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This Recommendation was developed by the Japanese Society of Intravenous Anesthesia Recommendation Making Working Group (JSIVA-WG) to promote the safe and effective practice of total intravenous anesthesia (TIVA), tailored to the current situation in Japan. It presents a policy validated by the members of JSIVA-WG and a review committee for practical anesthesia management. Anesthesiologists should acquire and maintain the necessary knowledge and skills to be able to administer TIVA properly. A secure venous access is critically important for TIVA. To visualize and understand the pharmacokinetics of intravenous anesthetics, use of real-time pharmacokinetic simulations is strongly recommended. Syringe pumps are essential for the infusion of intravenous anesthetics, which should be prepared according to the rules of each individual anesthesia department, particularly with regard to dilution. Syringes should be clearly labeled with content and drug concentration. When managing TIVA, particularly with the use of muscle relaxants, monitoring processed electroencephalogram (EEG) is advisable. However, the depth of sedation/anesthesia must be assessed comprehensively using various parameters, rather than simply relying on a single EEG index. TIVA should be swiftly changed to an alternative method that includes inhalation anesthesia if necessary. Use of antagonists at emergence may be associated with re-sedation risk. Casual administration of antagonists and sending patients back to surgical wards without careful observation are not acceptable.

The A11 region plays a role in numerous physiological functions, including pain and locomotor activity, and consists of a variety of neurons including GABAergic, calbindin positive (Calb + ), and dopaminergic (DA) neurons. However, the neurochemical nature of Calb + neurons and their regulatory role in the A11 region remain largely unknown. In this study, we examined the kind of functional markers co-expressed in the Calb + neurons using sections from 8-week-old rats. To examine a marker related to classical neurotransmitters, we performed in situ hybridization for vesicular glutamate transporter 2 (vGluT2) or glutamate decarboxylase (GAD) 65 and 67, in conjunction with Calb immunohistochemistry. We found cellular co-expression of Calb with vGluT2 or GAD65/67 throughout the A11 region. Nearly all Calb + /GAD65/67 + neurons were found in the rostral-middle aspect of the A11 region. In contrast, Calb + /vGluT2 + neurons were found predominantly in the middle-caudal aspect of the A11 region. For receptors and neuropeptides, we performed immunohistochemistry for androgen receptor (AR), estrogen receptors (ERα and ERβ), and calcitonin gene-related peptide (CGRP). We found that Calb + neurons co-expressed AR in the rostral aspect of the A11 region in both male and female rats. However, we rarely find cellular co-expression of Calb with ERα or ERβ in this region. For CGRP, we found both Calb + neurons with or without CGRP expression. These results demonstrate that Calb + neurons co-express many functional markers. Calb + neurons have a distinct distribution pattern and may play a variety of regulatory roles, depending on their location within the A11 region.

BackgroundAnastomotic leakage (AL) is one of the most serious complications after low anterior resection (LAR) for rectal cancer, and the significance of diverting stoma to prevent AL is still controversial. The aim of this study is to clarify the potential benefits and safety of diverting ileostomy (DI) following laparoscopic LAR in rectal cancer patients.MethodsThis was a retrospective cohort study of 417 rectal cancer patients who underwent laparoscopic LAR in a single institute. The risk factors for AL and the DI-related morbidity were assessed.ResultsDI was performed in 226 patients (54.2%). The incidence rates of symptomatic AL showed no significant difference between patients with and without DI (8.4% vs. 10.0%, p = 0.612). AL requiring a surgical intervention was relatively lower in patients with DI than in those without DI (1.8% vs. 4.7%, p = 0.097). DI construction was an independent risk factor for AL requiring a surgical intervention (OR 3.47, p = 0.041), as was the serum albumin level (p = 0.003), and being male was a relative risk factor (p = 0.058). Focusing on sex, the rate of AL requiring a surgical intervention was significantly different in male (1.7 and 7.9%, p = 0.021) but not in female patients (1.9 and 1.1%, p = 1.000) with and without DI. The DI construction-related morbidity was 9.7%, and no patient required a reoperation. Of 226 patients with DI, 209 (92.5%) underwent stoma closure 118 days (median 30–509 days) after LAR. The stoma closure-related morbidity was 9.1% and 1 patient (0.5%) required a reoperation due to anastomotic leakage.ConclusionsDI following laparoscopic LAR can decrease the risk of AL, requiring a surgical intervention, especially in male patients with malnutrition. However, due to DI-related morbidity, DI is not recommended in female patients.

Background The indications for lateral lymph node dissection (LLND) in rectal cancer have been controversial. The purpose of this study was to clarify the significance of lateral lymph node metastasis in low rectal cancer. Methods This was a retrospective study at a high-volume cancer center in Japan. In this study, 40 patients with pathologically positive LLN (LLN+) were matched with 175 negative (LLN−) patients by propensity score matching (PSM). COX regression analysis was used to identify independent risk factors related to prognosis. The relapse-free survival rate (RFS) and overall survival rate (OS) of the 2 groups before and after matching were analyzed. Results Of the 64 patients undergoing LLND, 40 (62.5%) patients had LLN+ disease. The LLN+ patients showed deeper infiltration of the primary tumor than the LLN− patients (T3-T4: 87.5% vs. 72.0%; p = 0.044), a greater number of metastatic lymph nodes (N2: 75.0% vs. 35.4%; p < 0.001), and a higher rate of local recurrence (30% vs. 9.1%; p < 0.001). Adjuvant chemotherapy was more common in the 40 LLN+ patients than in the 175 LLN− patients (70.0% vs. 46.8%; p = 0.008). After relapse, the rate of first-line chemotherapy administration for LLN+ patients was higher than that for the LLN− patients (62.5% vs. 29.5%; p = 0.005). The RFS of LLN+ patients was shorter than that of the LLN− patients ( p = 0.005). After PSM, although more LLN+ patients received adjuvant chemotherapy than the LLN− patients (70.0% vs. 40.0%; p = 0.007), the local recurrence rate remained higher (30% vs. 10%; p = 0.025). The differences between RFS ( p = 0.655) and OS rates ( p = 0.164) of the 2 patient groups were not significant. Conclusion Even after LLND, patients with LLN+ low rectal cancer still showed an elevated local recurrence rate. Controlling local recurrence by adjuvant chemotherapy alone is difficult, and the additional strategic treatments are needed.

Background. The role of central sensitization in refractory pain-related diseases has not yet been clarified. Methods. We performed a multicenter case-controlled study including 551 patients with various neurological, psychological, and pain disorders and 5,188 healthy controls to investigate the impact of central sensitization in these patients. Symptoms related to central sensitization syndrome (CSS) were assessed by the Central Sensitization Inventory (CSI) parts A and B. Patients were categorized into 5 groups based on CSI-A scores from subclinical to extreme. The Brief Pain Inventory (BPI), addressing pain severity and pain interference with daily activities, and the Patient Health Questionnaire (PHQ)-9, assessing depressive symptoms, were also administered. Results. CSI-A scores and CSI-B disease numbers were significantly greater in patients than in controls (p<0.001). Medium effect sizes (r = 0.37) for CSI-A scores and large effect sizes (r = 0.64) for CSI-B disease numbers were found between patients and control groups. Compared with the CSI-A subclinical group, the CSI-A mild, moderate, severe, and extreme groups had significantly higher BPI pain interference and severity scores, PHQ-9 scores, and CSS-related disease numbers based on ANCOVA. Greater CSI-B numbers resulted in higher CSI-A scores (p<0.001) and a higher odds ratio (p for trend <0.001). CSS-related symptoms were associated with pain severity, pain interference with daily activities, and depressive symptoms in various pain-related diseases. Conclusions. Our findings suggest that CSS may participate in these conditions as common pathophysiology.

The purpose of this study was to investigate the clinical, pathological, and prognostic differences between adenocarcinoma (ADC) and mucinous adenocarcinoma (MUC) in colorectal cancer (CRC). This was a retrospective study of a Japanese high-volume cancer Center over a 10-year period. From April 2007 to December 2016, a total of 3,296 patients with primary CRC were included in the study. The clinical characteristics of MUC and ADC were compared. Then, propensity score matching was performed according to a 1:2 ratio. Multivariate analysis was used for independent risk factors related to prognosis. The overall survival (OS) and disease-free survival (DFS) of 126 cases of MUC and 256 cases of ADC were studied, as well as the survival rate of each stage. MUC accounts for 3.82% of the total CRC. Compared to ADC, MUC is more common in female patients (47.62% vs. 38.77%; p=0.045), with higher carcinoembryonic antigen levels (56.35% vs. 34.95%; p<0.001), more ulcerative and infiltrative types (82.54% vs. 72.93%; p=0.016), higher incidence of perineural infiltration (51.59% vs. 41.04%; p=0.018), deeper infiltration (T3-T4: 90.48% vs. 65.84%; p<0.001), and more advanced cancer (stage III-IV: 59.52% vs. 44.79%; p=0.001). MUC is also more likely to recur (24.6% vs. 14.32%; p=0.001). Regarding the long-term survival rate, the OS (p<0.001) and DFS (p=0.05) is consequently worse. After propensity score matching, multivariate analysis showed that MUC was a common independent risk factor for DFS [odds ratio (OR)=4.277; 95% confidence interval (CI), 0.327-0.97; p=0.039], and also for OS (OR= 6.836; 95% CI, 0.274-0.831; p=0.009). In MUC, OS and DFS were still relatively worse (OS: p=0.017; DFS: p=0.038). However, only significant statistical differences were shown in stage II (OS: p=0.003; DFS: p=0.007). No significant differences were noted in the stages I, III, or IV. MUC is a high-risk factor for stage II CRC. Adjuvant chemotherapy should be routinely recommended for patients with MUC stage II, and special attention should be paid during their follow-up.

Background The safety of laparoscopic surgery (LAP) in elderly patients with colorectal cancer has not been demonstrated. The aim of this study was to compare the outcomes of LAP and open surgery (OP) and estimate the feasibility of LAP in colorectal cancer patients aged ≥80 years. Methods We conducted a propensity scoring matched case–control study of colon and rectal cancer patients aged ≥80 years using data from 41 hospitals between 2003 and 2007. A total of 1,526 colon cancer patients and 282 rectal cancer patients underwent surgery and were included in the analysis. The primary end point was 3-year overall survival (OS). Secondary end points included disease-free survival (DFS), cancer-specific survival (CSS), and postoperative complications. Results LAP and OP were compared in 804 colon cancer patients (402 pairs) and 114 rectal cancer patients (57 pairs) after all covariates were balanced, and no significant differences were observed, except for tumor size in colon cancer. OS, DFS, and CSS did not differ between the groups for either colon cancer ( P  = 0.916, 0.968, and 0.799, respectively) or rectal cancer ( P  = 0.765, 0.519, and 0.950, respectively). In colon cancer cases, LAP was associated with fewer morbidities than was OP (24.9 vs. 36.3 %, P  < 0.001); no such difference was observed for rectal cancer patients (47.4 vs. 40.4 %, P  = 0.450). Conclusions LAP is an acceptable alternative to OP in elderly patients with colorectal cancer.

The A11 dopaminergic cell group is the only group among the A8–A16 dopaminergic cell groups that includes neurons innervating the spinal cord, and a decrease in dopaminergic transmission at the spinal cord is thought to contribute to the pathogenesis of restless legs syndrome. However, the mechanisms regulating the neuronal activity of A11 dopaminergic neurons remain to be elucidated. Unraveling the neuronal composition, distribution and connectivity of A11 neurons would provide insights into the mechanisms regulating the spinal dopaminergic system. To address this, we performed immunohistochemistry for calcium-binding proteins such as calbindin (Calb) and parvalbumin (PV), in combination with the retrograde tracer Fluorogold (FG) injected into the spinal cord. Immunohistochemistry for Calb, PV, or tyrosine hydroxylase (TH), a marker for dopaminergic neurons, revealed that there were at least three types of neurons in the A11 region: neurons expressing Calb, TH, or both TH and Calb, whereas there were no PV-immunoreactive (IR) cell bodies. Both Calb- and PV-IR processes were found throughout the entire A11 region, extending in varied directions depending on the level relative to bregma. We found retrogradely labeled FG-positive neurons expressing TH, Calb, or both TH and Calb, as well as FG-positive neurons lacking both TH and Calb. These findings indicate that the A11 region is composed of a variety of neurons that are distinct in their neurochemical properties, and suggest that the diencephalospinal dopamine system may be regulated at the A11region by both Calb-IR and PV-IR processes, and at the terminal region of the spinal cord by Calb-IR processes derived from the A11 region.

BackgroundProficiency of the operating surgeon is one of the most critical factors potentially associated with reductions in complications and surgery-related mortality. With video-rating systems having shown potential for assessing laparoscopic surgeons’ proficiency, the Endoscopic Surgical Skill Qualification System (ESSQS) was developed by the Japan Society for Endoscopic Surgery to subjectively assess the proficiency of laparoscopic surgeons by rating applicants’ non-edited case videos. We conducted a study to evaluate how ESSQS skill-qualified (SQ) surgeon involvement influences short-term outcomes of laparoscopic gastrectomy performed for gastric cancer.MethodsData from the National Clinical Database regarding laparoscopic distal and total gastrectomy performed for gastric cancer between January 2016 and December 2018 were analyzed. Operative mortality, defined as 30-day mortality or 90-day in-hospital mortality, and anastomotic leakage rates were compared per involvement vs. non-involvement of an SQ surgeon. Outcomes were also compared per involvement of a gastrectomy-, colectomy-, or cholecystectomy-qualified surgeon. The association between the area of qualification and operative mortality/anastomotic leakage was also analyzed with a generalized estimating equation logistic regression model used to account for patient-level risk factors and institutional differences.ResultsOf 104,093 laparoscopic distal gastrectomies, 52,143 were suitable for inclusion in the study; 30,366 (58.2%) were performed by an SQ surgeon. Of 43,978 laparoscopic total gastrectomies, 10,326 were suitable for inclusion; 6501 (63.0%) were performed by an SQ surgeon. Gastrectomy-qualified surgeons outperformed non-SQ surgeons in terms of both operative mortality and anastomotic leakage. They also outperformed cholecystectomy- and colectomy-qualified surgeons in terms of operative mortality or anastomotic leakage in distal and total gastrectomy, respectively.ConclusionThe ESSQS appears to discriminate laparoscopic surgeons who can be expected to achieve significantly improved gastrectomy outcomes.

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for pain disorders and exert pharmacological effects by inhibiting cyclooxygenase (COX). Although previous studies have evaluated the COX inhibitory activity and selectivity of NSAIDs, none has compared COX inhibitory concentrations with the plasma concentrations of clinical doses or investigated the efficacy and adverse effects of different dosage forms. Therefore, in this study we evaluated the COX inhibitory activities and inhibition rates of clinical doses of the various NSAID formulations, especially diclofenac sodium. Methods Human blood and the drug (diclofenac sodium, celecoxib, ibuprofen, flurbiprofen, or etodolac) were mixed and incubated, and the supernatant was collected and quantified the COX inhibitory activity of each drug by ELISA. Logistic regression analyses were used to calculate the inhibition rates at maximum plasma drug concentration ( C max ) of clinical doses of marketed formulations. For diclofenac sodium, we also calculated the concentrations at which COX inhibition rates were 50% and 80% (IC 50 and IC 80 ). Results COX-2 inhibition rate at C max of clinical doses exceeded 50% except celecoxib 100 mg. For diclofenac sodium, the C max at the clinical doses of the oral and suppository formulations showed almost complete inhibition of COX-2 and an inhibition rate exceeding IC 80 for COX-1. The C max at repeated doses of the transdermal formulation showed an inhibition rate above IC 80 for COX-2 but below IC 80 for COX-1. Discussion This result explains why gastrointestinal disorders frequently occur with oral and suppository formulations of diclofenac sodium despite its relatively high COX-2 selectivity. Although the plasma drug concentration of the transdermal formulation is lower than oral and suppository formulations, it has an inhibition rate above IC 50 for COX-2, which is required for analgesic efficacy, and has a lower COX-1 inhibition rate than these formulations. Conclusion The findings explain why the transdermal formulation exerts an analgesic effect despite having a lower C max than other diclofenac sodium formulations.