[Questionnaire Survey on the Timing of Comprehensive Genomic Profiling for Advanced Recurrent Colorectal Cancer and Its Impact on Patients].

BACKGROUNDS: Comprehensive genomic profiling(CGP)has been covered by health insurance since June 2019. However, the clinical impact of CGP on patients with metastatic colorectal cancer(mCRC)remains unclear. To date, there are very limited reports regarding patient-oriented outcomes of CGP in mCRC. PATIENTS: A questionnaire was completed by patients with mCRC who had already received their CGP results after April 2021. Eight questions were posed, covering the degree of satisfaction and timing when CGP was conducted. RESULTS: Of the 51 patients with mCRC who had received their CGP test results by August 2021 in our department, 21 patients responded to our questionnaire. In total 66.7% patients with mCRC answered "(very)satisfied"with the CGP testing. 28.6% of the patients already knew about CGP testing before their local doctors informed them. Except for 3 patients who did not answer, 47.6% and 9.5% of patients with mCRC"agreed"and "moderately agreed"with the timing of the CGP test. CONCLUSION: Although most patients with mCRC failed to access promising new treatment via CGP, approximately half of the patients answered that they were satisfied with the CGP testing. Conversely, a few patients already knew about CGP testing before it was proposed by their doctors. Thus, the provision of information at an early stage is necessary.

[Educational Project of Self-Removal of the Intravenous Central Venous Access Port Guided by Patients with Advanced Colorectal Cancer Instructed by a Nurse in the University Hospital].

BACKGROUND: Fluorouracil infusion for 46±5h from the central venous(CV)port is required for mFOLFOX6, FOLFIRI, and FOLFOXIRI in patients with advanced colorectal cancer(CRC), followed by self-removal of the needle by patients. At our hospital, outpatients were instructed for self-removal of the needle, but the results were unsatisfactory. Therefore, instructions for self-removal of the needle from the CV port have been initiated at the patient ward since April 2019, making use of a hospital stay of 3 days. PATIENTS: We retrospectively enrolled patients with chemotherapy-introduced advanced CRC from the CV port who received instructions for self-removal of the needle in the outpatient department and ward between January 2018 and December 2021. RESULTS: Of all patients with advanced CRC, 21 received instructions at the outpatient department(OP)while 67 at patient ward(PW). Incidences of successful self-removal of the needle without the aid of others were similar: 47% in OP and 52% in PW(p=0.80). However, after several additional instructions involving their families, it was higher in PW than in OP(97.0 vs 76.1%, p=0.005). Incidences of successful self-removal of the needle without the aid of others in those aged≥75/<75, and≥65/<65 years were 0%/61.1%, and 35.4%/67.5%, respectively. OP was as a risk factor for failed self-removal of the needle in the logistic regression analysis(odds ratio: 11.19, 95%CI: 1.86- 67.30). CONCLUSION: Repeated instructions involving patients' families during the hospital stay improved the incidence of successful self-removal of the needle. Involvement of patients' families from the beginning may effectively improve self- removal of the needle, particularly in the elderly patients with advanced CRC.

Attentional differences in audiovisual face perception between full- and preterm very low birthweight toddlers.

AIM: To investigate whether rightward attention to the mouth during audiovisual speech perception may be a behavioural marker for early brain development, we studied very preterm and low birthweight (VLBW) and typically developing (TD) toddlers. METHODS: We tested the distribution of gaze points in Japanese-learning TD and VLBW toddlers when exposed to talking, silent and mouth moving faces at 12, 18 and 24 months (corrected age). Each participant was categorised based upon the area they gazed at most (Eye-Right, Eye-Left, Mouth-Right, Mouth-Left) per stimulus per age. A log-linear model was applied to three-dimensional contingency tables (region, side and group). RESULTS: VLBW toddlers showed fewer gaze points than TD toddlers. At 12 months, more VLBW toddlers than TD toddlers showed left attentional bias toward any one face; however, this difference in attention asymmetry receded somewhat by 24 months. In talking condition, TD toddlers showed right attentional bias from 12 to 24 months, whereas VLBW toddlers showed such bias upon reaching 24 months. Additionally, more TD toddlers than VLBW toddlers attended to the mouth. CONCLUSION: Delays in exhibiting the attentional bias for an audiovisual face or general faces displayed by typically developing children might suggest differential developmental timing for hemispheric specialisation or dominance.

Autistic traits of children born very preterm assessed using Autism Diagnostic Observation Schedule, Second Edition.

Preterm birth has been linked with increased incidence of autism spectrum disorder (ASD). Despite the remarkable difference in the clinical backgrounds between ASD children born preterm and term, cross-sectional studies have found no striking difference in their autistic traits. To highlight autistic traits related with preterm birth, children born very preterm (prospective birth cohort, n = 50) and term (case cohort, n = 16), who were diagnosed as "Autism" by the Autism Diagnostic Observation Schedule (ADOS), 2nd edition, were compared using the calibrated severity scores of ADOS-2 and T-scores of the Social Responsiveness Scale, 2nd edition. No significant difference was found in the calibrated severity scores between ASD children born preterm and term. There was a trend that T-scores were smaller for the preterm cohort, which did not reach a statistical significance. Even when detailed cross-sectional information was obtained using ADOS-2, no difference in autistic traits was observed between children born very preterm and term. Our findings were consistent with a previous study, which assessed the entire prospective cohort of children born very preterm and found no difference in original ADOS scores. Further studies are warranted to delineate how preterm birth affects the autistic traits and their parental perception in a large prospective cohort.

Hemopexin as a Potential Binding Partner of Arginine-Rich Cell-Penetrating Peptides in Serum.

Serum proteins affect the in vivo fate and cellular uptake of arginine-rich cell-penetrating peptides (CPPs) and drugs delivered by CPPs. Although the binding of CPPs to serum proteins may possibly reduce their cellular uptake to some extent, it may also prolong their circulation half-life in vivo. We aimed to identify novel binding proteins of arginine-rich CPPs in serum to better understand their in vivo fate and develop more sophisticated drug delivery systems using CPPs. Isothermal titration calorimetry analysis suggests that albumin, the most abundant protein in serum, binds to d-forms of oligoarginine; however, the dissociation constants are several tens of a micromolar. Candidate proteins with the potential of binding to arginine-rich CPPs in serum were then explored using nondenaturing polyacrylamide gel electrophoresis followed by mass spectrometry analysis. Studies using fluorescence correlation spectroscopy determined hemopexin as a potential binding partner of d-forms of arginine-rich CPPs, including d-octaarginine (r 8) and the d-form of the peptide, corresponding to HIV-1 Rev (34-50), with dissociation constants of submicromolar to micromolar range. Using flow cytometry and a split-luciferase-based system, the promotion effect of hemopexin on the total cellular uptake and cytosolic localization of cargos conjugated with these CPPs was confirmed. Therefore, this study elucidated hemopexin as a potential binding partner of d-arginine-rich CPPs that may affect their in vivo fate and cellular uptake.

[Challenge of Skin Treatment Led by Nurses and Pharmacists for Advanced Colorectal Cancer Patients Treated with Anti-EGFR Antibodies].

Preemptive skin treatment led by nurses and pharmacists was started for patients with metastatic colorectal cancer (mCRC)who received anti-EGFR antibody treatment. Incidence of skin-related toxicities, amount of topical moisturizers used, and administered cycles of anti-EGFR antibody were retrospectively compared between a preemptive skin treatment group and a control group. Thirty-four mCRC patients before the introduction of preemptive skin treatment led by nurses and 23 mCRC patients treated with preemptive skin treatment led by nurses were evaluated. The incidence of 6- and 12- week Grade 2 or higher skin-related toxicity was 23.5% in the control group and 8.7% in the preemptive group(p=0.18), and 67.7% in the control group and 30.4% in the preemptive group(p=0.0076), respectively. Mean amounts of moisturizer used were both lower in the control group than in the preemptive group at both 6 weeks and 7-12 weeks(6 weeks; 275 g vs 550 g, p=0.036, 7-12 weeks; 575 g vs 1,175 g, p=0.013). However, the amount of topical steroid used was similar in both groups. Preemptive moisturizer skin treatment led by nurses and pharmacists may decrease the incidence of skin- related toxicity.

Diagnostic rate of autism spectrum disorder in a high-survival cohort of children born very preterm: A cross-sectional study.

To investigate the diagnostic rate of autism spectrum disorder (ASD) in a high-survival cohort of very preterm children, 77 infants born very preterm (<32 weeks of gestation) were assessed at age 4-6 years old using the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Sixteen children (20.8%) were classified as both DSM-5-positive ASD and ADOS-2-identified "autism," which were defined as confirmed ASD in this study. Our result suggests that the prevalence of ASD in very preterm children might be much higher than reported in previous studies when all children were individually evaluated. Further studies in a large sample are required to clarify the true risk of ASD in preterm birth.

[Cross-Functional Project of Using Information-Sharing Tool for Metastatic Colorectal Cancer Patients in University Hospital].

Treatment for late-stage cancer patients should be discussed depending on the patients' will, however it is not sometimes fully discussed in our daily practice. Based on this background, the information-sharing tool for metastatic colorectal cancer patients, who are refractory to first-line and second-line chemotherapy and/or who are given a year to live, has been introduced in our university hospital since November 2019. To evaluate the utility of this tool, the influence of the tools on the outcome of the patients was evaluated. Regarding the comparison between the patients before and after the introduction of the information-sharing tool, the period between the day of the consent to the DNAR between the day of the death is longer in the patients after the introduction than those before the introduction(median 43 vs 6 days, p=0.025). The introduction of the information-sharing tool can provide the metastatic colorectal cancer patients with more opportunities to discuss how to spend the rest of their lives and with longer time at the place where they want to stay.

Primitive reflexes in very low birth weight infants later diagnosed with autism spectrum disorder.

BACKGROUND: As early screening and diagnosis is very important in treatment and intervention of Autism Spectrum Disorder, we investigated the relationship between primitive reflexes and Autism Spectrum Disorder (ASD). METHODS: Of 88 very low birth weight infants (<1500g) born from April 2010 to March 2012, subjects comprised 38 examined for 18 primitive reflexes between age 38 and 45 wks corrected age and followed-up over 6 yrs. ASD was diagnosed using Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) and Autism Diagnostic Observation Schedule Second Edition (ADOS-2). We compared the number of abnormal primitive reflexes between two groups (11 children with and 19 without ASD) after excluding eight children with cerebral palsy in this case-control study. RESULTS: Twenty cases showed one to four hypoactive reflex(es) and two showed one hyperactive reflex together with hypoactive reflex(es). Ten out of 11 cases with ASD had one to four abnormal reflex(es). The number of abnormal hypoactive primitive reflexes was significantly higher in the ASD group (p=0.002). CONCLUSIONS: The result suggests primitive reflexes can be one of the key elements in very early infancy to identify ASD in low birth weight infants. Abnormal hypoactive primitive reflex of low birth weight infants with ASD may inform future research of the pathogenesis of ASD.

Children's Perceived Competence Scale: reevaluation in a population of Japanese elementary and junior high school students.

BACKGROUND: It is important for children to maintain high self-perceived competence and self-esteem, and there are few measures to evaluate them through elementary to junior high school days in Japan. To evaluate psychometric properties of the Children's Perceived Competence Scale (CPCS). METHODS: Data were collected from 697 elementary school and 956 junior high school students. Some of these students completed measures for construct validity, whereas others repeated the CPCS. RESULTS: The results demonstrated the three-factor structure of the CPCS: cognitive (nine items), social (eight items) and physical (nine items). Factorial invariance was confirmed between elementary and junior high school students, as well as between boys and girls. Construct validity was excellent. Scores on the cognitive, physical and general self-worth domains declined with increasing age. Boys scored significantly higher than girls on physical and general self-worth domains. CONCLUSIONS: The CPCS is a valid and reliable measure of perceived competence in Japanese children aged 6-15 years. The CPCS may be applied to students from elementary through junior high school days as a measure of self-perceived and psychological state in Japan.

Self-perception of children with autism spectrum disorders.

BACKGROUND: We aimed to evaluate self-perceived competence and self-esteem of primary school children with autism spectrum disorder (ASD) in Japan and compare to those of children with other chronic physical diseases and healthy controls. METHODS: Data were collected from 227 children: ASD (N.=91), nephrotic syndrome (NS) (N.=52) and asthma (N.=84), using Children's Perceived Competence Scale (CPCS) in 2012-2014. CPCS measures perceived competence in cognitive, social and physical domains, and a general self-worth domain as self-esteem. RESULTS: Scores in the social domain of the ASD group were lower than those of all other groups after adjusting for school age grades and gender. Scores of the ASD group negatively correlated with psychosomatic symptoms in all domains and IQ in the physical domain. CONCLUSIONS: These findings are the first data set in Japan on self-perceived competence and self-esteem in primary school children with ASD. Those results were comparable to previous researches in adolescents with ASD. Low social domain scores in the ASD group indicate the CPCS may be one of the useful tools to evaluate difficulty in social competence from the children's point of view. Correlations between CPCS scores and psychosomatic symptoms in the ASD group suggest development of psychosomatic symptoms may be addressed early by attention to low scores, especially in general self-worth.

Overexpression of microRNAs from the Gtl2-Rian locus contributes to postnatal death in mice.

The Dlk1-Dio3 imprinted domain functions in embryonic development but the roles of noncoding RNAs expressed from this domain remain unclear. We addressed this question by generating transgenic (TG) mice harbouring a BAC carrying IG-DMR (intergenic-differentially methylated region), Gtl2-DMR, Gtl2, Rtl1/Rtl1as, and part of Rian. High postnatal lethality (>85%) of the BAC-TG pups was observed in the maternally transmitted individuals (MAT-TG), but not following paternal transmission (PAT-TG). The DNA methylation status of IG-DMR and Gtl2-DMR in the BAC-allele was paternally imprinted similar to the genomic allele. The mRNA-Seq and miRNA-Seq analysis revealed marked expression changes in the MAT-TG, with 1,500 upregulated and 2,131 downregulated genes. The long noncoding RNAs and 12 miRNAs containing the BAC locus were markedly enhanced in the MAT-TG. We identified the 24 target genes of the overexpressed miRNAs and confirmed the downregulation in the MAT-TG. Notably, overexpression of mir770, mir493, and mir665 from Gtl2 in the MAT-TG embryos led to decreased expression of the 3 target genes, Col5a1, Pcgf2, and Clip2. Our results suggest that decreased expression of the 3 target genes concomitant with overexpression of the miRNAs within Gtl2 may be involved in the postnatal death in the MAT-TG. Because this imprinted domain is well conserved between mice and humans, the results of genetic and molecular analysis in mice hold important implications for related human disorders such as Temple syndrome.

Children's Perceived Competence Scale: Reference values in Japan.

To support children with chronic diseases, reference values to measure developmental changes in self-perception and self-esteem are considered a useful yardstick. To develop reference values to measure self-perceived competence and self-esteem in Japanese children, the Children's Perceived Competence Scale (CPCS) was administered to 768 children of elementary school grade 1 (6 years) to grade 6 (11 years) at four public schools in Japan, from November to December 2012. After excluding 74 with chronic diseases and/or incomplete responses, 694 children were included. CPCS measures children's self-perceived competence in cognitive, social, physical domains, and general self-worth, namely self-esteem. There was a tendency for scores of cognitive and general self-worth to decrease with increasing grade. Scores among grade 5 respondents were significantly lower than those among grade 4 respondents for both social and physical domains. Scores among boys and girls differed significantly, with boys scoring higher for physical domain in grades 3 and 6 and for general self-worth domain in grade 6. The CPCS reference values to measure self-perceived competence and self-esteem in Japanese children were developed in this study. These reference values are useful to inform practitioners supporting children with psychological or psychiatric problems or those with chronic diseases.

Perineural but not systemic low-dose dexamethasone prolongs the duration of interscalene block with ropivacaine: a prospective randomized trial.

PURPOSE: To determine the effects of intravenous and perineural dexamethasone on the duration of interscalene brachial plexus block (ISB) with ropivacaine in patients undergoing arthroscopic shoulder surgery. PATIENTS AND METHODS: In this prospective, randomized, placebo-controlled trial, patients presenting for arthroscopic shoulder surgery with an ISB were randomized to receive ropivacaine 0.75% (group C), ropivacaine 0.75% plus perineural dexamethasone 4 mg (group Dperi), or ropivacaine 0.75% plus intravenous dexamethasone 4 mg (group Div). The primary outcome was the duration of analgesia, defined as the time between performance of the block and the first request for analgesic. RESULTS: Thirty-nine patients were randomized. The median times of sensory block in groups C, Dperi, and Div were 11.2 hours (interquartile range [IQR] 8.0-15.0 hours), 18.0 hours (IQR 14.5-19.0 hours), and 14.0 hours (IQR 12.7-15.1 hours), respectively. Significant differences were observed between groups Dperi and C (P=0.001). Kaplan-Meier analysis for the first analgesic request showed significant differences between groups Dperi and C (P=0.005) and between groups Dperi and Div (P=0.008), but not between groups C and Div. CONCLUSION: Perineural but not intravenous administration of 4 mg of dexamethasone significantly prolongs the duration of effective postoperative analgesia resulting from a single-shot ISB with ropivacaine 0.75%.

[Lower thoracic epidural analgesia improves postoperative analgesia following vaginal total hysterectomy].

BACKGROUND: In our hospital, lumbar epidural analgesia had been used for postoperative analgesia following vaginal total hysterectomy (VTH). But some patients experienced severe abdominal pain or numbness of the legs. Therefore we planned a randomized prospective study to compare lower thoracic epidural analgesia and lumbar epidural analgesia following VTH. METHODS: Fifty patients were allocated to two groups: those who received lower thoracic epidural analgesia(T group)and the other who received lumbar epidural analgesia (L group). Both groupsreceived the same continuous epidural analgesia using fentanyl and ropivacaine after the operation. RESULTS: The T group required significantly lower frequency of analgesic agents compared with that of the L group (2.5±1.9 times vs. 1.2±1.1 times, P< 0.05). Fewer patients in the T group had felt numbness in their legs compared to the L group (8% vs. 55%, P<0.05). CONCLUSIONS: Lower thoracic epidural analgesia is more effective to provide postoperative analgesic effect following VTH compared with lumbar epidural analgesia.

[Dextran-induced anaphylactic shock during general anesthesia: a case report].

We describe a case of dextran-induced anaphylactic shock during general anesthesia. A 34-year-old woman was scheduled for partial hepatic resection under general anesthesia. General anesthesia was induced with intravenous remifentanil, thiamylal and rocuronium, and was maintained with oxygen, air, sevoflurane and remifentanil. The patient developed hypotension (from 90/50 to 49/27 mmHg in 20 min) together with tachycardia (111 beats x min(-1)) and desaturation (83%) subsequent to intravenous infusion of Saviosol (dextran 40). We made a diagnosis of anaphylactic shock on the basis of clinical manifestations and administered adrenaline and hydrocortisone. The patient's blood pressure and oxygen saturation immediately improved, and the operation was resumed. No postoperative complications were evident, and the postoperative course was uneventful. Although low molecular weight dextran is often used as plasma expander or to prevent thromboembolism, it can cause severe hypotension or bronchospasm during general anesthesia.

Involvement of caspase cascade in capsaicin-induced apoptosis of dorsal root ganglion neurons.

Capsaicin induces apoptosis in some types of neurons, but the exact molecular mechanism remains unclear. In this study, capsaicin was systemically administrated in newborn rats and the dorsal root ganglion (DRG) neurons were examined for caspase-immunoreactivity. Capsaicin-induced neuronal apoptosis was revealed by TUNEL. TUNEL-positive neurons rapidly increased, reaching the peak at 24 h post-injection when 10.6% of DRG neurons were apoptotic. Neurons expressing immunoreactivity for activated caspases-9 and -3 concomitantly increased. At 24 h, 15.9% and 17.7% of DRG neurons exhibited immunoreactivity for caspase-9 and caspase-3, respectively. DNA fragmentation signal and caspase-immunoreactivity were detected in less than 0.5% of DRG neurons of vehicle control rats. The immunoreactivity and TUNEL-positivity returned to the vehicle control level by 120 h. Double label immunohistochemistry revealed co-expression of caspase-9 and DNA fragmentation or caspase-3 and DNA fragmentation. These results suggest that the caspase cascade is involved in the primary neuronal apoptosis induced by neurotoxin capsaicin.

Activation of the caspase cascade underlies the rat trigeminal primary neuronal apoptosis induced by neonatal capsaicin administration.

The systemic administration of capsaicin is known to cause a massive loss of sensory primary neurons in newborn rats. Here we examined the trigeminal ganglion neurons immunohistochemically for the possible induction of activated forms of caspases-9 and -3 following a subcutaneous injection of capsaicin in newborn rats. The DNA fragmentation signal was labeled by a TUNEL method. TUNEL-positive neurons were rare (< 0.5%) at 24 h after injection of the vehicle without capsaicin. After the capsaicin injection, TUNEL-positive neurons began to increase by 12 h, reached a peak at 24 h (11.4%), and returned to the control level by 120 h. Vehicle control levels of caspase- 9-immunoreactive (ir) and caspase-3-ir neurons were low (< 0.5%). Neonatal capsaicin administration induced caspase-9-immunoreactivity (ir) and -3-ir. The temporal distributions of caspase-9-ir and caspase-3-ir neurons were similar to those of TUNEL-positive neurons with peak expressions at 24 h of 13.2 and 11.1%, respectively. A double-stain analysis at 24 h post-injection indicated 72% of TUNEL-positive neurons were caspase-9-ir, and 70% caspase-3-ir. Conversely, 78 and 68% of caspase-9-ir and caspase-3-ir neurons, respectively, were TUNEL-positive. Comparison of two adjacent sections immunostained for the two different antigens revealed the co-expression of the two caspases. These results suggest that neonatal capsaicin triggers the caspase cascade and, thereby, induces trigeminal primary neuronal apoptosis.

Prolonged nuclear retention of activated extracellular signal-regulated kinase 1/2 is required for hepatocyte growth factor-induced cell motility.

We examined the signaling pathway by which hepatocyte growth factor (HGF) induces cell motility, with special focus on the role of extracellular signal-regulated kinase (ERK) in the nucleus. We used Madin-Darby canine kidney cells overexpressing ERK2 because of their prominent motility response to HGF. HGF stimulation of the cells induces not only a rapid, marked, and sustained activation and rapid nuclear accumulation of ERK1/2, but also a prolonged nuclear retention of the activated ERK1/2. Interruption of the ERK1/2 activation by PD98059 treatment of the cells 30 min after HGF stimulation abolishes the HGF-induced cell motility. Enforced cytoplasmic retention of the activated ERK1/2 by the expression of an inactive form of MKP-3 cytoplasmic phosphatase inhibits the cell motility response. Although epidermal growth factor stimulation of the cells induces the activation and nuclear accumulation of ERK1/2, it does not induce the prolonged nuclear retention of the activated ERK1/2, and fails to induce cell motility. In the nucleus, activated ERK1/2 continuously phosphorylate Elk-1, leading to the prolonged expression of c-fos, which results in the expression of several genes such as matrix metalloproteinase (mmp)-9; MMP-9 activity is required for the induction of the cell motility response. Our results indicate that the sustained activity of ERK1/2 in the nucleus is required for the induction of HGF-induced cell motility.