Prognostic significance of NY-ESO-1 antigen and PIGR expression in esophageal tumors of CHP-NY-ESO-1-vaccinated patients as adjuvant therapy.

The aim of this study was to determine the efficacy and the biomarkers of the CHP-NY-ESO-1 vaccine complexed with full-length NY-ESO-1 protein and a cholesteryl pullulan (CHP) in patients with esophageal squamous cell carcinoma (ESCC) after surgery. We conducted a randomized phase II trial. Fifty-four patients with NY-ESO-1-expressing ESCC who underwent radical surgery following cisplatin/5-fluorouracil-based neoadjuvant chemotherapy were assigned to receive either CHP-NY-ESO-1 vaccination or observation as control. Six doses of CHP-NY-ESO-1 were administered subcutaneously once every two weeks, followed by nine more doses once every four weeks. The endpoints were disease-free survival (DFS) and safety. Exploratory analysis of tumor tissues using gene-expression profiles was also performed to seek the biomarker. As there were no serious adverse events in 27 vaccinated patients, we verified the safety of the vaccine. DFS in 2 years were 56.0% and 58.3% in the vaccine arm and in the control, respectively. Twenty-four of 25 patients showed NY-ESO-1-specific IgG responses after vaccination. Analysis of intra-cohort correlations among vaccinated patients revealed that 5% or greater expression of NY-ESO-1 was a favorable factor. Comprehensive analysis of gene expression profiles revealed that the expression of the gene encoding polymeric immunoglobulin receptor (PIGR) in tumors had a significantly favorable impact on outcomes in the vaccinated cohort. The high PIGR-expressing tumors that had higher NY-ESO-1-specific IgA response tended to have favorable prognosis. These results suggest that PIGR would play a major role in tumor immunity in an antigen-specific manner during NY-ESO-1 vaccinations. The IgA response may be relevant.

Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug.

Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor cells. The high purity of Vγ2Vδ2 cells expanded by PTA increased engraftment success in immunodeficient NOG mice. Even low levels of contaminating αß T cells resulted in some mice with circulating human αß T cells rather than Vγ2Vδ2 cells. Vγ2Vδ2 cells from engrafted NOG mice upregulated CD25 and secreted tumor necrosis factor-α and interferon-γ in response to PTA-treated tumor cells. Thus, PTA expands Vγ2Vδ2 T cells to higher purity than zoledronic acid. The high purities allow the successful engraftment of immunodeficient mice without further purification and may speed up the development of allogeneic Vγ2Vδ2 T cell therapies derived from HLA-matched normal donors for patients with poor autologous Vγ2Vδ2 T cell responses.

High prevalence of shoplifting in patients with eating disorders.

PURPOSE: Shoplifting, prevalent in patients diagnosed with bulimia nervosa (BN), is a serious behavioral problem in eating disorder (ED) patients. However, little is known about its overall presence, etiology, and consequences. This study aimed to determine whether shoplifting occurs before or after the onset of ED and to investigate the prevalence and correlates of shoplifting in ED patients. METHODS: This was a cross-sectional study of 284 treatment-seeking female patients aged 13-45 with EDs [171 anorexia nervosa (AN); 113 BN]. Shoplifting, impulsive behaviors (self-injury, suicide attempt, sexual promiscuity, alcohol, and illicit drug use), depression, self-esteem, and clinical features of EDs were assessed with an interview. RESULTS: Lifetime shoplifting prevalence was 28.5% (81/284) with 70.4% (57/81) occurring before ED onset. Multivariate logistic regression analysis revealed that depression [odds ratio (OR), 2.63; 95% confidence interval (CI), 1.24-5.60], alcohol abuse (OR, 3.91; 95% CI 1.34-11.38), illicit substance use (OR, 14.42; 95% CI, 1.65-125.86), and self-esteem (OR, 0.90; 95% CI; 0.82-0.99) were associated with lifetime shoplifting, while illness duration, BN, and ED symptom severity were not. CONCLUSIONS: Shoplifting is common in ED patients and precedes ED onset in most patients with a shoplifting history, although the causal relationship between shoplifting and EDs remains inconclusive. Shoplifting may be associated with impulsive behaviors (e.g., alcohol and illicit drug use), depression, and low self-esteem, but not with ED severity. Future research should focus on the unrecognized role of shoplifting as a marker to identify patients at risk of impulsive behaviors and consider treatment options. LEVEL OF EVIDENCE: Level V, observational cross-sectional descriptive study.

Association between hallucinations and sensory processing difficulties in children and adolescents.

Introduction: Hallucinations are serious symptoms that can lead to high levels of distress, functional impairment, and increased risk of suicide in both adults and children. However, their etiology and treatment remain unclear. Hallucinations and sensory processing difficulties (SPDs) are associated with various psychiatric disorders, including mood, anxiety, and post-traumatic stress disorder. This study aimed to investigate the potential association between hallucinations and SPDs in a pediatric population. Methods: We conducted a cross-sectional study with 335 children aged 6-18 years who visited the child psychiatry outpatient clinic at Osaka Metropolitan University Hospital between April 2020 and March 2023 and continued treatment for at least three months. After excluding those with intellectual disabilities or uncontrolled epilepsy, 304 participants were included in the analyses. The presence of hallucinations was assessed through interviews with the children and their parents. SPDs were evaluated using the Short Sensory Profile. Binomial logistic regression analysis was conducted to assess the association between hallucinations and SPDs, adjusting for age, sex, autism spectrum disorder, socioeconomic difficulties (low-income, single-parent households), and the presence of mood and anxiety disorders. Results: Hallucinations were present in 64 children (21%). Logistic regression analysis showed a significant positive association between SPDs and hallucinations, even after adjusting for age, sex, autism spectrum disorder, socioeconomic difficulties, and the presence of mood and anxiety disorders (odds ratio, 1.02; 95% CI, 1.008-1.036; p = 0.002). Conclusion: The results of this study suggest a potential association between hallucinations and SPDs in pediatric patients. Further prospective studies are needed to explore the causal relationship between these factors and determine whether interventions for SPDs can alleviate hallucinations in children.

Comparison of γδ T cell responses and farnesyl diphosphate synthase inhibition in tumor cells pretreated with zoledronic acid.

Exposing human tumor cells to nitrogen-containing bisphosphonates, such as zoledronic acid (Zol), greatly increases their susceptibility to killing by γδ T cells. Based on this finding and other studies, cancer immunotherapy using γδ T cells and nitrogen-containing bisphosphonates has been studied in pilot clinical trials and has shown benefits. Although Zol treatment can render a wide variety of human tumor cells susceptible to γδ T cell killing, there has not been a systematic investigation to determine which types of tumor cells are the most susceptible to γδ T cell-mediated cytotoxicity. In this study, we determined the Zol concentrations required to stimulate half maximal tumor necrosis factor-α production by γδ T cells cultured with various tumor cell lines pretreated with Zol and compared these concentrations with those required for half maximal inhibition of farnesyl diphosphate synthase (FPPS) in the same tumor cell lines. The inhibition of tumor cell growth by Zol was also assessed. We found that FPPS inhibition strongly correlated with γδ T cell activation, confirming that the mechanism underlying γδ T cell activation by Zol is isopentenyl diphosphate (IPP) accumulation due to FPPS blockade. In addition, we showed that γδ T-cell receptor-mediated signaling correlated with γδ T cell tumor necrosis factor-α production and cytotoxicity. Some lymphoma, myeloid leukemia, and mammary carcinoma cell lines were relatively resistant to Zol treatment, suggesting that assessing tumor sensitivity to Zol may help select those patients most likely to benefit from immunotherapy with γδ T cells.

Zoledronic acid-induced expansion of γδ T cells from early-stage breast cancer patients: effect of IL-18 on helper NK cells.

Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2 T cells and helper NK cells from patients with either low or high frequencies of Vγ2Vδ2 T cells. Treatment of breast cancer patients with Zol alone decreased the number of Vγ2Vδ2 T cells and reduced their ex vivo responsiveness. These results demonstrate that Zol can elicit immunological responses by γδ T cells from early-stage breast cancer patients, but that frequent in vivo treatment reduces Vγ2Vδ2 T cell numbers and their responsiveness to stimulation.

Delayed recognition of autism spectrum disorder and attention-deficit/hyperactivity disorder in a girl with ornithine transcarbamylase deficiency: A case report.

RATIONALE: Ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder, is a rare congenital metabolic error that leads to hyperammonemia. Psychiatric symptoms of hyperammonemia are nonspecific and can cause autism spectrum disorder (ASD)-like symptoms and attention-deficit/hyperactivity disorder (ADHD)-like symptoms. Some studies report that OTC deficiency is often initially diagnosed as ASD or ADHD. However, there are no reports of OTC deficiency comorbid with ASD and ADHD. PATIENT CONCERNS: The patient is 17-year-old girl diagnosed with OTC deficiency at 3 years of age. She had behavioral problems since childhood, including depressed mood, irritability, and impulsive behavior; however, they were considered OTC-mediated nonspecific psychiatric symptoms. Therefore, the patient had not been appropriately assessed for ASD and ADHD. She presented with depressed mood and self-harm at 17 years of age. DIAGNOSES: We diagnosed her with ASD and ADHD based on her medical history and semistructured interviews. INTERVENTIONS: We focused her ASD and ADHD traits and discussed strategies with her for better adaptive living. OUTCOMES: Our interventions resulted in her better social adjustment. LESSONS: Physicians should consider the possibility of comorbid ASD and ADHD in individuals with OTC, facilitating appropriate and intervention for better outcomes.

Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens.

Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of αß T cells. Little is known, however, about the role of PD-1 in γδ T cells. In this study, we investigated the expression and function of PD-1 in human γδ T cells. Expression of PD-1 was rapidly induced in primary γδ T cells following antigenic stimulation, and the PD-1(+) γδ T cells produced IL-2. When PD-1(+) γδ T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-γ production and cytotoxicity in response to PD-L1(+) Daudi cells were diminished compared to the levels seen in response to PD-L1(-) Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1(+) γδ T cells were challenged by PD-L1(+) tumors pretreated with zoledronate (Zol), which induced γδ TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1(+) γδ T cells were challenged by PD-L1(-) tumors. In addition, cytotoxic activity of PD-1(+) γδ T cells against Zol-treated PD-L1(+) tumors was comparable to that against Zol-treated PD-L1(-) tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in γδ T cells.

Associations between Internet Addiction, Psychiatric Comorbidity, and Maternal Depression and Anxiety in Clinically Referred Children and Adolescents.

Purpose: Internet addiction (IA) has become a global problem and is one of the most common reasons for children to be referred for intervention because IA results in social and educational dysfunction and conflict with parents. IA is associated with various comorbid psychiatric disorders, with notable association between IA and family factors. However, little is known about parental psychopathology. This study aimed to examine the prevalence of IA and association between IA and maternal depression and anxiety in clinical samples after adjusting for comorbidities. Patients and Methods: A cross-sectional study was conducted between April 2020 and August 2021 at the Department of Neuropsychiatry of Osaka Metropolitan University Hospital in Japan. A total of 218 clinically referred children and adolescents (aged 8 to 15 years) were assessed using the Internet Addiction Test, which is one of the most popular questionnaires to evaluate IA, the Child Behavior Checklist (CBCL), and The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. IA was defined as a total score on the Internet Addiction Test ≥ 50. Of those, for the evaluation of maternal depression and anxiety, the 132 mothers of the children who were referred after January 2021 completed K6 as well. Results: A total of 68 participants (31.2%) presented with IA and had higher total and externalizing scores of CBCL, social anxiety disorder, and oppositional defiant disorder compared to those without IA. IA was associated with the six-item Kessler scale scores of mothers, being raised by single parents, and anxiety disorders after adjusting for age, sex, and family income (95% CI: 1.023-1.215). Conclusion: Maternal depression and anxiety may be one of the risk factors for children and adolescents to develop IA. Care for maternal depression and anxiety may contribute to intervention for children and adolescents with IA.

Associations Between Chronic Irritability and Sensory Processing Difficulties in Children and Adolescents.

Irritability is one of the most common reasons for which children and adolescents are referred for psychiatric evaluation and care. However, clinical irritability is difficult to define; thus, its prevalence varies widely. Chronic irritability may be associated with sensory processing difficulties (SPD), but little is known about the relationship between these two factors in clinical populations. In this study, we examined the prevalence of chronic irritability and its association with SPD in 166 children aged 5-16 years who were referred to the psychiatric outpatient clinic of the Osaka City University Hospital. Chronic irritability and parent-reported scores for the Short Sensory Profile, Infant Behavior Checklist-Revised, Child Behavior Checklist, and Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (Present and Lifetime version) questionnaires were used for assessment. A total of 22 children (13.2%) presented with chronic irritability (i.e., the irritability group) and were more likely to have oppositional defiant disorder, externalizing problems, and attention issues than those without chronic irritability (i.e., the control group). SPD were reported in eight (36%) patients in the irritability group and in 21 (15%) in the control group (p = 0.029). Moreover, compared to the control group, the irritability group showed a significant difference in almost all items of the Short Sensory Profile. Chronic irritability was associated with more severe overall SPD, even after adjusting for possible confounding factors (internalizing and externalizing problems, age, sex, and low income). We provide evidence to support our hypothesis that chronic irritability is associated with SPD in children and adolescents. Therefore, SPD should be assessed to provide appropriate interventions in children and adolescents with chronic irritability.

Preschool-onset obsessive-compulsive disorder with complete remission.

Early-onset obsessive-compulsive disorder (OCD) is more severe than later-onset OCD. There are no reports of any early-onset OCD patients being cured, especially with respect to preschoolers. In this case report, we describe the successful treatment and cure of a 6-year-old preschool girl with severe OCD since the age of 3. At the age of 3, the patient began to fear contamination and danger to herself and her family, leading to excessive hand-washing, and several months later, ritualized checking. The OCD symptoms waxed and waned for about 3 years and thereafter worsened gradually over a few weeks, culminating in a refusal to eat and dress. At the age of 6, after a week of inpatient pediatric treatment with no improvement, the patient was transferred to Osaka City University Hospital to seek psychiatric treatment. The patient fully recovered from OCD following family-based cognitive-behavioral therapy (CBT) and short-term use of low-dose fluvoxamine in an inpatient setting. After treatment, the OCD symptoms disappeared with complete remission for over 3 years. Now, aged 9, the patient has good global functioning and is well adjusted in her daily life with no need for any treatment. To the best of our knowledge, this is the first report of preschool-onset OCD with long-term complete remission with inpatient treatment in a preschooler with severe OCD. Some preschoolers with very early-onset OCD may have good prognosis without continuous pharmacotherapy, although the symptoms with the onset are severe enough to require hospitalization. Preschool-onset OCD is likely to be misdiagnosed as separation anxiety disorder. Our findings suggest that family-based CBT, which is the treatment of choice for preschool-onset OCD, can be applicable to inpatient treatment. Early detection and intensive intervention of OCD in preschoolers may improve the chance of remission.

Anti-Tumor Activity and Immunotherapeutic Potential of a Bisphosphonate Prodrug.

Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV. Using a similar approach, we synthesized bisphosphonate prodrugs and found that they efficiently limit tumor cell growth. Pivoxil bisphosphonate esters enter cells where esterases convert them to their active acids. The bisphosphonate esters stimulated γδ T cells to secrete TNF-α in response to a variety of tumor cells more efficiently than their corresponding acids. The most active compound, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1- bisphosphonate (7), specifically expanded γδ T cells and stimulated them to secrete interferon-γ and kill tumor cells. In preclinical studies, combination therapy with compound 7 and γδ T cells prolonged survival of mice inoculated with either human bladder cancer or fibrosarcoma cells. Therefore, bisphosphonate prodrugs could enhance the effectiveness of adoptive cancer immunotherapy with γδ T cells.

Targeting Cancer Cells with a Bisphosphonate Prodrug.

Nitrogen-containing bisphosphonates have antitumor activity in certain breast cancer and myeloma patients. However, these drugs have limited oral absorption, tumor cell entry and activity, and cause bone side effects. The potencies of phosphorylated antiviral drugs have been increased by administering them as prodrugs, in which the negative charges on the phosphate moieties are masked to make them lipophilic. We synthesized heterocyclic bisphosphonate (BP) prodrugs in which the phosphonate moieties are derivatized with pivaloyloxymethyl (pivoxil) groups and that lack the hydroxy "bone hook" on the geminal carbon. When the lipophilic BP prodrugs enter tumor cells, they are converted into their active forms by intracellular esterases. The most active BP prodrug, tetrakispivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (7), was found to potently inhibit the in vitro growth of a variety of tumor cell lines, especially hematopoietic cells, at nanomolar concentrations. Consistent with this fact, compound 7 inhibited the prenylation of the RAP1A small GTPase signaling protein at concentrations as low as 1-10 nm. In preclinical studies, 7 slowed the growth of human bladder cancer cells in an immunodeficient mouse model. Thus, 7 is significantly more active than zoledronic acid, the most active FDA-approved BP, and a potential anticancer therapeutic.

New enzymatic assay for glycohemoglobin.

BACKGROUND: Previous methods to measure glycohemoglobin (GHb) have been time-consuming or imprecise; we therefore developed a new enzymatic assay for GHb. METHODS: Blood cells were first hemolyzed, and hemoglobin was digested with protease to yield fructosyl amino acid. Fructosyl amino acid oxidase acts on the fructosyl amino acid and generates hydrogen peroxide, which reacts with chromogens in the presence of peroxidase. Total hemoglobin was measured spectrometrically in the same reaction tube. The results were reported as the ratio of the concentrations of GHb and hemoglobin. RESULTS: The measured values were comparable to those determined with a HPLC method and with an immunoassay in blood samples from 2854 patients with diabetes. Regression analysis for the enzymatic assay (y) vs the HPLC method (x) produced the following: r = 0.979; slope, 0.994 [95% confidence interval (CI), 0.986-1.001]; y-intercept, 0.04% (95% CI, -0.09% to 0.01%); n = 2854. For the enzymatic assay (y) vs the immunoassay (x), the regression statistics were as follows: r = 0.982; slope, 1.002 (95% CI, 0.995-1.009); y-intercept, 0% (95% CI, -0.05% to 0.05%); n = 2854. CONCLUSIONS: The values measured by the new enzymatic assay are sufficiently correlated with those of the conventional HPLC method and immunoassay, but the proposed assay for GHb is rapid and has high precision.