disease and demographic characteristics were similar among groups. The 20 (42.6%) with DR vs 14 (23.3%) without had hepatic encephalopathy and/or spontaneous bacterial peritonitis episodes over the past 6 months (p = 0.034). One third of both DR and non-DR groups developed infection during follow-up but in only 7 and 5, respectively, the infection was microbiologically documented. In a 3-month-follow-up period, mortality was higher in patients colonized with XDR compared to those without (log rank p = 0.027). In multivariate analysis, colonization with XDR bacteria [HR = 1.074, (CI:1.024-1.126), p = 0.003] and MELD score [HR = 2.579 (1.109-5.996), p = 0.028] were independently associated with low survival. Asymptomatic GI colonization with DR bacteria is a risk factor for increased mortality in decompensated cirrhosis. Frequent hospitalizations for complications of the underlying disease and selective pressure induced by the use of antimicrobials are probably the main determinants.

Optimization of steroid injection intervals for prevention of stricture after esophageal endoscopic submucosal dissection: A randomized controlled trial.

BACKGROUND: Esophageal endoscopic submucosal dissection enables en bloc resection of large superficial esophageal cancer; however, this procedure may induce severe stricture. Intralesional steroid injection is an effective treatment for prevention of stricture after endoscopic resection; however, there have been no studies assessing the duration of such treatment. The aim of this study was to reduce treatment duration and to evaluate the effectiveness of weekly and biweekly steroid injections in preventing esophageal stricture after endoscopic resection. PATIENTS METHOD: We performed a randomized controlled trial comparing patients receiving weekly or biweekly intralesional triamcinolone injections. Patients with a mucosal defect greater than 75% (3/4) of the luminal circumference after esophageal endoscopic submucosal dissection for superficial esophageal cancers were enrolled. The primary endpoint was the duration of steroid injection treatment. RESULTS: The median duration of treatment was 37.0 days in the weekly group and 34.2 days in the biweekly group (P = 0.059). Among patients with a mucosal defect larger than 50 mm, there was a significant difference in the median duration of treatment between the weekly and biweekly groups (42.5 days vs 29.0 days, P = 0.013). CONCLUSION: Biweekly steroid injection of triamcinolone reduces treatment duration, particularly in those with mucosal defects larger than 50 mm. (Acta gastro-enterol. belg., 2016, 79, 315-320).

Clinical significance of the muscle-retracting sign during colorectal endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: During colorectal endoscopic submucosal dissection (ESD), the feature of a muscle layer being pulled toward a neoplastic tumor is sometimes detected. We call this feature the muscle-retracting sign (MR sign). The aim of this study was to evaluate whether the MR sign is associated with particular types of neoplastic lesions and whether it has any clinical significance for ESD sessions. PATIENTS AND METHODS: A total of 329 patients underwent ESD for 357 colorectal neoplasms. The frequency of positivity for the MR sign was evaluated in different morphologic and histopathologic types of neoplasm. The success rate of complete resection and the incidence of complications were also evaluated according to whether lesions were positive or negative for the MR sign. RESULTS: The rates of positivity for the MR sign in the various lesion types were as follows: laterally spreading tumor - granular nodular mixed type (LST-G-M), 9.6 %; laterally spreading tumor - granular homogeneous type (LST-G-H) and laterally spreading tumor - nongranular type (LST-NG), 0 %; sessile type, 41.2 %. The resection rate was 100 % (329 /329) in lesions negative for the MR sign; however, it was 64.3 % (18 /28) in lesions positive for the MR sign, which was significantly lower (P < 0.001). CONCLUSIONS: The MR sign was present only in some protruding lesions, and more importantly, it was associated with a high risk of incomplete tumor removal by ESD. Our data indicate that lesions positive for the MR sign lesions should be dissected with great caution; alternatively, based on the features of the individual case, a switch to surgery should be considered for the benefit of the patient.

Involvement of nuclear factor kappa B in the maintenance of persistent inflammatory hypernociception.

The pathophysiology of chronic inflammatory pain remains poorly understood. In this context, we developed an experimental model in which successive daily injection of prostaglandin E2 (PGE2) for 14days into rat hind paws produces a persistent state of hypernociception (i.e. decrease in mechanical nociceptive threshold). This state persists for more than 30days after discontinuing PGE2 injection. In the present study, we investigated the participation of nuclear factor kappa B (NF-κB), in the maintenance of this process. Mechanical hypernociception was evaluated using the electronic von Frey test. Activation of NF-κB signaling was measured through the determination of NF-κB p65 subunit translocation to the nucleus of dorsal root ganglion neurons (DRG) by immunofluorescence and western blotting. Herein, we detected an increase in NF-κB p65 subunit translocation to the nucleus of DRG neurons along with persistent inflammatory hypernociception compared with controls. Intrathecal treatment with either dexamethasone or PDTC (NF-κB activation inhibitor) after ending of the induction phase of the persistent inflammatory hypernociception, curtailed the hypernociception period as well as reducing NF-κB p65 subunit translocation. Treatment with antisense oligonucleotides against the NF-κB p65 subunit for 5 consecutive days also reduced persistent inflammatory hypernociception. Inhibition of PKA and PKCε reduced persistent inflammatory hypernociception, which was associated with inhibition of NF-κB p65 subunit translocation. Together these results suggest that peripheral activation of NF-κB by PKA and PKC in primary sensory neurons plays an important role in maintaining persistent inflammatory pain.

Totally intracorporeal delta-shaped B-I anastomosis following laparoscopic distal gastrectomy using the Tri-Staple™ reloads on the manual Ultra handle: a prospective cohort study with historical controls.

BACKGROUND: A delta-shaped anastomosis in totally laparoscopic Billroth I gastrectomy could be performed easily and sufficiently using only laparoscopic linear staplers. However, the restricted maneuverability and severe blurring of these staplers along with their limited hemostability induced strain. In this study, we determined the feasibility and safety of performing delta-shaped anastomosis using the Endo GIA™ Reloads with Tri-Staple™ Technology combined with Endo GIA™ Ultra Universal stapler (Tri-Staple) with a particular focus on short-term surgical outcomes. METHODS: We performed a single-institutional prospective interventional study (UMIN 000008014). The Tri-Staple was prospectively used on 23 consecutive patients who underwent a curative totally laparoscopic Billroth I gastrectomy with delta-shaped anastomosis. These patients were matched with the 19 patients previously treated using the ENDOPATH(®) ETS Articulating Linear Cutters (ETS) on clinical and demographic characteristics. RESULTS: There were no differences between the groups in anastomosis-related local complications, morbidity, non-anastomosis-related local complications, total systemic complications, and short-term outcomes with the exception of significantly reduced blood loss in the Tri-Staple group (ETS vs. Tri-Staple: 37 [10-306] vs. 15 [5-210] mL, p = 0.02). Intraoperative bleeding from the staple line was significantly reduced in the Tri-Staple group. The postoperative drain indwelling period (ETS vs. Tri-Staple, 6 [4-10] vs. 4 [2-43] days, p = 0.032), fasting period (5 [3-7] vs. 3 [3-24] days, p = 0.022), and hospital stay (14 [10-47] vs. 11 [6-58] days, p = 0.025) were significantly shorter in the Tri-Staple group. There was no mortality in this series. Acceleration assessed as indices of blurring of stapler tip might have a significant adverse influence on staple-line bleeding at stapling sites. CONCLUSION: Totally laparoscopic Billroth I distal gastrectomy using Tri-Staple was feasible and safe with favorable short-term surgical outcomes. Reduced blurring while stapling may be a novel endpoint which newly developed stapling devices should target.

Potential advantages of robotic radical gastrectomy for gastric adenocarcinoma in comparison with conventional laparoscopic approach: a single institutional retrospective comparative cohort study.

BACKGROUND: We have previously reported that laparoscopic approach improved short-term postoperative courses even for advanced gastric adenocarcinoma, but not morbidity, in comparison with open approach. The objective of this study was to determine the impact of the use of the surgical robot, da Vinci Surgical System, in minimally invasive radical gastrectomy on short-term outcomes. METHODS: A single institutional retrospective cohort study was performed (UMIN000011749). Five hundred twenty-six patients who underwent radical gastrectomy were enrolled. Eighty-eight patients who agreed to uninsured use of the surgical robot underwent robotic gastrectomy, whereas the remaining 438 patients who wished for laparoscopic (lap) approach with health insurance coverage underwent conventional laparoscopic gastrectomy. RESULTS: In the robotic group, morbidity (robotic vs lap 2.3 vs 11.4 %, p = 0.009) and hospital stay following surgery (robotic vs lap 14 [2-31] vs 15 [8-136] days, p = 0.021) were significantly improved, even though operative time (p = 0.003) and estimated blood loss (p = 0.026) were slightly greater. In particular, local (robotic vs lap 1.1 vs 9.8 %, p = 0.007) rather than systemic (robotic vs lap 1.1 vs 2.5 %, p = 0.376) complication rates were attenuated using the surgical robot. Multivariate analyses revealed that non-use of the surgical robot (OR 6.174 [1.454-26.224], p = 0.014), total gastrectomy (OR 4.670 [2.503-8.713], p < 0.001), and D2 lymphadenectomy (OR 2.095 [1.124-3.903], p = 0.020) were the significant independent risk factors determining postoperative complications. CONCLUSIONS: The use of the surgical robot might reduce surgery-related complications, leading to further improvement in short-term postoperative courses following minimally invasive radical gastrectomy.

Endoscopic submucosal dissection (ESD) versus simplified/hybrid ESD.

The development of endoscopic submucosal dissection (ESD) has enabled en bloc resection of lesions regardless of size and shape. However, ESD of colorectal tumors is technically difficult. Early stage colorectal tumors can be removed by endoscopic mucosal resection (EMR) but larger tumors may require piecemeal resection. Therefore, ESD with snaring has been proposed for more reliable EMR and easier ESD. This is a good option to fill the gap between EMR and ESD, and a good step to the introduction of full ESD.

Endoscopic submucosal dissection for gastric neoplasm in patients with co-morbidities categorized according to the ASA Physical Status Classification.

BACKGROUND: Endoscopic submucosal dissection (ESD) has come to be widely performed for reduced invasiveness; however, its safety in patients with co-morbidities is not fully examined. We aimed to evaluate the safety and efficacy of gastric ESD with co-morbidities categorized according to ASA Physical Status Classification. METHODS: Two hundred and forty patients of ASA 1 (no co-morbidities), 268 of ASA 2 (mild), and 19 of ASA 3 (severe) were treated by ESD for gastric neoplasms. We retrospectively compared clinicopathological features and treatment results of these three groups. RESULTS: Cases (by percent) treated with anticoagulant/platelet agents were more common in the higher ASA grades (ASA 1, 5.8%; ASA 2, 29.1%; ASA 3, 31.6%; P < 0.0001). There were no significant differences in case numbers treated under guideline criteria, curative resection (ASA 1, 79.6%; ASA 2, 79.9%; ASA 3, 78.9%), or complications related to the ESD procedure (e.g., postoperative bleeding, perforation, thermal injury). By a patient risk prediction model on surgery, i.e., P-POSSUM, morbidity was halved, and no patients died compared to a predicted death rate of 0.5-2%; however, total and complications unrelated to ESD procedure (e.g., aspiration pneumonia, ischemic heat attack) were more common in higher ASA grades (ASA 1, ASA 2, ASA 3: 15.4, 23.9, 26.3%, respectively, P = 0.014; 0.4, 7.1, 0%, respectively, P = 0.00087). Deviation rates from clinical pathway were more frequent and hospital stay (days) longer in higher ASA grades (ASA 1, ASA 2, ASA 3: 11.3, 17.9, 26.3%, respectively, P = 0.014; 8, 8, 9%, respectively, P = 0.0053). CONCLUSIONS: ESD is an efficient treatment for gastric neoplasms with co-morbidities. However, additional caution is required because co-morbidity is a risk factor for both total complications and complications unrelated to the ESD procedure, and may cause deviations in the clinical course and prolonged hospital stay.

1,635 Endoscopic submucosal dissection cases in the esophagus, stomach, and colorectum: complication rates and long-term outcomes.

BACKGROUND: Endoscopic submucosal dissection (ESD) enables en bloc resection of early gastrointestinal neoplasms; however, most ESD articles report small series, with short-term outcomes performed by multiple operators on single organ. We assessed short- and long-term treatment outcomes following ESD for early neoplasms throughout the gastrointestinal tract. METHODS: We performed a longitudinal cohort study in single tertiary care referral center. A total of 1,635 early gastrointestinal neoplasms (stomach 1,136; esophagus 138; colorectum 361) were treated by ESD by single operator. Outcomes were complication rates, en bloc R0 resection rates, and long-term overall and disease-specific survival rates at 3 and 5 years for both guideline and expanded criteria for ESD. RESULTS: En bloc R0 resection rates were: stomach: 97.1 %; esophagus: 95.7 %; colorectum: 98.3 %. Postoperative bleeding and perforation rates respectively were: stomach: 3.6 and 1.8 %; esophagus: 0 and 0 %; colorectum: 1.7 and 1.9 %. Intra criteria resection rates were: stomach: 84.9 %; esophagus: 81.2 %; colorectum: 88.6 %. Three-year survival rates for lesions meeting Japanese ESD guideline/expanded criteria were for all organ-combined: 93.4/92.7 %. Five-year rates were: stomach: 88.1/84.6 %; esophagus: 81.6/57.3 %; colorectum: 94.3/100 %. Median follow-up period was 53.4 (range, 0.07-98.6) months. Follow-up rate was 94 % (1,020/1,085). There was no recurrence or disease-related death. CONCLUSIONS: In this large series by single operator, ESD was associated with high curative resection rates and low complication rates across the gastrointestinal tract. Disease-specific and overall long-term prognosis for patients with lesions within intra criteria after curative resection appeared to be excellent.

Principles of quality controlled endoscopic submucosal dissection with appropriate dissection level and high quality resected specimen.

Endoscopic submucosal dissection (ESD) has enabled en bloc resection of early stage gastrointestinal tumors with negligible risk of lymph node metastasis, regardless of tumor size, location, and shape. However, ESD is a relatively difficult technique compared with conventional endoscopic mucosal resection, requiring a longer procedure time and potentially causing more complications. For safe and reproducible procedure of ESD, the appropriate dissection of the ramified vascular network in the level of middle submucosal layer is required to reach the avascular stratum just above the muscle layer. The horizontal approach to maintain the appropriate depth for dissection beneath the vascular network enables treatment of difficult cases with large vessels and severe fibrosis. The most important aspect of ESD is the precise evaluation of curability. This approach can also secure the quality of the resected specimen with enough depth of the submucosal layer.

Stimulation of peripheral kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kγ/AKT/nNOS/NO signaling pathway.

BACKGROUND: In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral µ-opioid receptor (MOR) activation are able to direct block PGE(2)-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE(2)-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated. RESULTS: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE(2)-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3Kγ/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3Kγ null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3Kγ (≅ 43%). CONCLUSIONS: The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3Kγ/AKT signaling. This study extends a previously study of our group suggesting that PI3Kγ/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.

Principles of Quality Controlled Endoscopic Submucosal Dissection with Appropriate Dissection Level and High Quality Resected Specimen

Endoscopic submucosal dissection (ESD) has enabled en bloc resection of early stage gastrointestinal tumors with negligible risk of lymph node metastasis, regardless of tumor size, location, and shape. However, ESD is a relatively difficult technique compared with conventional endoscopic mucosal resection, requiring a longer procedure time and potentially causing more complications. For safe and reproducible procedure of ESD, the appropriate dissection of the ramified vascular network in the level of middle submucosal layer is required to reach the avascular stratum just above the muscle layer. The horizontal approach to maintain the appropriate depth for dissection beneath the vascular network enables treatment of difficult cases with large vessels and severe fibrosis. The most important aspect of ESD is the precise evaluation of curability. This approach can also secure the quality of the resected specimen with enough depth of the submucosal layer.

Robot-assisted surgery for gastric cancer: experience at our institute.

OBJECTIVE: The robot-assisted surgical system was developed for minimally invasive surgery and is thought to have the potential to overcome the shortcomings of laparoscopic surgery. We introduced this system for the treatment of gastric cancer in 2008. Here we report our initial experiences of robot-assisted surgery using the da Vinci system. METHODS: A retrospective review of robot-assisted gastrectomy for gastric cancer patients was performed in our institute. The clinicopathological features and surgical outcomes were analyzed. Whereas the procedures of the gastrectomy were similar to those of the usual laparoscopic surgery, several aspects such as the port placement and the role of the assistant were modified from those for conventional laparoscopic surgery. RESULTS: From January 2008 to December 2010, 61 patients with gastric cancer underwent robot-assisted surgery. Gastrectomy was distal in 46 patients, total in 14, proximal in 1 and no operation was converted to the open procedure. D2 lymph node dissection was performed on 28 patients in the distal gastrectomy group and on 11 in the total gastrectomy group. Complications occurred in 2 cases (4%): these consisted of ruptured sutures and hemorrhage from the anastomotic site. CONCLUSIONS: This study demonstrated that robot-assisted gastrectomy using the da Vinci system can be applied safely and effectively for patients with gastric cancer.