Targeting SNCA in the treatment of malignant ascites in gastrointestinal cancer.

Peritoneal tumor dissemination and subsequent malignant tumor ascites (MTA) occur unexpectedly and repeatedly in patients with gastrointestinal (GI) cancers, and worsen quality of life and prognosis of the patients. Various treatments have been clinically developed for these patients, while most of the MTA cases are refractory to the treatments. Thus, effective treatments are urgently needed to improve the clinical outcomes. In this study, we identified α-synuclein (SNCA) as an immunological determinant of MTA progression in GI cancer through translational research using mouse tumor models and clinical specimens collected from gastric cancer patients. We found that the SNCA+ subsets were significantly increased in CD3+ T cells, CD56+ NK cells, and CD11b+ myeloid cells within MTA and peripheral blood cells (PBCs) of MTA cases, albeit almost absent in PBCs of healthy donors, and spleen of naive mice. Of note, the SNCA+ T-cell subset was rarely seen in patients that intraperitoneal lavage fluid without tumor cells was collected before surgery as a tumor-free control, suggesting a possible cancer-induced product, especially within the peritoneal cavity. In vivo treatment with anti-SNCA blocking mAb significantly induced anti-tumor effects in mouse MTA models, and synergistically improved anti-PD1 therapeutic efficacy, providing a significantly better prognosis. These suggest that SNCA is involved in severe immunosuppression in the MTA cases, and that blocking SNCA is effective in dramatically improving the immune status in the hosts. Targeting SNCA will be a promising strategy to improve clinical outcomes in the treatment of GI cancer patients, especially with MTA.

MUC1-C Dependence for the Progression of Pancreatic Neuroendocrine Tumors Identifies a Druggable Target for the Treatment of This Rare Cancer.

Patients with pancreatic neuroendocrine tumors (pNETs) have limited access to effective targeted agents and invariably succumb to progressive disease. MUC1-C is a druggable oncogenic protein linked to driving pan-cancers. There is no known involvement of MUC1-C in pNET progression. The present work was performed to determine if MUC1-C represents a potential target for advancing pNET treatment. We demonstrate that the MUC1 gene is upregulated in primary pNETs that progress with metastatic disease. In pNET cells, MUC1-C drives E2F- and MYC-signaling pathways necessary for survival. Targeting MUC1-C genetically and pharmacologically also inhibits self-renewal capacity and tumorigenicity. Studies of primary pNET tissues further demonstrate that MUC1-C expression is associated with (i) an advanced NET grade and pathological stage, (ii) metastatic disease, and (iii) decreased disease-free survival. These findings demonstrate that MUC1-C is necessary for pNET progression and is a novel target for treating these rare cancers with anti-MUC1-C agents under clinical development.

MUC1-C regulates NEAT1 lncRNA expression and paraspeckle formation in cancer progression.

The MUC1 gene evolved in mammals for adaptation of barrier tissues in response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA in response to loss of homeostasis. There is no known intersection of MUC1 with NEAT1 or paraspeckles. Here, we demonstrate that the MUC1-C subunit plays an essential role in regulating NEAT1 expression. MUC1-C activates the NEAT1 gene with induction of the NEAT1_1 and NEAT1_2 isoforms by NF-κB- and MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression of the SFPQ, NONO and FUS RNA binding proteins (RBPs) that associate with NEAT1_2 and are necessary for paraspeckle formation. MUC1-C integrates activation of NEAT1 and RBP-encoding genes by recruiting the PBAF chromatin remodeling complex and increasing chromatin accessibility of their respective regulatory regions. We further demonstrate that MUC1-C and NEAT1 form an auto-inductive pathway that drives common sets of genes conferring responses to inflammation and loss of homeostasis. Of functional significance, we find that the MUC1-C/NEAT1 pathway is of importance for the cancer stem cell (CSC) state and anti-cancer drug resistance. These findings identify a previously unrecognized role for MUC1-C in the regulation of NEAT1, RBPs, and paraspeckles that has been co-opted in promoting cancer progression.

XIST and MUC1-C form an auto-regulatory pathway in driving cancer progression.

The long non-coding RNA X-inactive specific transcript (lncRNA XIST) and MUC1 gene are dysregulated in chronic inflammation and cancer; however, there is no known interaction of their functions. The present studies demonstrate that MUC1-C regulates XIST lncRNA levels by suppressing the RBM15/B, WTAP and METTL3/14 components of the m6A methylation complex that associate with XIST A repeats. MUC1-C also suppresses the YTHDF2-CNOT1 deadenylase complex that recognizes m6A sites and contributes to XIST decay with increases in XIST stability and expression. In support of an auto-regulatory pathway, we show that XIST regulates MUC1-C expression by promoting NF-κB-mediated activation of the MUC1 gene. Of significance, MUC1-C and XIST regulate common genes associated with inflammation and stemness, including (i) miR-21 which is upregulated across pan-cancers, and (ii) TDP-43 which associates with the XIST E repeats. Our results further demonstrate that the MUC1-C/XIST pathway (i) is regulated by TDP-43, (ii) drives stemness-associated genes, and (iii) is necessary for self-renewal capacity. These findings indicate that the MUC1-C/XIST auto-regulatory axis is of importance in cancer progression.

Identification of MUC1-C as a Target for Suppressing Progression of Head and Neck Squamous Cell Carcinomas.

The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less is known about involvement of MUC1-C in the pathogenesis of squamous cell carcinomas (SCC). Here, we report that the MUC1 gene is upregulated in advanced head and neck SCCs (HNSCC). Studies of HNSCC cell lines demonstrate that the MUC1-C subunit regulates expression of (i) RIG-I and MDA5 pattern recognition receptors, (ii) STAT1 and IFN regulatory factors, and (iii) downstream IFN-stimulated genes. MUC1-C integrates chronic activation of the STAT1 inflammatory pathway with induction of the ∆Np63 and SOX2 genes that are aberrantly expressed in HNSCCs. In extending those dependencies, we demonstrate that MUC1-C is necessary for NOTCH3 expression, self-renewal capacity, and tumorigenicity. The findings that MUC1 associates with ∆Np63, SOX2 and NOTCH3 expression by single-cell RNA sequencing analysis further indicate that MUC1-C drives the HNSCC stem cell state and is a target for suppressing HNSCC progression. SIGNIFICANCE: This work reports a previously unrecognized role for MUC1-C in driving STAT1-mediated chronic inflammation with the progression of HNSCC and identifies MUC1-C as a druggable target for advanced HNSCC treatment.

Impact of central nervous system metastasis after complete resection of lung adenocarcinomas harboring common EGFR mutation - A real-world database study in Japan: The CReGYT-01 EGFR study.

OBJECTIVES: To clarify the impact of central nervous system (CNS) metastasis on performance status (PS) at relapse, on subsequent treatment(s), and on survival of patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutation. METHODS: We conducted the multicenter real-world database study for patients with radical resections for lung adenocarcinomas between 2015 and 2018 at 21 centers in Japan. EGFR mutational status was examined at each center. RESULTS: Of 4181 patients enrolled, 1431 underwent complete anatomical resection for lung adenocarcinoma harboring common EGFR mutations. Three-hundred-and-twenty patients experienced disease relapse, and 78 (24%) had CNS metastasis. CNS metastasis was significantly more frequent in patients with conventional adjuvant chemotherapy than those without (30% vs. 20%, P = 0.036). Adjuvant chemotherapy did not significantly improve relapse-free survival at any pathological stage (adjusted hazard ratio for stage IA2-3, IB, and II-III was 1.363, 1.287, and 1.004, respectively). CNS metastasis did not affect PS at relapse. Subsequent treatment, mainly consisting of EGFR-tyrosine kinase inhibitors (TKIs), could be equally given in patients with or without CNS metastasis (96% vs. 94%). Overall survival after relapse was equivalent between patients with and without CNS metastasis. CONCLUSION: The efficacy of conventional adjuvant chemotherapy may be limited in patients with lung adenocarcinoma harboring EGFR mutations. CNS metastasis is likely to be found in practice before deterioration in PS, and may have little negative impact on compliance with subsequent EGFR-TKIs and survival after relapse. In this era of adjuvant TKI therapy, further prospective observational studies are desirable to elucidate the optimal management of CNS metastasis.

Smoking and diabetes cause telomere shortening among alcohol use disorder patients.

The length of telomeres located at the ends of chromosomes has attracted attention as an indicator of cellular and individual aging. Various diseases or stresses cause telomere shortening, and it has been reported that alcohol use disorder patients actually have shorter telomeres than healthy patients. However, the factors that contribute to the reduction in telomere length among alcohol use disorder patients have not been clarified in detail. Therefore, in this study, we explored the factors that reduce telomere length in alcohol use disorder patients. A questionnaire survey and a measurement of leukocyte telomere length were conducted among alcohol use disorder patients. The mean telomere length of leukocyte was measured by ∆∆Ct analysis using a real-time PCR. We compared the telomere length between alcohol use disorder patients and the control group (Japanese special health check-up examinee). Moreover, we searched for factors associated with telomere length from drinking/smoking characteristics and history of comorbidities. A total of 74 subjects had alcohol use disorder, and 68 were in the control group. Compared to the control group, alcohol use disorder patients had significantly shorter telomere lengths (p < 0.001). A multivariate analysis revealed that a longer duration of smoking resulted in a significantly shorter telomere length (p = 0.0129). In addition, a comparison of the telomere length between the groups with and without a history of suffering from each disease revealed that telomere length was significantly shorter in the group with diabetes than in the group without diabetes (p = 0.0371). This study reveals that in individuals with alcohol dependence, particularly, prolonged smoking habits and the presence of diabetes contribute to telomere shortening. Medication and support for abstinence from alcohol has been mainly provided for alcohol use disorder patients. Our findings demonstrate a potential support approach via smoking cessation programs and controlling diabetes, which may be helpful to suppress the shortening of healthy life expectancy among alcohol use disorder patients.

MUC1-C is a target of salinomycin in inducing ferroptosis of cancer stem cells.

The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to MUC1-C for self-renewal in the progression of human cancers has emphasized the need for development of anti-MUC1-C agents. However, there are presently no approved small molecules for targeting MUC1-C-dependent CSCs. In screening for small molecules, we identified salinomycin (SAL), an inducer of ferroptosis, as a potent inhibitor of MUC1-C signaling. We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-κB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. Our results show that SAL-induced MUC1-C suppression downregulates a MUC1-C→MYC pathway that activates genes encoding (i) glutathione-disulfide reductase (GSR), and (ii) the LDL receptor related protein 8 (LRP8), which inhibit ferroptosis by generating GSH and regulating selenium levels, respectively. GSR and LRP8 contribute to the function of glutathione peroxidase 4 (GPX4), an essential negative regulator of ferroptotic cell death. We demonstrate that targeting MUC1-C genetically or with the GO-203 peptide inhibitor suppresses GPX4 expression and GPX activity in association with the induction of ferroptosis. Studies of CSCs enriched by serial passage as tumorspheres further demonstrate that the effects of SAL are mediated by downregulation of MUC1-C and thereby overcoming resistance to ferroptosis. As confirmation of these results, rescue of MUC1-C downregulation with the MUC1-C cytoplasmic domain (i) reversed the suppression of GSR, LRP8 and GPX4 expression, and (ii) attenuated the induction of ferroptosis. These findings identify SAL as a unique small molecule inhibitor of MUC1-C signaling and demonstrate that MUC1-C is an important effector of resistance to ferroptosis.

MUC1-C Is a Common Driver of Acquired Osimertinib Resistance in NSCLC.

INTRODUCTION: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance. METHODS: H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity. RESULTS: We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs. CONCLUSIONS: Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.

Prognostication Using the Japanese Risk Calculator for Lung Cancer Surgery.

INTRODUCTION: Various calculation models to predict surgical risk have been developed globally. These have been reported to be helpful for estimating the long-term prognosis. In Japan, a similar model for lung cancer surgery was developed in 2017; however, there have been no reports investigating its association with the long-term prognosis. The objective of this study was to assess the association of the model's predictions with the long-term prognosis. PATIENTS AND METHODS: In this retrospective single-institutional study, we analyzed lung cancer patients who underwent radical lobectomy between 2010 and 2016. We calculated the predicted rates of mortality (PRM) and composite outcomes of mortality with major morbidity (PRMM) in eligible patients (N = 1054) using this model and classified them into 2 classes (class A, PRM ≥0.8% and PRMM ≥5.9%; class B, others) based on their models' predictions. We assessed the prognostic impact and clinical utility of the model's predictions. RESULTS: Class A included patients with significantly poorer postoperative overall survival than class B (log-rank, P < .001; hazard ratio, 3.160; 95% confidence interval, 2.390-4.178). Time-dependent receiver operating characteristic curve analyses revealed that the model's predictions correlated strongly with 1- and 2-year overall survival and decision curve analysis showed that they had high net benefits for prediction of those. CONCLUSION: The Japanese risk calculator could stratify the long-term prognosis for lung cancer patients after surgery. This model may be a valuable tool not only for multidisciplinary thoracic oncology teams to discuss treatment strategies for high-risk cases but also for them to share the decision-making process with patients.

Comparison of hand-sewn and circular stapled esophagogastric anastomoses in the neck after esophagectomy for thoracic esophageal cancer: a propensity score-matched analysis.

Esophagectomy is a highly invasive surgical procedure; however, anastomotic leakage is one of the major surgical complications that should be prevented. Institutions have their own inherited or specialized anastomosis methods. The superior anastomosis procedure remains unknown despite the many studies to determine the optimal method. The present study enrolled 341 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January 2009 and January 2019. The anastomosis method was changed from circular stapled anastomosis to hand-sewn anastomosis in February 2014 to reduce the risk of anastomotic leakage. We retrospectively compared short-term results (anastomotic leakage and stricture) between hand-sewn and circular stapled anastomoses. Analysis of heterogeneity after propensity score matching between the 107 patients in the hand-sewn anastomosis group and 107 patients in the circular stapled anastomosis group revealed almost equal distributions. The incidence rate of anastomotic leakage was significantly lower in the hand-sewn anastomosis group than in the circular stapled anastomosis group (9 vs. 20%, hazard ratio: 2.521; 95% confidence interval: 1.112-5.716; P = 0.027). No significant difference was found in the incidence of anastomotic stricture (16 vs. 18%, P = 0.844). Furthermore, no significant difference was found in the incidence of anastomotic leakage in any of the tumor locations between the two anastomosis procedures. For esophagogastric anastomosis in the neck after esophagectomy, hand-sewn anastomosis is superior to circular stapled anastomosis with regard to reducing the risk of anastomotic leakage.

Transient Methionine Deprivation Triggers Histone Modification and Potentiates Differentiation of Induced Pluripotent Stem Cells.

Human induced pluripotent stem cells (iPSCs) require high levels of methionine (Met). Met deprivation results in a rapid decrease in intracellular S-adenosyl-methionine (SAM), poising human iPSCs for differentiation and leading to the apoptosis of undifferentiated cells. Met deprivation triggers rapid metabolic changes, including SAM, followed by reversible epigenetic modifications. Here, we show that short-term Met deprivation impairs the pluripotency network through epigenetic modification in a 3D suspension culture. The trimethylation of lysine 4 on histone H3 (H3K4me3) was drastically affected compared with other histone modifications. Short-term Met deprivation specifically affects the transcription start site (TSS) region of genes, such as those involved in the transforming growth factor ß pathway and cholesterol biosynthetic process, besides key pluripotent genes such as NANOG and POU5F1. The expression levels of these genes decreased, correlating with the loss of H3K4me3 marks. Upon differentiation, Met deprivation triggers the upregulation of various lineage-specific genes, including key definitive endoderm genes, such as GATA6. Upon differentiation, loss of H3K27me3 occurs in many endodermal genes, switching from a bivalent to a monovalent (H3K4me3) state. In conclusion, Met metabolism maintains the pluripotent network with histone marks, and their loss potentiates differentiation.

Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

Methionine metabolism regulates pluripotent stem cell pluripotency and differentiation through zinc mobilization.

Pluripotent stem cells (PSCs) exhibit a unique feature that requires S-adenosylmethionine (SAM) for the maintenance of their pluripotency. Methionine deprivation in the medium causes a reduction in intracellular SAM, thus rendering PSCs in a state potentiated for differentiation. In this study, we find that methionine deprivation triggers a reduction in intracellular protein-bound Zn content and upregulation of Zn exporter SLC30A1 in PSCs. Culturing PSCs in Zn-deprived medium results in decreased intracellular protein-bound Zn content, reduced cell growth, and potentiated differentiation, which partially mimics methionine deprivation. PSCs cultured under Zn deprivation exhibit an altered methionine metabolism-related metabolite profile. We conclude that methionine deprivation potentiates differentiation partly by lowering cellular Zn content. We establish a protocol to generate functional pancreatic ß cells by applying methionine and Zn deprivation. Our results reveal a link between Zn signaling and methionine metabolism in the regulation of cell fate in PSCs.

Preoperative maximum phonation time as a predictor of pneumonia in patients undergoing esophagectomy.

PURPOSE: Esophagectomy is a highly invasive procedure, associated with several postoperative complications including pneumonia, anastomotic leakage, and sepsis, which may result in multiorgan failure. Pneumonia is considered a major predictor of poor long-term prognosis, so its prevention is important for patients undergoing surgery for esophageal cancer. METHODS: The subjects of this study were 137 patients who underwent esophagectomy at Keio University Hospital, Tokyo, Japan, between January, 2012 and December, 2016. Patients who underwent R0 or R1 resection or esophagectomy with organ excision were included. Patients who underwent salvage surgery or resection of recurrent laryngeal nerve, and those with preoperative recurrent laryngeal nerve palsy, were excluded. We investigated the effect of the maximum phonation time on the development of postoperative pneumonia. RESULTS: Pneumonia developed more frequently in patients with a long operative time, clinically left recurrent nerve lymph node metastasis, and a short preoperative maximum phonation time (p = 0.074, 0.046, and 0.080, respectively). Pneumonia was also more common in men with an abnormal maximum phonation time (p = 0.010). CONCLUSIONS: The maximum phonation time is a significant predictor of postoperative pneumonia after esophagectomy in men.

Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer.

Intraperitoneal (i.p.) tumor dissemination and the consequent malignant ascites remain unpredictable and incurable in patients with gastrointestinal (GI) cancer, and practical advances in diagnosis and treatment are urgently needed in the clinical settings. Here, we explored tumor biological and immunological mechanisms underlying the i.p. tumor progression for establishing more effective treatments. We established mouse tumor ascites models that murine and human colorectal cancer cells were both i.p. and subcutaneously (s.c.) implanted in mice, and analyzed peritoneal exudate cells (PECs) obtained from the mice. We then evaluated anti-tumor efficacy of agents targeting the identified molecular mechanisms using the ascites models. Furthermore, we validated the clinical relevancy of the findings using peritoneal lavage fluids obtained from gastric cancer patients. I.p. tumor cells were giant with large nuclei, and highly express AURKA, but less phosphorylated TP53, as compared to s.c. tumor cells, suggesting polyploidy-like cells. The i.p. tumors impaired phagocytic activity and the consequent T-cell stimulatory activity of CD11b+Gr1+PD1+ myeloid cells by GDF15 that is regulated by AURKA, leading to treatment resistance. Blocking AURKA with MLN8237 or siRNAs, however, abrogated the adverse events, and induced potent anti-tumor immunity in the ascites models. This treatment synergized with anti-PD1 therapy. The CD11b+PD1+ TAMs are also markedly expanded in the PECs of gastric cancer patients. These suggest AURKA is a determinant of treatment resistance of the i.p. tumors. Targeting the AURKA-GDF15 axis could be a promising strategy for improving clinical outcome in the treatment of GI cancer.

Correlation Between Smoking Status and Short-term Outcome of Thoracoscopic Surgery for Lung Cancer.

BACKGROUND: Smoking has a major role in the risk of postoperative pulmonary complications. This study aimed to elucidate the correlation between smoking status and pulmonary complications after thoracoscopic surgery for lung cancer. METHODS: A total of 1751 patients who underwent thoracoscopic lobectomy or segmentectomy for lung cancer between April 2011 and March 2020 were assessed. The rate of pulmonary complications was evaluated according to smoking status and preoperative duration of smoking cessation. Univariate and multivariate logistic regression analyses were performed. RESULTS: Pulmonary complications were observed in 50 patients (2.9%), whereas 3 (0.2%) died within 90 days of surgery. The rate of pulmonary complications was higher in smokers than in nonsmokers (4.6% vs 0.9%; P < .001), and smoking history was an independent risk factor for pulmonary complications (odds ratio, 3.31; P = .007). The complication rate in patients with a cessation period of more than 2 months was significantly lower than that in patients who ceased smoking within 2 months (4.0% vs 8.5%; P = .043), but it was still higher than that in nonsmokers (4.0% vs 0.9%; P < .001). In the multivariable analysis for smokers, preoperative short-term smoking cessation within 2 months, male sex, histologic type, tumor size, and cardiopulmonary comorbidities were associated with pulmonary complications instead of pack-year smoking history. CONCLUSIONS: Smoking habits and preoperative smoking cessation were independently associated with pulmonary complications after thoracoscopic surgery for lung cancer. A preoperative smoking cessation period of 2 months or more is preferable for reducing the risk of such complications.

Intracranial calcification and psychotic symptoms after irradiation in a patient with Fanconi anemia: A case report.

Background: Patients with Fanconi anemia (FA) are at high risk for the development of malignancies, and are often treated with radiation therapy. Radiation therapy during childhood can cause intracranial calcification after a latent period, which has been associated with psychiatric symptoms. Despite the high sensitivity of patients with FA to radiation, intracranial calcification has rarely been reported in these patients. Case Presentation: A 17-year-old girl presented with psychiatric symptoms and cognitive impairment. She had been diagnosed with FA at 3 years old, and had received a bone marrow transplant at 5 years old with a preparative regimen that included total body irradiation. Results of IQ tests revealed a characteristic pattern of decline between the ages of 15 and 17 years. Computed tomography indicated multiple intracranial calcifications in regions associated with psychotic symptoms, including the frontal lobe and thalamus. The patient's psychiatric symptoms improved with the administration of blonanserin. Limitations: The patient did not have regular intracranial imaging, making it difficult to confirm a direct relationship between intracranial calcification, psychiatric symptoms, and cognitive impairment. It is unclear whether the intracranial calcification in this case can be explained entirely by irradiation. Conclusion: This case suggests a link between FA, intracranial calcification, and psychosis, in which intracranial calcification may have caused psychiatric symptoms. At present, evidence regarding the characteristics of psychiatric symptoms of intracranial calcification and its treatment is lacking. The current case will be helpful for elucidating the pathogenesis of this disorder and developing appropriate treatment protocols.

Increased risk of rhinovirus infection in children during the coronavirus disease-19 pandemic.

BACKGROUND: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. METHODS: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. RESULTS: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. CONCLUSIONS: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.