The impact of preoperative psychiatric intervention for postoperative delirium after major oral and maxillofacial surgery with free flap reconstruction.

BACKGROUND: Postoperative delirium (POD) is a severe complication associated with various adverse outcomes, especially in older patients. Although the incidence and risk factors for POD have been explored in general surgery, they have not been fully elucidated. Early identification of high-risk patients and active preoperative intervention are considered essential for the prevention of POD. Recently, psychiatric consultation intervention have been shown to prevent delirium. This study investigated the effect of preoperative psychiatric interventions on preventing POD in our specific surgical context. MATERIALS AND METHODS: This retrospective, single-center observational study included 86 patients who underwent major oral and maxillofacial surgery with free flap reconstruction between 2016 and 2023. The effect of psychiatric intervention were compared between patients with and without delirium. RESULTS: Preoperative psychiatric intervention did not reduce the incidence of POD. The incidence of POD was 29.1 %. Univariate analyses showed no significant associations between POD and any clinical variables. CONCLUSION: There was no difference in the incidence of POD between patients who received preoperative psychiatric intervention and those who did not, and further investigation is needed to determine the efficacy of preoperative psychiatric intervention in the prevention of POD.

Acanthopanax senticosus ameliorates steatohepatitis through HNF4 alpha pathway activation in mice.

Non-alcoholic fatty liver disease is a common liver disease worldwide, and is associated with dysregulation of lipid metabolism, leading to inflammation and fibrosis. Acanthopanax senticosus Harms (ASH) is widely used in traditional medicine as an adaptogen food. We examined the effect of ASH on steatohepatitis using a high-fat diet mouse model. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet with ASH extract (ASHE). After 6 weeks, liver RNA transcriptome sequencing (RNA-Seq) was performed, followed by Ingenuity Pathway Analysis (IPA). Our findings revealed that mice fed a high-fat diet with 5% ASHE exhibited significantly reduced liver steatosis. These mice also demonstrated alleviated inflammation and reduced fibrosis in the liver. IPA of RNA-Seq indicated that hepatocyte nuclear factor 4 alpha (HNF4 alpha), a transcription factor, was the activated upstream regulator (P-value 0.00155, z score = 2.413) in the liver of ASHE-fed mice. Adenosine triphosphate binding cassette transporter 8 and carboxylesterase 2, downstream targets of HNF4 alpha pathway, were upregulated. Finally, ASHE-treated HepG2 cells exposed to palmitate exhibited significantly decreased lipid droplet contents. Our study provides that ASHE can activate HNF4 alpha pathway and promote fat secretion from hepatocytes, thereby serving as a prophylactic treatment for steatohepatitis in mice.

Quantification of muscle tone by using shear wave velocity during an anaesthetic induction: a prospective observational study.

OBJECTIVES: The quantitative assessment of muscle stiffness or weakness is essential for medical care. Shear wave elastography is non-invasive ultrasound method and provides quantitative information on the elasticity of soft tissue. However, the universal velocity scale for quantification has not been developed. The aim of the study is to determine the shear wave velocities of abdominal muscle during anesthetic induction and to identify methods to cancel the effects of confounders for future development in the quantitative assessment of muscle tone using the universal scale. METHODS: We enrolled 75 adult patients undergoing elective surgery with ASA-PS I - III in the period between December 2018 and March 2021. We measured and calculated the shear wave velocity (SWV) before and after opioid administration (i.e., the baseline at rest and opioid-induced rigidity condition), and after muscle relaxant administration (i.e., zero reference condition). The SWV value was adjusted for the subcutaneous fat thickness by our proposed corrections. The SWVs after the adjustment were compared among the values in baseline, rigidity, and relaxation using one-way repeated-measures ANOVA and post hoc Tukey-Kramer test. A p-value of < 0.05 was considered to be statistically significant. UMIN Clinical Trials Registry identifier UMIN000034692, registered on October 30, 2018. RESULTS: The SWVs in the baseline, opioid-induced rigidity, and muscle relaxation conditions after the adjustment were 2.08 ± 0.48, 2.41 ± 0.60, and 1.79 ± 0.30 m/s, respectively (p < 0.001 at all comparisons). CONCLUSION: The present study suggested that the SWV as reference was 1.79 m/s and that the SWVs at rest and opioid-induced rigidity were ~ 10% and ~ 30% increase from the reference, respectively. The SWV adjusted for the subcutaneous fat thickness may be scale points for the assessment of muscle tone.

Successful recording of direct cortical motor-evoked potential from a pediatric patient under remimazolam anesthesia: a case report.

BACKGROUND: Intraoperative motor-evoked potential (MEP) monitoring reduces postoperative motor deficits. Propofol-based total intravenous anesthesia is the gold standard for intraoperative myogenic MEPs. Although there is no contraindication to administering propofol in adults with peanut, soy, or egg allergies, its safety in children with these allergies remains unclear. CASE PRESENTATION: A 12-year-old girl required general anesthesia under intraoperative direct cortical MEP (dc-MEP) monitoring due to supratentorial glioma. Remimazolam-based anesthesia was selected, instead of propofol, due to the patient's egg hypersensitivity. Stable myogenic MEPs were recorded throughout the surgery with remimazolam at 0.9 mg/kg/h and remifentanil at 0.35 µg/kg/min, following adjustments of stimulation intensity and titration of remimazolam infusion. Neither intraoperative memory nor motor deficits were present after surgery. CONCLUSIONS: We present a pediatric case whose dc-MEP was recorded under remimazolam anesthesia. The cardiovascular stability and avoidance of propofol infusion syndrome with remimazolam were superior to propofol.

Evaluation of contrast-enhanced ultrasonography with Sonazoid® in visualization of local anesthetic distribution in rectus sheath block: a prospective, clinical study.

PURPOSE: Clear visualization of ultrasound (US) images is crucial for successful US-guided nerve block. However, accurate determination of local anesthetic (LA) distribution from US images remains difficult. Sonazoid®, which comprises perflubutane microbubbles, is used to diagnose hepatic and breast tumors. This study aimed to investigate the visibility of Sonazoid® in perioperative US-guided nerve block. METHODS: We performed rectus sheath block (RSB) in patients scheduled for laparoscopic abdominal surgery (n = 10). 10 mL of a mixture containing equal amounts of 0.75% ropivacaine and iohexol with the addition of Sonazoid® diluted 100-fold was administered. We investigated the correlation and agreement between Sonazoid® and iohexol distributions. The brightness of the solution and tissues was calculated: a grayscale value between 0 (dark) and 255 (bright) was measured in all pixels of the region of interest. Adverse events were also investigated. RESULTS: Sonazoid® was clearly visualized and distinguished from the surrounding tissues both during and after RSB. The spread of Sonazoid® and iohexol was significantly correlated (spearman's ρ = 0.53, p = 0.0004). Bland-Altman analyses revealed significant mean difference between two methods (15.6 mm; 95% confidence interval [CI]: 10.6, 20.6; standard deviation (SD) 15.65; p < 0.0001). Limits of agreement were - 14.94 to 46.24 mm. Sonazoid® significantly increased the mean grayscale values at the posterior rectus sheath (93.7 vs. 201.9, p < 0.0001). There were no complications. CONCLUSION: Sonazoid diluted 100-fold® was clearly visualized real-time, and the enhancement was sustained and measurable after RSB. Sonazoid® could potentially be used for the contrast agent of US-guided nerve block.

Antiemetic effects of baclofen in a shrew model of postoperative nausea and vomiting: Whole-transcriptome analysis in the nucleus of the solitary tract.

AIMS: The molecular genetic mechanisms underlying postoperative nausea and vomiting (PONV) in the brain have not been fully elucidated. This study aimed to determine the changes in whole transcriptome in the nucleus of the solitary tract (NTS) in an animal model of PONV, to screen a drug candidate and to elucidate the molecular genetic mechanisms of PONV development. METHODS: Twenty-one female musk shrews were assigned into three groups: the Surgery group (shrew PONV model, n = 9), the Sham group (n = 6), and the Naïve group (n = 6). In behavioral studies, the main outcome was the number of emetic episodes. In genetic experiments, changes in the transcriptome in the NTS were measured. In a separate study, 12 shrews were used to verify the candidate mechanism underlying PONV. RESULTS: A median of six emetic episodes occurred in both the Sham and Surgery groups. Whole-transcriptome analysis indicated the inhibition of the GABAB receptor-mediated signaling pathway in the PONV model. Baclofen (GABAB receptor agonist) administration eliminated emetic behaviors in the shrew PONV model. CONCLUSIONS: Our findings suggest that the GABAB receptor-mediated signaling pathway is involved in emesis and that baclofen may be a novel therapeutic or prophylactic agent for PONV.

Crucial involvement of catecholamine neurotransmission in postoperative nausea and vomiting: Whole-transcriptome profiling in the rat nucleus of the solitary tract.

The genetic mechanisms of postoperative nausea and vomiting (PONV) and the involvement of the catecholamine system in the brain have not been elucidated. Eating kaolin clay as a type of pica has been examined as an alternative behavior to emesis. Here, we evaluated changes in whole-transcriptome analysis in the nucleus of the solitary tract (NTS) in a rat pica model as a surrogate behavior of PONV to elucidate the molecular genetic mechanisms of the development of PONV and the involvement of the catecholamine system in the NTS. First, kaolin pica behaviors were investigated in 71 female Wistar rats following isoflurane anesthesia, surgical insult or morphine administration. Multiple linear regression analysis showed that 3 mg/kg morphine increased kaolin intake by 2.8 g (P = 0.0002). Next, total RNA and protein were extracted from the dissected NTS, and whole-transcriptome sequencing (RNA-seq) was performed to identify PONV-associated genes and to verify the involvement of the catecholamine system. The gene expression levels of tyrosine hydroxylase and dopamine beta-hydroxylase in the catecholamine biosynthesis pathway decreased significantly in the PONV model. Release of noradrenaline, a catecholamine pathway end product, may have increased at the synaptic terminal of the NTS neuron after pica behavior. Systematic administration of α2 adrenergic receptor agonists after surgery reduced kaolin intake from 3.2 g (control) to 1.0 g (P = 0.0014). These results indicated that catecholamine neurotransmission was involved in the development of PONV in the NTS.

Effects of magnesium sulfate administration in attenuating chronic postsurgical pain in rats.

Chronic postsurgical pain (CPSP) is a serious issue for many postoperative patients. Though there are numerous treatment options for the prevention of CPSP, none of them is optimal as the mechanisms of the transition from acute to chronic postoperative pain have not been elucidated. Ketamine and opioids have been administered for chronic postoperative pain treatment but induce severe adverse reactions and/or physical dependency. Here, we examined whether pre-administration of the nonselective N-methyl-d-aspartate (NMDA) receptor antagonist magnesium sulfate attenuates CPSP behavior and alters the expression of glutamate ionotropic receptor NMDA type subunit 1a (Grin1 mRNA) in a rat skin/muscle incision and retraction (SMIR) model. We assessed the effects of a single subcutaneous magnesium sulfate injection on nociceptive behaviors including guarding pain, mechanical hyperalgesia, and heat hypersensitivity in rats after SMIR surgery. We used reverse transcription-quantitative PCR (RT-qPCR) to evaluate Grin1 mRNA expression in the dorsal horn of the spinal cord on postoperative day 14. Compared with the vehicle, magnesium sulfate administration before SMIR surgery reduced mechanical hyperalgesia for 17 d Grin1 gene expression was significantly higher on the ipsilateral side than the contralateral side (P = 0.001) on postoperative day 14. The magnesium sulfate injection prevented Grin1 mRNA upregulation in the spinal cord dorsal horn. A single magnesium sulfate injection mitigated SMIR-induced mechanical hyperalgesia possibly by modulating Grin1 expression. Preoperative magnesium sulfate administration could prove to be a simple and safe CPSP treatment.

Postoperative Pain Management in Patients With Ulcerative Colitis.

Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract including ulcerative colitis (UC) and Crohn's disease. Pain management can be challenging in patients with IBD because there are limitations on the use of analgesics. Use of nonsteroidal anti-inflammatory drugs is not recommended in patients with IBD because there is risk of relapse of IBD and an overall increase in disease activity. Opioids, although frequently used for treating severe acute pain, can have additional risks and complications in patients with IBD such as ileus, toxic megacolon, and narcotic bowel syndrome. Furthermore, little information is available in the literature on pain management in these patients undergoing noncolorectal surgery. This report describes 2 patients with UC in whom postoperative pain following oral and maxillofacial surgery was managed by intravenous patient-controlled analgesia with pentazocine. Apart from the development of acute dystonia in 1 case that was likely due to the use of droperidol for prevention of postoperative nausea and vomiting, postoperative pain was well controlled by pentazocine in both patients without any complications or UC exacerbations.

Long non-coding RNA MIR4300HG polymorphisms are associated with postoperative nausea and vomiting: a genome-wide association study.

BACKGROUND: Genetic factors such as single-nucleotide polymorphisms (SNPs) play a key role in the development of postoperative nausea and vomiting (PONV). However, previous findings are not widely applicable to different populations because of population-specific genetic variation. We developed a Japanese-specific DNA microarray for high-throughput genotyping. The aim of the current study was to identify SNPs associated with PONV on a genome-wide scale using this microarray in a sample of Japanese surgical patients. METHODS: Associations between 659,636 SNPs and the incidence of PONV 24 h after surgery in a limited sample of 24 female patients were assessed using the microarray. After imputation of genotypes at 24,330,529 SNPs, 78 SNPs were found to be associated with the incidence of PONV. We chose 4 of the 78 SNPs to focus on by in silico functional annotation. Finally, we genotyped these 4 candidate SNPs in 255 patients using real-time PCR to verify association with the incidence of PONV. RESULTS: The T > C variant of rs11232965 in the long non-coding RNA MIR4300HG was significantly associated with reduced incidence of PONV among genotypes and between alleles (p = 0.01 and 0.007). CONCLUSIONS: We identified a novel SNP (rs11232965) in the long non-coding RNA MIR4300HG that is associated with PONV. The rs11232965-SNP variant (T > C) is protective against the incidence of PONV. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry (Identifier: UMIN000022903 , date of registration: June 27, 2016, retrospectively registered.

Successful management of an infant with hypertensive heart failure associated with Wilms' tumor: a case report.

BACKGROUND: Wilms' tumor with hyperreninemia may result in critical cardiovascular decompensation. We report a case of severe hypertensive heart failure followed by tumor resection in a 3-month-old infant with Wilms' tumor. CASE PRESENTATION: A 3-month-old girl was admitted to the intensive care unit for Wilms' tumor with hypertension and hypoxia. Her systolic blood pressure was 110 mmHg, and her SpO2 was 92%. She presented with severe hypertensive heart failure and received mechanical ventilation and antihypertensive therapy for hypertension and heart failure. An alpha 2-adrenergic receptor agonist was used for sedation as part of her antihypertensive therapy. On hospital day 16, nephrectomy with tumor resection was performed under general anesthesia. Her systolic blood pressure did not vary more than 20 mmHg during surgery due to appropriate preoperative management. Hemodynamic collapse did not occur. CONCLUSIONS: The highlight of this case report is the successful management of an infant with Wilms' tumor, particularly with respect to preoperative hemodynamic control and sedation.

Effect of forced-air warming by an underbody blanket on end-of-surgery hypothermia: a propensity score-matched analysis of 5063 patients.

BACKGROUND: Underbody blankets have recently been launched and are used by anesthesiologists for surgical patients. However, the forced-air warming effect of underbody blankets is still controversial. The aim of this study was to determine the effect of forced-air warming by an underbody blanket on body temperature in anesthetized patients. METHODS: We retrospectively analyzed 5063 surgical patients. We used propensity score matching to reduce the bias caused by a lack of randomization. After propensity score matching, the change in body temperature from before to after surgery was compared between patients who used underbody blankets (Under group) and those who used other types of warming blankets (Control group). The incidence of hypothermia (i.e., body temperature < 36.0 °C at the end of surgery) was compared between the two groups. A p value < 0.05 was considered to indicate statistical significance. RESULTS: We obtained 489 propensity score-matched pairs of patients from the two groups, of whom 33 and 63 had hypothermia in the Under and Control groups, respectively (odds ratio: 0.49, 95% confidence interval: 0.31-0.76, p = 0.0013). CONCLUSIONS: The present study suggests that the underbody blanket may help reduce the incidence of intraoperative hypothermia and may be more efficient in warming anesthetized patients compared with other types of warming blankets. TRIAL REGISTRATION: UMIN Clinical Trials Registry (Identifier: UMIN000022909 ; retrospectively registered on June 27, 2016).

Increased burden of rare deleterious variants of the KCNQ1 gene in patients with large­vessel ischemic stroke.

The impact of rare and damaging variants in genes associated with platelet function in large­vessel ischemic stroke (LVIS) remains unknown. The aim of this study was to investigate the contribution of some of these variants to the genetic susceptibility to LVIS in Polish patients using a deep re­sequencing of 54 selected genes, coding for proteins associated with altered platelet function. Targeted pooled re­sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of LVIS) and 500 age­, smoking status­, and sex­matched controls (no history of any type of stroke), and from the same population as patients with LVIS. After quality control and prioritization based on allele frequency and damaging probability, individual genotyping of all deleterious rare variants was performed in patients from the original cohort, and stratified to concomitant cardiac conditions differing between the study and stroke groups. We demonstrated a statistically significant increase in the number of rare and potentially damaging variants in some of the investigated genes in the LVIS pool (an increase in the genomic variants burden). Furthermore, we identified an association between LVIS and 6 rare functional and damaging variants in the Kv7.1 potassium channel gene (KCNQ1). The predicted functional properties (partial loss­of function) for the three most damaging variants in KCNQ1 coding locus were further confirmed in vitro by analyzing the membrane potential changes in cell lines co­transfected heterogeneously with human muscarinic type 1 receptor and wild­type or mutated KCNQ1 cDNA constructs using fluorescence imaging plate reader. The study demonstrated an increased rare variants burden for 54 genes associated with platelet function, and identified a putative role for rare damaging variants in the KCNQ1 gene on LVIS susceptibility in the Polish population.

Effects of low-dose ketamine infusion on remifentanil-induced acute opioid tolerance and the inflammatory response in patients undergoing orthognathic surgery.

PURPOSE: Remifentanil is associated with acute opioid tolerance that can lead to increased postoperative consumption of opioid analgesics. The purpose of this study was to determine whether a low dose of ketamine prevents remifentanil-induced acute opioid tolerance and affects the neutrophil-lymphocyte ratio (NLR), a newly recognized biomarker of inflammation. MATERIALS AND METHODS: Forty patients undergoing orthognathic surgery were enrolled in this prospective, randomized, double-blind study and randomly assigned to intraoperative administration of one of the following anesthetic regimens: high-dose remifentanil (0.6 µg/kg/minute); low-dose remifentanil (0.2 µg/kg/minute); or high-dose remifentanil with ketamine (remifentanil 0.6 µg/kg/minute with 0.5 mg/kg ketamine just after induction followed by an intraoperative infusion of ketamine 5 µg/kg/minute until wound closure). Fentanyl by intravenous patient-controlled analgesia was used for postoperative pain control. Visual Analog Scale pain scores and fentanyl consumption were recorded in the first 24 hours postoperatively. Perioperative serum C-reactive protein level and NLR were also determined. RESULTS: Baseline characteristics were similar in the three study groups. There were no between-group differences in Visual Analog Scale pain scores during the study period. The high-dose remifentanil group had a significantly higher requirement for fentanyl than the other two groups. Addition of ketamine did not affect the C-reactive protein level but increased the NLR; this increase was associated with decreased fentanyl consumption. CONCLUSION: High-dose intraoperative remifentanil induced postoperative acute opioid tolerance that was prevented by infusion of low-dose ketamine. Ketamine increased the postoperative NLR associated with decreased fentanyl requirement for postoperative pain control.

Acute Management of Massive Epistaxis After Nasotracheal Extubation.

Epistaxis is one of the most common complications of nasotracheal intubation and can be life-threatening. However, there is little discussion in the current literature on the acute management of massive epistaxis after nasotracheal extubation. This is a report of 2 patients who experienced severe unanticipated nasal bleeding immediately after extubation, 1 after a surgical procedure for oral cancer and another after restorative dental treatment. In both cases the significant epistaxis was managed successfully with a Foley balloon catheter used to pack the posterior nasal cavity. The Foley catheter technique may be useful for managing and arresting sudden postextubation epistaxis.

Association of frequent genetic variants in platelet activation pathway genes with large-vessel ischemic stroke in Polish population.

Platelets are critically involved in the development of cerebral ischemia. Our study aimed to establish an association between frequent (minor allele frequency (MAF) > 5%) genetic polymorphisms in 84 candidate genetic loci previously linked to platelet reactivity by the use of next-generation sequencing of exons from pooled DNA samples in Polish patients with a history of large-vessel ischemic stroke. Genetic analysis was performed on blood samples obtained from 500 patients (diagnosed with acute non-cardioembolic ischemic stroke with coexisting large-artery atherosclerosis) and age/sex/history of smoking matching 500 controls of Polish origin with high risk of cardiovascular disease. Sequencing of 10 pools (five for each ischemic and control groups) was performed on the Ilumina HiSeq2500 sequencer which generated an average of 36.1 (22.7-45.9 range) million pair-end 101 bp reads and 5.3 (3-7 range) Gbp per pooled sample consisting of 100 subjects. In total, we observed 789 frequent polymorphisms in the sequenced 84 genes (703 of single-nucleotide polymorphism (SNP) type and 86 indels). When the MAF between control and stroke groups was compared, only two intronic polymorphisms (1 SNP and 1 indel) in RGS7 (rs127445 36) and ANKS1B (rs398098426) genes, respectively, show statistically significant differences, which persisted after individual genotyping of the variants and adjustment for potential confounding factors. From the remaining variants, 35 polymorphisms displayed various degrees of nominal significance (from 0.6.3 × 10-5 to 5 × 10-2) and 754 polymorphisms did not show any statistical significance when comparison was evaluated for differences in MAF between the study groups. In conclusion, the results of the study demonstrate statistically significant differences in two frequent intronic genetic variants (in RGS7 and ANKS1B) that could be associated with the platelet function between ischemic stroke patients with coexisting large-vessel atherosclerosis and control patients having high vascular risk.

Intraoperative auditory evoked potential recordings are more reliable at signal detection from different sensor sites on the forehead compared to bispectral index.

Bispectral index (BIS) and auditory evoked potential (AEP) monitoring require the attachment of forehead sensors, posing difficulties when the surgical field involves the forehead. This study analyzed the relationship between BIS values and AEP indices from different sites on the head to establish alternative sensor locations for AEP recording. Thirty patients scheduled for elective surgery under sevoflurane anesthesia were randomly assigned to the forehead, nose or mandible groups (n = 10 patients per group). AEP sensors were placed at the assigned position for each group and BIS sensors were placed on the forehead. BIS value and AEP index were simultaneously recorded from induction until emergence from general anesthesia. Relationships between BIS values and AEP indices were analyzed using a regression method and compared between groups using Pearson's correlation coefficients. Square regression models better expressed the relationships than linear models in all groups. The z-transformed coefficient in the forehead group was the same as the nose group (p = 0.24) and significantly different in the mandible group (p = 0.0046). These findings suggest that AEPs can be accurately recorded from sensors placed on the nose. Nasal AEP might be useful for monitoring electrical activity in the brain during surgeries involving the forehead.

Pharmacogenetics of chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is associated with distressing adverse effects observed in patients during cytotoxic chemotherapy. One of the potential factors explaining suboptimal response to currently used antiemetics is variability in genes encoding enzymes and proteins that play a role in the action of antiemetic drugs. Pharmacogenomics studies of CINV are sparse and focus mainly on polymorphisms associated with serotonin receptor, drug metabolism and drug transport. Currently, the role of pharmacogenetics in mechanisms of CINV has not been fully unraveled, and it is premature to implement results of pharmacogenetic association studies of antiemetic drugs in clinical practice. More uniform studies, with genetic profiles and biomarkers relevant for the proposed target and transporter mechanisms, are needed.

Association between the low-dose irinotecan regimen-induced occurrence of grade 4 neutropenia and genetic variants of UGT1A1 in patients with gynecological cancers.

The occurrence of severe neutropenia during treatment with irinotecan (CPT-11) is associated with the *6 and *28 alleles of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). However, the correlation between these variants and the occurrence of severe neutropenia in a low-dose CPT-11 regimen for the treatment of gynecological cancers has not been extensively studied. There are also no studies regarding the association between the 421C>A mutation in ATP-binding cassette sub-family G member 2 (ABCG2) and the occurrence of severe neutropenia in CPT-11-treated patients with gynecological cancers. The present study was designed to determine the factors associated with the occurrence of grade 4 neutropenia during chemotherapy for gynecological cancers with combinations of CPT-11 and cisplatin or mitomycin C. In total, 44 patients with gynecological cancer were enrolled in the study. The association between the absolute neutrophil count (ANC) nadir values, the total dose of CPT-11 and the genotypes of UGT1A1 or ABCG2 was studied. No correlation was observed between the ANC nadir values and the total dose of CPT-11. The ANC nadir values in the UGT1A1*6/*28 and *6/*6 groups were significantly lower compared with those in the *1/*1 group (P<0.01). Univariate analysis showed no association between the occurrence of grade 4 neutropenia and the ABCG2 421C>A mutation. Subsequent to narrowing the factors by univariate analysis, multivariate logistic regression analysis only detected significant correlations between the occurrence of grade 4 neutropenia and the UGT1A1*6/*6 and *6/*28 groups (P=0.029; odds ratio, 6.90; 95% confidence interval, 1.22-38.99). No associations were detected between the occurrence of grade 4 neutropenia and the heterozygous variant (*1/*6 or *1/*28) genotype, type of regimen or age. In conclusion, the UGT1A1*6/*28 and *6/*6 genotypes were found to be associated with the occurrence of severe neutropenia in the low-dose CPT-11 regimen for gynecological cancers. This finding indicates that the determination of UGT1A1 variants may be as useful in CPT-11 chemotherapy for gynecological conditions as it is in colorectal and lung cancer patients treated with this drug.

Association of µ-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.

Genetic variants, such as single-nucleotide polymorphisms (SNPs), of the µ-opioid receptor gene (OPRM1) might be associated with individual differences in opioid sensitivity, as well as with the incidence and severity of postoperative nausea and vomiting (PONV). The goal of the present study was to determine, in a cohort of Japanese surgical patients, genotypes and haplotypes of several SNPs in the OPRM1 gene, and their association with PONV during the early (first 24 h) postoperative period. We examined the incidence and severity of PONV, during the first 24 h after surgery, in 85 Japanese patients receiving intravenous patient-controlled analgesia fentanyl analgesia for postoperative pain control. Eight tag SNPs of the OPRM1 gene (rs1799971, A/G; rs510769, G/A; rs4870266, G/A; rs3798683, G/A; rs1323042, A/C; rs609623, C/T; rs9397685, A/G; and rs644261, C/G) were selected based on their minor allele frequency (>10%) and linkage disequilibrium strength (<80%), and genotyped for haplotype analysis and determination of associations with PONV. Only one out of eight investigated SNPs, rs9397685, in the intronic part of the OPRM1 gene was associated with differences in the occurrence and severity of PONV. We also found four common haplotypes with a frequency of >10% in the investigated patients, including GGGAACAC (33%), AGGGACAC (19%), GGGAACGC (12%), and AGAGACAC (10%). The severity of PONV in carriers of the GGGAACGC haplotype was significantly lower than in the carriers of the other haplotypes (P < 0.05). One intronic SNP, rs9397685, and haplotypes constructed from eight SNPs within the OPRM1 gene locus might be involved in the severity of PONV associated with general anesthesia and opioid administration. This novel finding, if validated and verified in larger and additional ethnic cohorts, might contribute to better knowledge of the contribution of the OPRM1 gene to PONV.