ß-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.

Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that ß-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of ß-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant ß-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.

γδ T cells turn the tables on immune-evasive colon cancer.

Why is checkpoint blockade immunotherapy still effective in tumors that are unrecognizable to CD8+ T cells? In a recent study published in Nature, de Vries et al.1 provide evidence that the lesser-known γδ T cell population may mediate beneficial responses to immune checkpoint blockade when cancer cells lose HLA expression.

NKG2D signaling regulates IL-17A-producing γδT cells in mice to promote cancer progression.

γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance, homeostasis, and cancer. γδT cells recognize stressed cells or cancer cells through the NKG2D receptor to kill these cells and maintain normality. Contrary to the well-established anti-tumor function of these NKG2D-expressing γδT cells, we show here that, in mice, NKG2D regulates a population of pro-tumor γδT cells capable of producing IL-17A. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduced the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increased the frequency of γδT cells. Together, these data support the hypothesis that, in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

Successful Double-lumen Tube Intubation in the Lateral Position for a Patient with a Giant Superior Mediastinal Tumor.

OBJECTIVE: Anesthetic management of patients with giant mediastinal tumors is challenging from the perspective of both cardiovascular and respiratory management, and airway assessment is important for both concerns. We report the successful induction of general anesthesia and double-lumen tube intubation in the right lateral position for a patient with a giant mediastinal tumor with tracheal compression, using pre-operative chest radiograph imaging to minimize tracheal compression during induction. METHODS: A 41-year-old man required thoracoscopic giant superior mediastinal tumor resection. His trachea was compressed and displaced because of the tumor. Because preoperative chest radiography revealed that the tracheal diameter increased in the right lateral position, we chose this position for induction. RESULTS: Prompt and smooth intubation with a 35-Fr double-lumen tube (DLT) was achieved, and no adverse events associated with intubation were encountered. CONCLUSION: Safe and smooth induction with a DLT was performed owing to the perioperative chest radiograph imaging examination, which revealed the most advantageous position regarding minimal tracheal compression.

Gut γδ T cells as guardians, disruptors, and instigators of cancer.

Colorectal cancer is the third most common cancer worldwide with nearly 2 million cases per year. Immune cells and inflammation are a critical component of colorectal cancer progression, and they are used as reliable prognostic indicators of patient outcome. With the growing appreciation for immunology in colorectal cancer, interest is growing on the role γδ T cells have to play, as they represent one of the most prominent immune cell populations in gut tissue. This group of cells consists of both resident populations-γδ intraepithelial lymphocytes (γδ IELs)-and transient populations that each has unique functions. The homeostatic role of these γδ T cell subsets is to maintain barrier integrity and prevent microorganisms from breaching the mucosal layer, which is accomplished through crosstalk with enterocytes and other immune cells. Recent years have seen a surge in discoveries regarding the regulation of γδ IELs in the intestine and the colon with particular new insights into the butyrophilin family. In this review, we discuss the development, specialities, and functions of γδ T cell subsets during cancer progression. We discuss how these cells may be used to predict patient outcome, as well as how to exploit their behavior for cancer immunotherapy.

Sialorphin Potentiates Effects of [Met5]Enkephalin without Toxicity by Action other than Peptidase Inhibition.

This dose-response study investigated the effects of sialorphin on [Met5]enkephalin (ME)-induced inhibition of contractions in mouse vas deferens and antinociception in male rats. Differences were compared among combinations of three chemical peptidase inhibitors: amastatin, captopril, and phosphoramidon. The ratio of potencies of ME in mouse vas deferens pretreated with both sialorphin (100 µM) and a mixture of the three peptidase inhibitors (1 µM each) was higher than that with the mixture of peptidase inhibitors alone at any dose. Intrathecal administration of sialorphin (100-400 nmol) significantly and dose dependently increased ME (3 nmol)-induced antinociception with the mixture of three peptidase inhibitors (10 nmol each). The degree of antinociception with a combination of any two of the peptidase inhibitors (10 nmol each) in the absence of sialorphin was less than that in the presence of sialorphin (200 nmol). Pretreatment with both sialorphin (200 nmol) and the mixture of three peptidase inhibitors (10 nmol each) produced an approximately 100-fold augmentation in ME (10 nmol)-induced antinociception, but without signs of toxicity such as motor dysfunction in rats. Radioligand receptor binding assay revealed that sialorphin did not affect either binding affinity or maximal binding capacity of [d-Ala2,N-MePhe4,Gly-ol5]enkephalin. These results indicate that sialorphin potentiates the effects of ME without toxicity by a mechanism other than peptidase inhibition and with no effect on its affinity to µ-opioid receptors. SIGNIFICANCE STATEMENT: Sialorphin is regarded as an endogenous peptidase inhibitor that interacts with enkephalin-degrading enzymes. The results of these in vitro and in vivo studies confirm that sialorphin potentiates the effects of [Met5]enkephalin without toxicity by an action other than peptidase inhibition. This suggests that sialorphin offers the advantage of reducing or negating the side effects of opioid drugs and endogenous opioid peptides.

Prospective randomized study evaluating the usefulness of a surgical smoke evacuation system in operating rooms for breast surgery.

BACKGROUND: No prospective evaluation of surgical smoke evacuation systems has yet been conducted anywhere in the world. A prospective randomized study was conducted to clarify the usefulness of a surgical smoke evacuation system in terms of reducing the quantity of environmental pollutants found in operating room air and reducing the occupational exposure of doctors and nurses involved in surgical procedures to surgical smoke, volatile organic compounds, formaldehyde, etc. METHODS: Operating room environment conditions with and without the use of a surgical smoke evacuation system were measured, and the personal exposure levels of doctors and nurses involved in surgical procedures were also surveyed. Use of the evacuation system was determined randomly, and the procedures involved were breast-conserving surgery and mastectomy, which were treated as stratification factors. RESULTS: The average total volatile organic compound concentration in the operating room was significantly lower when the evacuation system was used compared with when it was not used. The findings were similar for formaldehyde concentration. Multiple regression analysis for healthcare professionals' personal exposure levels showed that the evacuation system was a factor that significantly impacted their formaldehyde and acetaldehyde personal exposure levels, which were greatly reduced by the use of the system. CONCLUSION: This study's findings demonstrate the effectiveness of the evacuation systems, which should increase awareness that their benefits take priority over the drawbacks. TRIAL REGISTRATION: The study was conducted after explaining to participants that it was a study of operating room environments in which their participation was voluntary and obtaining their consent. The study was also approved by the Tokai University Hospital clinical research review committee (no. 5R-022) and registered with the UMIN registry (UMIN000029092) on 13, September, 2017- retrospectively registered.

Efficacy and safety of remimazolam versus propofol for general anesthesia: a multicenter, single-blind, randomized, parallel-group, phase IIb/III trial.

PURPOSE: This trial was conducted to confirm the non-inferiority of remimazolam versus propofol in the induction and maintenance of general anesthesia in surgical patients. METHODS: Surgical patients (n = 375) were randomized to remimazolam started at 6 or 12 mg/kg/h by continuous intravenous (IV) infusion until the loss of consciousness (LoC), followed by 1 mg/kg/h to be adjusted as appropriate until the end of surgery or IV propofol administered as a slow bolus of 2.0-2.5 mg/kg until LoC followed by 4-10 mg/kg/h until the end of surgery. Efficacy was measured via the combined primary endpoint of no intraoperative awakening/recall, no need for rescue sedatives, and no body movements. Adverse events and adverse drug reactions (ADRs) were monitored for safety. RESULTS: Efficacy rates were 100% in all treatment groups, and the non-inferiority of remimazolam was demonstrated [95% confidence interval (- 0.0487; 0.0250)]. The time to LoC was longer in the remimazolam 6 (p < 0.0001) and 12 mg/kg/h (p = 0.0149) groups versus propofol. The time to extubation was longer in both remimazolam groups versus the propofol group (p ≤ 0.0001). The incidence of ADRs was similar in the remimazolam groups (39.3% and 42.7%, respectively) compared with the propofol group (61.3%). Decreased blood pressure occurred in 20.0% and 24.0% of patients treated with 6 and 12 mg/kg/h remimazolam, respectively, compared with 49.3% of patients receiving propofol. Injection site pain was reported in 18.7% of propofol patients but not in those receiving remimazolam. CONCLUSIONS: This trial demonstrated that remimazolam was well tolerated and non-inferior to propofol with regard to efficacy as a sedative hypnotics for general anesthesia. CLINICAL TRIAL REGISTRATION: This trial is registered with the Japan Pharmaceutical Information Center - Clinical Trials Information (JapicCTI). JapicCTI number: 121973.

Safety and efficacy of remimazolam in induction and maintenance of general anesthesia in high-risk surgical patients (ASA Class III): results of a multicenter, randomized, double-blind, parallel-group comparative trial.

PURPOSE: Remimazolam, an ultra-short-acting benzodiazepine sedative is equally effective as propofol in induction and maintenance of general anesthesia with improved hemodynamic stability in American Society of Anesthesiologists (ASA) Class I and II patients. This trial investigated remimazolam's efficacy and safety in vulnerable patients (ASA Class III) undergoing elective general surgery. METHODS: A multicenter, randomized, double-blind, parallel-group trial in 67 adult surgical patients undergoing general anesthesia with two remimazolam induction doses (6 mg kg-1 h-1-group A and 12 mg kg-1 h-1-group B) has been conducted in 6 trials sites in Japan. Remimazolam was infused up to 2 mg kg-1 h-1 for maintenance of anesthesia in both groups. RESULTS: The functional anesthetic capability of the investigated drug was 100% in both arms. The mean time to loss of consciousness (LoC) was significantly shorter in group B (81.7 s) compared to group A (97.2 s), p = 0.0139. The mean bispectral index (BIS) value during maintenance of anesthesia ranged from 46.0 to 68.0 and from 44.7 to 67.5 in group A and B, respectively. There was no statistically significant difference between the remimazolam arms concerning the incidence of blood pressure (BP) decrease (67.7% in group B vs. 54.8% in group A), recovery profile or the incidence or severity of adverse events (AEs) or adverse drug reactions (ADRs). CONCLUSION: Both induction regimens (6 and 12 mg kg-1 h-1) were equally efficacious and safe in surgical patients ASA Class III. A significantly shorter time to LoC was observed with the higher remimazolam dosage. Clinical trial registration This trial is registered with the Japan Pharmaceutical Information Center-Clinical Trials Information (JapicCTI). JapicCTI number: 121977.

Protein malnutrition prevents heat conservation induced by amino acid infusion during general anesthesia in rats.

The intravenous administration of an amino acid (AA) mixture during general anesthesia reduces anesthesia-induced hypothermia. AA-induced skeletal muscle protein synthesis and thermogenesis play important roles in the antihypothermic effects of AAs. We hypothesized that a preanesthetic dietary protein deficiency impairs the antihypothermic effects of AAs during general anesthesia due to a reduction in thermogenesis caused by a decrease in muscle protein synthesis. Sprague-Dawley rats were divided into 4 groups: fed a control diet plus saline (CON-SAL) or the AA mixture (CON-AA), and fed a protein-free diet plus saline (PF-SAL) or the AA mixture (PF-AA). SAL solution or AA mixture solution was infused for 180 minutes during sevoflurane anesthesia, and rectal temperatures were measured. Rectal temperatures were significantly higher in the CON-AA group than in the PF-AA group 90 to 180 minutes after initiating the intravenous infusion of the test solutions. There was no significant difference between the PF-SAL and PF-AA groups. Plasma insulin concentrations were significantly higher in the CON-AA group than in the PF-AA group (P < .05). The phosphorylation states of protein kinase B, mammalian target of rapamycin, and eukaryotic initiation factor 4E-binding protein 1 were significantly greater in the CON-AA group than in the PF-AA group (P < .05, P < .05, and P < .01, respectively). Our results indicated that a dietary protein deficiency before general anesthesia impaired the antihypothermic effects of an AA mixture infusion during general anesthesia by decreasing muscle protein synthesis through the insulin-stimulated phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin complex 1 signaling pathway followed by metabolic heat production.

Successful Intubation Using the Airtraq Double Lumen® with the Universal Adapter for Smartphones® in a Case of Intubation Difficulty.

OBJECTIVE: The Universal Adapter for Smartphones® c an record s till images and movies during intubation using the monitor display and recording functions of a smartphone. Here, we describe the successful use of the Airtraq Double Lumen® with the Universal Adapter for Smartphones® for airway management during anesthesia in a patient with intubation difficulty. METHODS: A 78-year-old man required thoracoscopic upper lobectomy for a pulmonary tumor. Preoperative examination revealed micrognathia, mouth opening equivalent to a three-finger width, Mallampati Class II, mentum-hyoid bone distance equal to a 2.5-finger width, hyoid bone-thyroid cartilage distance equal to a two-finger width, and Class I findings in the Upper Lip Bite Test. After inducing anesthesia and confirming the feasibility of mask ventilation, we administered 70 mg of rocuronium and inserted the Airtraq Double Lumen®. The Universal Adapter for Smartphones® connected to a 4-inch iPod Touch® was attached to its eye cup, through which the iPod Touch displayed images for easy visualization of the glottal area. RESULTS: Prompt and smooth intubation with a 35-Fr double-lumen tube (DLT) was achieved. There were no adverse events associated with intubation. CONCLUSION: Combination of the Universal Adapter for Smartphones® and the Airtraq Double Lumen® can facilitate smooth tracheal intubation with a DLT in cases of difficult intubation.

Anesthetic Management in Tracheal Dilatation for Severe Tracheal Stenosis.

We report the anesthetic management of a 65-year-old woman with recurrent, severe tracheal stenosis who underwent tracheal dilatation. She had visited the Department of Respiratory Medicine at our hospital for respiratory distress approximately 20 years ago, and had undergone laser ablation under local anesthesia. Because of recurrence and aggravation of respiratory distress, she now presented at the Department of Thoracic Surgery, and was scheduled for surgery. Percutaneous cardiopulmonary support was prepared, and she was sedated with midazolam and dexmedetomidine. Under bronchoscopic guidance, a 5-mm intubation tube was placed directly above the stenosis site. Laser ablation (by argon plasma coagulation) and balloon dilatation were performed, and the tube was replaced with one with a larger diameter, which was subsequently replaced with another with an even larger diameter. Ultimately, a 7-mm tube was placed beyond the stenosis site, and the operation was completed. After restoration of spontaneous respiration and consciousness, the patient was extubated in the operating room and returned to the intensive care unit. In anesthetic management of patients with tracheal stenosis, treatment of hypoxia is important. In this case, we collaborated with the attending physician, clinical engineers, and operating room nurses throughout, and consequently, were able to perform the operation safely.

A Case of Mediastimal Emphysema Possibly Caused by the Insertion of a Laryngoscope.

Insertion of a laryngoscope to a patient with a strong pharyngeal reflex resulted in pharyngeal injury and subsequent development of mediastinal emphysema. An increase in airway pressure accompanying a strong pharyngeal reflex, as well as pharyngeal injury were thought to be factors associated with the development of mediastinal emphysema.

A Case of Superior Mesenteric Artery Occlusion Caused by Delayed Administration of Anticoagulants in a Patient with Nonvalvular Atrial Fibrillation.

A 86-year-old female with nonvalvular atrial fibrillation (NOVAF) who did not receive prophylactic anticoagulant treatment visited our hospital because of gastrointestinal symptoms. At first, acute gastroenteritis was suspected, but later she developed ileus and she was diagnosed with superior mesenteric artery occlusion (SMAO). We successfully performed the anesthetic management of this patient and subtotal resection of the small intestine was performed. Heparin was initiated after surgery, but she developed cerebral infarction later, and finally she died due to infection and anemia caused by melena. Although this patient was at high risk of thrombosis, she did not receive anticoagulant treatment. It might result in developing SMAO, and once SMAO occurred, thrombosis recurred even on anticoagulant treatment. This case suggested the importance of primary prevention of thrombosis in patients with NVAF.

Evaluation of lead aprons and their maintenance and management at our hospital.

Lead aprons are worn by medical workers to reduce the effects of the radiation doses to which they are exposed during radiography and surgery performed with radioscopic apparatus. Regarding the management of such aprons, the Radiation Protection Section of the Japanese Society of Radiological Technology issued the "Guidelines for the Management of Lead Aprons" in 2000, and common management criteria have been set for all institutions. However, we found that the lead aprons used in operating rooms had not been closely inspected before 2014 in our hospital. Thus, we examined the extent of damage of such aprons in our operation room via computed tomography (CT) scout imaging, as well as visual and tactile inspections. Although no abnormality was detected upon visual and tactile inspections, CT images revealed that protective aprons used for 6 years or more had damaged internal radiation shields, thus risking radiation exposure. In response to these results, we fully realized the need to examine the date of the initial use of currently used lead aprons, to routinely perform visual and tactile inspections, and to regularly evaluate the extent of damage to the internal radiation shields via fluoroscopy in cooperation with the radiation management section.

Usefulness of Acoustic Monitoring of Respiratory Rate in Patients Undergoing Endoscopic Submucosal Dissection.

Aim. The study assessed the usefulness of a recently developed method for respiratory rate (RR) monitoring in patients undergoing endoscopic submucosal dissection (ESD) under deep sedation. Methods. Study subjects comprised 182 consecutive patients with esophageal cancer or gastric cancer undergoing ESD. The usefulness of acoustic RR monitoring was assessed by retrospectively reviewing the patients' records for age, gender, height, weight, past history, serum creatinine, RR before ESD, and total dose of sedative. Results. Respiratory suppression was present in 37.9% of (69/182) patients. Continuous monitoring of RR led to detection of respiratory suppression in all these patients. RR alone was decreased in 24 patients, whereas both RR and blood oxygen saturation were decreased in 45 patients. Univariate analysis showed female gender, height, weight, and RR before treatment to be significantly associated with respiratory suppression. Multivariate analysis showed RR before treatment to be the only significant independent predictor [odds ratio (OR) 0.83, 95% confidence interval (CI) 0.73-0.95, and P = 0.006] of respiratory suppression. Conclusion. In this study, the difference in RR before treatment between patients with and without respiratory suppression was subtle. Therefore, we suggest that acoustic RR monitoring should be considered in patients undergoing ESD under sedation to prevent serious respiratory complications.

Reduction in amino-acid-induced anti-hypothermic effects during general anesthesia in ovariectomized rats with progesterone replacement.

PURPOSE: The aim of the present study was to determine whether the ovarian hormones, estrogen and progesterone, had different influences on amino-acid-induced anti-hypothermic effects during general anesthesia. METHODS: Ovariectomized Sprague-Dawley female rats were divided into four groups: those administered 17ß-estradiol plus saline or an amino acid mixture (E2-Sal and E2-AA, respectively) and progesterone plus saline or an amino acid mixture (P-Sal and P-AA, respectively). Five weeks after ovariectomy, rats were given either E2 or P and then administered either Sal or AA solution for 180 min during anesthesia with sevoflurane. Rectal temperatures were measured. RESULTS: Rectal temperatures were significantly higher in the E2-AA group than in the E2-Sal group 165 and 180 min after initiating the infusion of the test solutions. However, no significant differences were observed between the P-treated groups. The phosphorylation of 4E-BP1 and S6K1 was significantly greater in the E2-AA group than in the E2-Sal group (P < 0.05, P < 0.001, respectively). In contrast, the phosphorylation of 4E-BP1 was significantly lower in the P-AA group than in the P-Sal group (P < 0.001). CONCLUSIONS: These results suggest that progesterone reduces amino-acid-induced anti-hypothermic effects during general anesthesia.

Predicting Preoperative Hemodynamic Changes Using the Visual Analog Scale.

PURPOSE: This study aimed to investigate how both visual analog scale cutoff scores and State-Trait Anxiety Inventory scores relate to hemodynamic changes in patients entering the operating theater. DESIGN: A prospective observational study. METHODS: The study subjects included 130 prospectively enrolled patients who were scheduled for abdominal surgery under combined epidural-general anesthesia and who underwent preoperative anxiety level measurements using both scales. FINDINGS: The heart rate and systolic blood pressure on entering the operating theater were significantly higher than those at baseline in the high and low/moderate anxiety groups. Variations in heart rate and systolic blood pressure were significantly higher, whereas peripheral blood flow was significantly lower in the high anxiety group compared with the low/moderate anxiety group. CONCLUSIONS: Using the visual analog scale to measure anxiety can improve our understanding of the hemodynamic changes that occur when patients enter the operating theater.

mab21-l3 regulates cell fate specification of multiciliate cells and ionocytes.

Cell fate specifications of multiciliate cells (MCCs) and ionocytes are commonly suppressed by the Notch pathway in developing epithelia, but are governed by different master regulators, suggesting the existence of a common regulator linking the Notch pathway to both MCC and ionocyte specifications. Here we show that a mab21 family gene, mab21-l3, represents the missing link. In Xenopus embryonic epidermis, mab21-l3 expression is specifically found in MCCs and ionocytes and is downregulated by the Notch pathway. Knockdown of mab21-l3 in Xenopus downregulates both MCC-specific and ionocyte-specific master genes, resulting in drastic loss of MCCs and ionocytes. In mouse tracheal epithelial cells, mab21-l3 expression is also downregulated by the Notch pathway and is required for MCC differentiation. Moreover, conditional gain of function of mab21-l3 rescues Notch-induced loss of MCCs and ionocytes in Xenopus. These results indicate that mab21-l3 acts downstream of the Notch pathway in cell fate specifications of MCCs and ionocytes.