Lipopolysaccharide-producing Veillonella infantium and Escherichia fergusonii cause vagus nerve-mediated cognitive impairment in mice.

Gut microbiota communicates bidirectionally with the brain through the nervous, immune, and endocrine systems of the gut. In our preliminary study, the fecal microbiota of volunteers with mild cognitive impairment (Fmci) exhibited a higher abundance of Escherichia fergusonii (NK2001), Veillonella infantium (NK2002), and Enterococcus faecium (NK2003) populations compared with those of healthy volunteers. Therefore, we examined the effects of Fmci, NK2001 (gram-negative), NK2002 (gram-negative-like), and NK2003 (gram-positive) on cognitive impairment-like behavior, neuroinflammation, and colitis in mice with or without antibiotics. Fmci transplantation increased cognitive impairment-like behavior, hippocampal tumor necrosis factor (TNF)-α expression, and the size of toll-like receptor (TLR)4+Iba1+, TLR2+Iba1+, and NF-κB+Iba1+ cell populations independent of antibiotic treatment. Oral gavage of NK2001, NK2002, or NK2003, which induced TNF-α expression in Caco-2 cells, significantly increased cognitive impairment-like behavior and hippocampal TNF-α expression and Iba1-positive cell populations and decreased brain-derived neurotrophic factor (BDNF) expression in mice. Celiac vagotomy significantly decreased NK2001- or NK2002-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression and increased NK2001- or NK2002-suppressed hippocampal BDNF expression. However, NK2003-induced cognitive impairment-like behavior and hippocampal Iba1+ cell population and TNF-α expression were partially, but not significantly, attenuated by celiac vagotomy. Furthermore, celiac vagotomy did not affect NK2001-, NK2002-, or NK2003-induced lipopolysaccharide (LPS) levels in the blood and feces and TNF-α expression and NF-κB-positive cell population in the colon. In conclusion, LPS-producing NK2001 and NK2002 and LPS-nonproducing NK2003 may induce NF-κB-mediated neuroinflammation through the translocation of byproducts such as LPS and peptidoglycan into the brain through gut-blood/vagus nerve-brain and gut-blood-brain pathways, respectively, resulting in cognitive impairment.

Lactobacillus plantarum and Bifidobacterium longum Alleviate Liver Injury and Fibrosis in Mice by Regulating NF-κB and AMPK Signaling.

In a preliminary study, live biotherapeutic products (LBPs) Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 inhibited the secretion of alanine transaminase (ALT) and aspartate transaminase (AST) in LPS-stimulated HepG2 cells, while Escherichia coli K1 (Ec) increased ALT and ALT secretion. Therefore, we examined the effects of LC27 and LC67 on LPS-induced liver injury and fibrosis in mice and the correlation between their biomarkers in cell and animal experiments. Orally administered LC27 or LC67 significantly decreased blood ALT, AST, γ-glutamyl transferase (γGTP), TNF-α, triglyceride (TG), total cholesterol (TCh), total bile acid, and LPS levels, liver TNF-α, toll-like receptor-4 gene (Tlr4), α-smooth muscle actin (αSMA), and collagen-1 expression and αSMA+GFAP+ and NF-κB+F4/80+ cell populations, and colonic Tlr4, TNF-α, and IL-6 expression and NF-κB-positive cell population in LPS-treated mice. Furthermore, they increased AMPKa phosphorylation in the liver and colon. However, Ec increased the expression of TNF-α and IL-6 in blood, liver, and colon. The suppression of LPS-stimulated ALT and AST secretion in HepG2 cells by LBPs was positively correlated with their ameliorating effects on LPS-induced blood γGTP, ALT, and AST levels and liver αSMA and collagen-1 expression in mice. Based on these findings, LC27 and LC67 may improve liver injury and fibrosis by regulating NF-κB and AMPK signaling pathway and a protocol that can assay the inhibitory activity of LBPs on LPS-induced ALT and AST secretion in HepG2 may be useful for guessing their antihepatitic effects in the in vivo experiments.

Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum.

Neuropsychiatric disorders including Alzheimer's disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-ß (Aß), TNF-α and interleukin (IL)-1ß expression, hippocampal NF-κB+Iba1+ cell population, and Aß accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1ß expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1ß expression decreased. NKc also decreased TNF-α and IL-1ß expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

Lactobacillus casei and Its Supplement Alleviate Stress-Induced Depression and Anxiety in Mice by the Regulation of BDNF Expression and NF-κB Activation.

Stress-induced depression and anxiety (DA) are closely connected to gastrointestinal inflammation and dysbiosis, which can suppress brain-derived neurotrophic factor (BDNF) in the brain. Herein, we isolated the BDNF expression-inducing probiotics Lactobacillus casei HY2782 and Bifidobacterium lactis HY8002 in lipopolysaccharide-stimulated SH-SY5Y cells. Then, we investigated the effects of HY2782, HY8002, anti-inflammatory L-theanine, and their supplement (PfS, probiotics-fermented L-theanine-containing supplement) on DA in mice exposed to restraint stress (RS) or the fecal microbiota of patients with inflammatory bowel disease and depression (FMd). Oral administration of HY2782, HY8002, or L-theanine alleviated RS-induced DA-like behaviors. They also decreased RS-induced hippocampal interleukin (IL)-1ß and IL-6 levels, as well as NF-κB-positive cell numbers, blood corticosterone level, and colonic IL-1ß and IL-6 levels and NF-κB-positive cell numbers. L-theanine more potently suppressed DA-like behaviors and inflammation-related marker levels than probiotics. However, these probiotics more potently increased RS-suppressed hippocampal BDNF level and BDNF+NeuN+ cell numbers than L-theanine. Furthermore, HY2782 and HY8002 suppressed RS-increased Proteobacteria and Verrucomicrobia populations in gut microbiota. In particular, they increased Lachnospiraceae and Lactobacillacease populations, which are closely positively associated with hippocampal BDNF expression, and suppressed Sutterellaceae, Helicobacteriaceae, Akkermansiaceae, and Enterobacteriaceae populations, which are closely positively associated with hippocampal IL-1ß expression. HY2782 and HY8002 potently alleviated FMd-induced DA-like behaviors and increased FMd-suppressed BDNF, serotonin levels, and BDNF-positive neuronal cell numbers in the brain. They alleviated blood corticosterone level and colonic IL-1ß α and IL-6 levels. However, L-theanine weakly, but not significantly, alleviated FMd-induced DA-like behaviors and gut inflammation. BDNF expression-inducing probiotic (HY2782, HY8002, Streptococcus thermophilus, and Lactobacillus acidophilus)-fermented and anti-inflammatory L-theanine-containing supplement PfS alleviated DA-like behaviors, inflammation-related biomarker levels, and gut dysbiosis more than probiotics or L-theanine. Based on these findings, a combination of BDNF expression-inducing probiotics with anti-inflammatory L-theanine may additively or synergistically alleviate DA and gut dysbiosis by regulating gut microbiota-mediated inflammation and BDNF expression, thereby being beneficial for DA.

Development and effects of an internet-based family resilience-promoting program for parents of children with cancer: A randomized controlled trial.

PURPOSE: The diagnosis of cancer in children can negatively impact their parents, owing to the complex treatment processes. Families with high levels of resilience can overcome these difficulties and thus perform higher family functions. We aimed to develop an internet-based family resilience-promoting program for parents of children with cancer and evaluate its effect on the levels of family resilience, depression, and family function. METHODS: This prospective, parallel-group, randomized-controlled study that was conducted at Yonsei Cancer Center from June to October 2021 included 41 parents of children with cancer. In total, four sessions of the internet-based family resilience-promoting program, led by a nurse, were conducted individually for parents. Levels of family resilience, depression, and family function were measured before, immediately after, and 4 weeks after the program. The data were analyzed using the linear mixed-effect model, and program satisfaction was evaluated through an internet-based questionnaire and interview. RESULTS: The experimental group (the family resilience-promoting program participants) differed more significantly from the control group in the level of change in family resilience (ß = 13.214, p = 0.003, effect size = 0.374) and family function (ß = 1.256, p = 0.018, effect size = 0.394). However, there was no significant difference between the groups in the level of depression (ß = 2.133, p = 0.187, effect size = 0.416). All the program participants showed a high program satisfaction score of 4.75 out of 5.00 points overall. CONCLUSIONS: The applicability of the internet-based family resilience-promoting program as an appropriate nursing intervention was verified. Its application can help the families of children with cancer adapt to the stressful situation of their children's cancer diagnosis and treatment.

Alleviation of Porphyromonas gingivalis or Its Extracellular Vesicles Provoked Periodontitis and Cognitive Impairment by Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391.

Porphyromonas gingivalis (PG) is closely involved in the outbreak of periodontitis and cognitive impairment (CI). Herein, we examined the effects of anti-inflammatory Lactobacillus pentosus NK357 and Bifidobacterium bifidum NK391 on PG- or its extracellular vesicles (pEVs)-induced periodontitis and CI in mice. Oral administration of NK357 or NK391 significantly decreased PG-induced tumor necrosis factor (TNF)-α, receptor activator of nuclear factors κB (RANK), and RANK ligand (RANKL) expression, gingipain (GP)+lipopolysaccharide (LPS)+ and NF-κB+CD11c+ populations, and PG 16S rDNA level in the periodontal tissue. Their treatments also suppressed PG-induced CI -like behaviors, TNF-α expression and NF-κB-positive immune cells in the hippocampus and colon, while PG-suppressed hippocampal BDNF and N-methyl-D-aspartate receptor (NMDAR) expression increased. The combination of NK357 and NK391 additively alleviated PG- or pEVs-induced periodontitis, neuroinflammation, CI-like behaviors, colitis, and gut microbiota dysbiosis and increased PG- or pEVs-suppressed BDNF and NMDAR expression in the hippocampus. In conclusion, NK357 and NK391 may alleviate periodontitis and dementia by regulating NF-κB, RANKL/RANK, and BDNF-NMDAR signaling and gut microbiota.

Effect of fermented red ginseng on gut microbiota dysbiosis- or immobilization stress-induced anxiety, depression, and colitis in mice.

Background: Red ginseng (RG) alleviates psychiatric disorders. Fermented red ginseng (fRG) alleviates stress-induced gut inflammation. Gut dysbiosis causes psychiatric disorders with gut inflammation. To understand the gut microbiota-mediated action mechanism of RG and fRG against anxiety/depression (AD), we investigated the effects of RG, fRG, ginsenoside Rd, and 20(S)-ß-D-glucopyranosyl protopanaxadiol (CK) on gut microbiota dysbiosis-induced AD and colitis in mice. Methods: Mice with AD and colitis were prepared by exposing to immobilization stress (IS) or transplanting the feces of patients with ulcerative colitis and depression (UCDF). AD-like behaviors were measured in the elevated plus maze, light/dark transition, forced swimming, and tail suspension tests. Results: Oral gavage of UCDF increased AD-like behaviors and induced neuroinflammation, gastrointestinal inflammation, and gut microbiota fluctuation in mice. Oral administration of fRG or RG treatment reduced UCDF-induced AD-like behaviors, hippocampal and hypothalamic IL-6 expression, and blood corticosterone level, whereas UCDF-suppressed hippocampal BDNF+NeuN+ cell population and dopamine and hypothalamic serotonin levels increased. Furthermore, their treatments suppressed UCDF-induced colonic inflammation and partially restored UCDF-induced gut microbiota fluctuation. Oral administration of fRG, RG, Rd, or CK also decreased IS-induced AD-like behaviors, blood IL-6 and corticosterone and colonic IL-6 and TNF-α levels, and gut dysbiosis, while IS-suppressed hypothalamic dopamine and serotonin levels increased. Conclusion: Oral gavage of UCDF caused AD, neuroinflammation, and gastrointestinal inflammation in mice. fRG mitigated AD and colitis in UCDF-exposed mice by the regulation of the microbiota-gut-brain axis and IS-exposed mice by the regulation of the hypothalamic-pituitary-adrenal axis.

Lactobacillus gasseri NK109 and Its Supplement Alleviate Cognitive Impairment in Mice by Modulating NF-κB Activation, BDNF Expression, and Gut Microbiota Composition.

Aging-related gut microbiota dysbiosis initiates gut inflammation and microbiota dysbiosis, which induce the occurrence of psychiatric disorders including dementia. The alleviation of gut microbiota dysbiosis by probiotics is suggested to be able to alleviate psychiatric disorders including cognitive impairment (CI). Therefore, to understand how probiotics could alleviate CI, we examined the effects of anti-inflammatory Lactobacillus gasseri NK109 and its supplement (NS, mixture of NK109 and soybean embryo ethanol extract) on cognitive function in aged (Ag), 5XFAD transgenic (Tg), or mildly cognition-impaired adult fecal microbiota (MCF)-transplanted mice. Oral administration of NK109 or NS decreased CI-like behaviors in Ag mice. Their treatments suppressed TNF-α and p16 expression and NF-κB-activated cell populations in the hippocampus and colon, while BDNF expression was induced. Moreover, they partially shifted the ß-diversity of gut microbiota in Ag mice to those of young mice: they decreased Bifidobacteriaceae, Lactobacillaceae, and Helicobacteriaceae populations and increased Rikenellaceae and Prevotellaceae populations. Oral administration of NK109 or NS also reduced CI-like behaviors in Tg mice. Their treatments induced BDNF expression in the hippocampus, decreased hippocampal TNF-α and Aß expression and hippocampal and colonic NF-κB-activated cell populations. NK109 and NS partially shifted the ß-diversity of gut microbiota in Tg mice: they decreased Muribaculaceae and Rhodospiraceae populations and increased Helicobacteriaceae population. Oral administration of NK109 or NS decreased MCF transplantation-induced CI-like behaviors in mice. NK109 and NS increased hippocampal BDNF expression, while hippocampal and colonic TNF-α expression and NF-κB-activated cell populations decreased. These findings suggest that dementia can fluctuate the gut microbiota composition and NK109 and its supplement NS can alleviate CI with systemic inflammation by inducing BDNF expression and suppressing NF-κB activation and gut microbiota dysbiosis.

Extracellular vesicles derived from Porphyromonas gingivalis induce trigeminal nerve-mediated cognitive impairment.

INTRODUCTION: Porphyromonas gingivalis (PG)-infected periodontitis is in close connection with the development of Alzheimer's disease (AD). PG-derived extracellular vesicles (pEVs) contain inflammation-inducing virulence factors, including gingipains (GPs) and lipopolysaccharide (LPS). OBJECTIVES: To understand how PG could cause cognitive decline, we investigated the effects of PG and pEVs on the etiology of periodontitis and cognitive impairment in mice. METHODS: Cognitive behaviors were measured in the Y-maze and novel object recognition tasks. Biomarkers were measured using ELISA, qPCR, immunofluorescence assay, and pyrosequencing. RESULTS: pEVs contained neurotoxic GPs and inflammation-inducible fimbria protein and LPS. Gingivally exposed, but not orally gavaged, PG or pEVs caused periodontitis and induced memory impairment-like behaviors. Gingival exposure to PG or pEVs increased TNF-α expression in the periodontal and hippocampus tissues. They also increased hippocampal GP+Iba1+, LPS+Iba1+, and NF-κB+Iba1+ cell numbers. Gingivally exposed PG or pEVs decreased BDNF, claudin-5, and N-methyl-D-aspartate receptor expression and BDNF+NeuN+ cell number. Gingivally exposed fluorescein-5-isothiocyanate-labeled pEVs (F-pEVs) were detected in the trigeminal ganglia and hippocampus. However, right trigeminal neurectomy inhibited the translocation of gingivally injected F-EVs into the right trigeminal ganglia. Gingivally exposed PG or pEVs increased blood LPS and TNF-α levels. Furthermore, they caused colitis and gut dysbiosis. CONCLUSION: Gingivally infected PG, particularly pEVs, may cause cognitive decline with periodontitis. PG products pEVs and LPS may be translocated into the brain through the trigeminal nerve and periodontal blood pathways, respectively, resulting in the cognitive decline, which may cause colitis and gut dysbiosis. Therefore, pEVs may be a remarkable risk factor for dementia.

The Alleviation of Gut Microbiota-Induced Depression and Colitis in Mice by Anti-Inflammatory Probiotics NK151, NK173, and NK175.

Gut microbiota dysbiosis is strongly associated with psychiatric disorders and inflammatory bowel disease (IBD). Herein, we examined whether the fecal microbiota of IBD patients with depression (IBDD) and their gut microbiota culture (iGm) could cause depression and colitis in mice and anti-inflammatory probiotics could mitigate depression in iGm-transplanted or immobilization stress (IS)-exposed mice. Fecal microbiota transplantation (FMT) from IBDD patients, which exhibited Enterobacteriaceae-rich gut microbiota, and its gut microbiota culture (iGm) increased depression-like behaviors in mice. Their treatments heightened the blood lipopolysaccharide (LPS) level and colonic IL-1ß and IL-6 expression. However, FMT from healthy volunteers or sulfasalazine treatment alleviated cGm-induced depressive-like behaviors and hippocampal and colonic inflammation in mice. Moreover, oral administration of Lactobacillus plantarum NK151, Bifidobacterium longum NK173, and Bifidobacterium bifidum NK175, which inhibited LPS-induced IL-6 expression in macrophages, alleviated cGm-induced depression-like behaviors, hippocampal NF-κB+Iba1+ cell numbers and IL-1ß and IL-6 expression, blood LPS, IL-6, and creatinine levels, and colonic NF-κB+CD11c+ number and IL-1ß and IL-6 expression in mice. Treatment with NK151, NK173, or NK175 mitigated immobilization stress (IS)-induced depressive-like behaviors, neuroinflammation, and gut inflammation in mice. NK151, NK173, or NK175 also decreased IS-induced blood LPS, IL-6, and creatinine levels. The transplantation of Enterobacteriaceae-rich gut microbiota can cause depression and colitis, as IS exposure, and anti-inflammatory NK151, NK173, and NK175, may alleviate stress-induced fatigue, depression, and colitis by regulating the expression of proinflammatory and anti-inflammatory cytokines through the suppression of gut bacterial LPS.

Transplantation of fecal microbiota from patients with inflammatory bowel disease and depression alters immune response and behavior in recipient mice.

Gut dysbiosis is closely associated with the occurrence of inflammatory bowel disease (IBD) and psychiatric disorder. Here, to understand the difference of gut microbiota composition and physiological effect between IBD patients with (IBD/D+) or without depression (IBD/D-), we analyzed the fecal microbiota composition of patients with IBD with (/D+) or without depression (/D-) and healthy volunteers (HVs) and examined the effects of these fecal microbiota transplantations (FMTs) on the occurrence of systemic inflammation and anxiety/depression in mice. FMTs from patients with IBD/D+ or IBD/D- caused IBD-like colitis in the transplanted mice: they increased the myeloperoxidase activity, IL-1ß and IL-6 expression, and NF-κB+/CD11c+ cell population in the colon. Transplantation of the IBD/D+ patient feces (IBD/D+-F) caused IBD-like colitis more strongly than that of IBD/D--F. FMTs from patients with IBD/D+ also caused anxiety-/depression-like behaviors, increased the NF-κB+/Iba1+ and lipopolysaccharide (LPS)+/Iba1+ cell populations, and decreased the BDNF+/NeuN+ cell population in the hippocampus. They increased LPS levels in the blood. FMTs from patients with IBD/D- caused anxiety-like, but not depression-like, behaviors. α-/ß-diversities and composition of gut microbiota in IBD-F were different from those of HV feces (HV-F). The Enterobacteriaceae and Enterococcaceae populations and LPS levels were higher in the IBD-F than in the HV-F. The Enterococcaceae population was higher in IBD/D+-F vs. IBD/D--F. However, the transplantation of HV-F into mice previously transplanted with IBD/D+-F significantly reduced depression-like behaviors, NF-κB+/Iba1+ and LPS+/Iba1+ cell populations in the hippocampus, LPS levels in the feces and blood, and IL-1ß expression in the colon. These findings suggest that the outbreak of depression/anxiety may be dependent on the systemic inflammation with a leaky gut through the gut dysbiosis-attributable overproduction of bacterial LPS and suppression of tight junction protein expression in patients with IBD.

Lactobacillus rhamnosus and Bifidobacterium longum alleviate colitis and cognitive impairment in mice by regulating IFN-γ to IL-10 and TNF-α to IL-10 expression ratios.

Gut lactobacilli and bifidobacteria on the immune homeostasis. Therefore, to understand the mechanism in vivo, we selected human fecal Lactobacillus rhamnosus NK210 and Bifidobacterium longum NK219, which strongly suppressed the IFN-γ to IL-10 expression (IIE) ratio in lipopolysaccharide-stimulated macrophages. Thereafter, we examined their effects on the endotoxin, antibiotics, or antitumor drug-stimulated immune imbalance in mice. Intraperitoneal injection of lipopolysaccharide and oral gavage of ampicillin increased IFN-γ and TNF-α expression in the spleen, colon, and hippocampus, while IL-10 expression decreased. However, intraperitoneal injection of cyclophosphamide suppressed IFN-γ, TNF-α, and IL-10 expression. LPS exposure induced splenic natural killer cell cytotoxicity against YAC-1 cells (sNK-C) and peritoneal macrophage phagocytosis against Candida albicans (pMA-P) activities, while cyclophosphamide and ampicillin treatments suppressed sNK-C and pMA-P activities. However, LPS, ampicillin, cyclophosphamide all increased IIE and TNF-α to IL-10 expression (TIE) ratios. Oral administration of NK210 and/or NK219 significantly reduced LPS-induced sNK-C, pMA-P, and IFN-γ expression, while cyclophosphamide- or ampicillin-suppressed sNK-C and pMA-P activities, cyclophosphamide-suppressed IFN-γ, TNF-α, and IL-10 expression, and ampicillin-suppressed IL-10 expression increased. Nevertheless, they suppressed LPS-, ampicillin-, or cyclophosphamide-induced IIE and TIE ratios, cognitive impairment, and gut dysbiosis. In particular, NK219, but not NK210, increased the IIE expression ratio in vitro and in vivo, and enhanced sNK-C and pMA-P activities in normal control mice, while cognitive function and gut microbiota composition were not significantly affected. These findings suggest that NK210, Lactobacillus sp, and NK219, Bifidobacterium additively or synergistically alleviate gut dysbiosis, inflammation, and cognitive impairment with immune imbalance by controlling IIE and TIE ratios.

Factors Influencing Resilience among Korean adolescents and young adult survivors of childhood cancer.

PURPOSE: The number of childhood cancer survivors has been steadily increasing because of improved cancer treatment outcomes. We aimed to examine the level of cancer stigma, coping, spirituality, hope, family communication, social support and resilience in adolescent and adult childhood cancer survivors and identify factors associated with resilience. METHOD: This study is a descriptive survey conducted on 139 childhood cancer survivors aged 15-29 years who had been diagnosed with cancer prior to the age of 19 years at a general hospital in Seoul. The questionnaire consisted of the Cancer Stigma Scale, Jalowiec Coping Scale, Functional Assessment of Chronic-Illness Therapy-Spirituality (FACIT-Sp), Hearth Hope Index (HHI), Parent-Adolescent Communication Inventory (PACI), Multidimensional Scale of Perceived Social Support (MSPSS), and Haase Resilience in Illness Scale (HARS). Collected data were analyzed using multiple linear regression analysis with SPSS 23.0. RESULTS: Resilience positively correlated with courageous coping, spirituality, hope, family communication and social support, and negatively correlated with cancer stigma and defensive coping. Regression analyses revealed that courageous coping (ß = 0.303, p < .001), hope (ß = 0.317, p = .001), and solid tumor diagnosis (ß = -0.144, p = .012) were significantly predictive of resilience among childhood cancer survivors, and these factors explained 65.2% of the variance. CONCLUSIONS: Resilience among childhood cancer survivors was higher with increasing courageous coping and hope and lower with solid tumors. These results suggest that coping and hope management should be included in the strategies to enhance the resilience of AYA cancer survivors.

Factors Affecting the Timing of a Central Line Associated Bloodstream Infection Onset in Children with Cancer.

PURPOSE: The purpose of this study is to identify controllable treatment-environment-related factors affecting the timing of a central line-associated bloodstream infection (CLABSI) onset in children with cancer with central venous catheters (CVC). DESIGN: This study is a secondary data analysis with the data extracted from electronic medical records in a tertiary hospital in South Korea. This study was conducted by reviewing electronic medical records of 470 pediatric cancer patients younger than the age of 18 years from 2010 to 2016. METHOD: The timing of a CLABSI onset was identified through the onset of CLABSI and the duration of catheterization. Cox proportional hazards regression analysis was used to estimate the impact of variables on the timing of CLABSI onset. The duration of catheterization was estimated using the Kaplan-Meier method. FINDING: Multivariable analysis by Cox proportional model analysis showed that there are six independent variables affecting the timing of a CLABSI onset: length of stay in hospital, catheter insertion location, use of antibiotics on day of catheter insertion, catheter function, number of blood transfusions per 100 days, and number of blood tests per 100 days. CONCLUSIONS: The findings of this study provide a foundation for the development of EBP-based CVC guidelines to effectively reduce CLABSIs and maintain a long-term CVC without a CLABSI.

Subclinical Hypothyroidism in Childhood Cancer Survivors.

PURPOSE: In childhood cancer survivors, the most common late effect is thyroid dysfunction, most notably subclinical hypothyroidism (SCH). Our study evaluated the risk factors for persistent SCH in survivors. MATERIALS AND METHODS: Survivors (n=423) were defined as patients who survived at least 2 years after cancer treatment completion. Thyroid function was assessed at this time and several years thereafter. Two groups of survivors with SCH were compared: those who regained normal thyroid function during the follow-up period (normalized group) and those who did not (persistent group). RESULTS: Overall, 104 of the 423 survivors had SCH. SCH was observed in 26% of brain or nasopharyngeal cancer survivors (11 of 43) and 21.6% of leukemia survivors (35 of 162). Sixty-two survivors regained normal thyroid function, 30 remained as persistent SCH, and 12 were lost to follow-up. The follow-up duration was 4.03 (2.15-5.78) years. Brain or nasopharyngeal cancer and Hodgkin disease were more common in the persistent group than in the normalized group (p=0.002). More patients in the persistent group received radiation (p=0.008). Radiation to the head region was higher in this group (2394±2469 cGy) than in the normalized group (894±1591 cGy; p=0.003). On multivariable analysis, lymphoma (p=0.011), brain or nasopharyngeal cancer (p=0.039), and head radiation dose ≥1800 cGy (p=0.039) were significant risk factors for persistent SCH. CONCLUSION: SCH was common in childhood cancer survivors. Brain or nasopharyngeal cancer, lymphoma, and head radiation ≥1800 cGy were significant risk factors for persistent SCH.

Symptom Interval and Patient Delay Affect Survival Outcomes in Adolescent Cancer Patients.

PURPOSE: Unique features of adolescent cancer patients include cancer types, developmental stages, and psychosocial issues. In this study, we evaluated the relationship between diagnostic delay and survival to improve adolescent cancer care. MATERIALS AND METHODS: A total of 592 patients aged 0-18 years with eight common cancers were grouped according to age (adolescents, ≥10 years; children, <10 years). We retrospectively reviewed their symptom intervals (SIs, between first symptom/sign of disease and diagnosis), patient delay (PD, between first symptom/sign of disease and first contact with a physician), patient delay proportion (PDP), and overall survival (OS). RESULTS: Mean SI was significantly longer in adolescents than in children (66.4 days vs. 28.4 days; p<0.001), and OS rates were higher in patients with longer SIs (p=0.001). In children with long SIs, OS did not differ according to PDP (p=0.753). In adolescents with long SIs, OS was worse when PDP was ≥0.6 (67.2%) than <0.6 (95.5%, p=0.007). In a multivariate analysis, adolescents in the long SI/PDP ≥0.6 group tended to have a higher hazard ratio (HR, 6.483; p=0.069) than those in the long SI/PDP <0.6 group (HR=1, reference). CONCLUSION: Adolescents with a long SI/PDP ≥0.6 had lower survival rates than those with a short SI/all PDP or a long SI/PDP <0.6. They should be encouraged to seek prompt medical assistance by a physician or oncologist to lessen PDs.

Poor bone health at the end of puberty in childhood cancer survivors.

BACKGROUND: Although the survival rate following childhood cancer is >80%, late effects are a major concern. We aimed to determine the clinical factors affecting bone health after puberty in childhood cancer survivors at risk for low bone mineral density (BMD). PROCEDURES: We performed dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, and total hip regions for survivors with the following bone densitometry indications (BDIXs): brain or nasopharyngeal cancer, head or neck area radiotherapy, or corticosteroid treatment (N = 92). Additionally, we evaluated 16 survivors without these BDIXs but with other clinical factors that could affect bone health. We assessed the effects of these factors on BMD using univariate and logistic regression analyses. Moderate BMD deficit was defined as a Z-score of <-1.0 and ≥-2.0, and severe BMD deficit was defined as <-2.0. RESULTS: Severe BMD deficits were found in 18 survivors (16.7%) and moderate BMD deficits were in 39 (36.1%) in at least one bone region. BMD deficits tended to increase as the number of BDIXs increased (P < 0.010). There were no severe BMD deficits in survivors without BDIXs. The duration since cancer treatment completion was correlated with higher BMD (P < 0.05). Endocrine dysfunction was a significant risk factor for decreased BMD in univariate and multivariate analyses (P < 0.05 for both). CONCLUSIONS: Decreased BMD was prevalent in our study cohort. Endocrine dysfunction was found to be a significant risk factor, and it should be managed in survivors to ensure future bone health.

Impact of psychological and cancer-related factors on HRQoL for Korean childhood cancer survivors.

PURPOSE: The purposes of this study were (1) to compare health-related quality of life (HRQoL) between Korean childhood cancer survivors and healthy controls and (2) to examine the impact of demographic, diagnosis/treatment, and psychological variables on physical and psychosocial health in survivors. METHODS: The HRQoL (PedsQL), Self-Concept Inventory, and Child Behavior Checklist were administered to childhood cancer survivors, age/gender-matched healthy counterparts, and their parents. Independent-samples t tests and hierarchical multiple regression analyses were conducted. RESULTS: Compared with healthy controls, childhood cancer survivors reported significantly lower scores across physical and psychosocial HRQoL. For survivors, demographic, diagnosis/treatment, current health status, and psychological variables explained more than 50 % of the variance in both subscales of HRQoL. Especially, self-concept, a psychological variable, explained a significant portion of the variance in physical and psychosocial HRQoL after controlling for cancer-related factors. Several cancer-related factors including time since treatment completion, having a history of allogeneic hematopoietic stem cell transplantation, multiple treatment modalities, and suffering from severe late effects also associated with specific dimension of HRQoL. CONCLUSIONS: Childhood cancer survivors do experience lower level of QoL and psychological factors, especially self-concept, should be considered when supporting the well-being of childhood cancer survivors.

Increasing and worsening late effects in childhood cancer survivors during follow-up.

Recent advances in childhood cancer treatment have increased survival rates to 80%. Two out of three survivors experience late effects (LEs). From a group of 241 survivors previously described, 193 were followed at the long-term follow-up clinic (LTFC) of Severance Hospital in Korea; the presence of LEs was confirmed by oncologists. We reported the change in LEs during 3 yr of follow-up. The median follow-up from diagnosis was 10.4 yr (5.1-26.2 yr). Among 193 survivors, the percentage of patients with at least one LE increased from 63.2% at the initial visit to 75.1% at the most recent visit (P = 0.011). The proportion of patients having multiple LEs and grade 2 or higher LEs increased from the initial visit (P = 0.001 respectively). Forty-eight non-responders to the LTFC were older and had less frequent and severe LEs than responders at initial visit (all P < 0.05). In multivariate analysis, younger age at diagnosis, older age at initial visit, a diagnosis of a brain tumor or lymphoma, and use of radiotherapy were significant risk factors for LEs (all P < 0.05). Adverse changes in LEs were seen among the survivors, regardless of most clinical risk factors. They need to receive comprehensive, long-term follow up.

Feasibility of sequential high-dose chemotherapy in advanced pediatric solid tumors.

The purpose of this study was to evaluate the feasibility and tumor response of 3 cycles of sequential high-dose chemotherapy (HDCT) in advanced pediatric solid tumor patients. Medical records of 11 children who underwent 2 consequent courses of reduced conditioning HDCT followed by final HDCT with autologous HSC infusion were reviewed in a retrospective manner. Each median time to an absolute neutrophil count > 0.5 x 10(9)/L was 12, 13, and 12 days. Major toxic reactions were fever, infection, and vomiting. One patient experienced transplantation-related mortality. Nine patients showed complete and partial responses to the therapy at 6 months follow-up after final HDCT. Finally, 6 patients are alive without evidence of disease at median follow-up of 24 months. Even though it is a preliminary result, the authors think that this treatment could be a feasible treatment option for advanced pediatric solid tumor patients.