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Histiocytic neoplasms (HNs) in adults have been reported to be associated with a high prevalence of coexisting haematological and solid malignancies. While a proportion of coexisting HNs and haematological malignancies share identical genetic alterations, the genetic association between HNs and solid malignancies has scarcely been reported. We report a case of Rosai-Dorfman disease (RDD) complicated by coexisting clear cell sarcoma (CCS). RDD is a rare HN. CCS is an ultrarare soft tissue sarcoma with a poor prognosis. Mutation analysis with whole-exome sequencing revealed six shared somatic alterations including NRAS p.G12S and TP53 c.559+1G>A in both the RDD and CCS tissue. This is the first evidence of a clonal relationship between RDD and solid malignancies using mutational analysis. We hypothesise that neural crest cells, which originate in CCS, are likely the common cells of origin for RDD and CCS. This case helps to unravel the underlying clinicopathological mechanisms of increased association of solid malignancies in HNs. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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BACKGROUND/AIMS: Lemons (Citrus limon ) contain various nutrients and are among the most popular citrus fruit. Besides their antioxidant, anticancer, antibacterial, and anti-inflammatory properties, clinical studies have indicated their anti-allergic properties. METHODS: Using the differential-interference contrast (DIC) microscopy, we examined the effects of lemon juice and peel constituents, such as citric acid, ascorbic acid, hesperetin and eriodictyol, on the degranulation from rat peritoneal mast cells. Using fluorescence imaging with a water-soluble dye, Lucifer Yellow, we also examined their effects on the deformation of the plasma membrane. RESULTS: Lemon juice dose-dependently decreased the number of degranulated mast cells. At concentrations equal to or higher than 0.25 mM, citric acid, hesperetin, and eriodictyol significantly reduced the number of degranulating mast cells in a dose-dependent manner, while ascorbic acid required much higher doses to exert significant effects. At 1 mM, citric acid, hesperetin, and eriodictyol almost completely inhibited exocytosis and washed out the Lucifer Yellow trapped on the mast cell surface, while ascorbic acid did not. CONCLUSION: This study provides in vitro evidence for the first time that lemon constituents, such as citric acid, hesperetin, and eriodictyol, potently exert mast cell-stabilizing properties. These properties are attributable to their inhibitory effects on plasma membrane deformation in degranulating mast cells.

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A 55-year-old woman suffered from diplopia and occipital pain after shoveling snow. She was diagnosed with the right vertebral artery dissecting aneurysm at the level of the axial vertebra and repeatedly had cerebral infarctions in the posterior circulation. She had subluxation of the atlantoaxial vertebra as an underlying disease. Right vertebral angiogram with the head rotated to the left showed the right vertebral artery occlusion and left vertebral angiogram with the head rotated to the right showed stenosis at the C1-C2 level, leading to the diagnosis of Bow hunter's stroke. After wearing a cervical collar and taking 100 |mg of aspirin, she had no recurrence of cerebral infarction and later underwent C1-C2 posterior fusion to prevent the recurrence of cerebral infarction. She finished taking aspirin 6 months after the surgery, and there has been no recurrence of cerebral infarction. We report here a case of Bow hunter's stroke, a rare disease, with good clinical outcomes after C1-C2 posterior fusion.

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INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.

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A questionnaire survey was conducted to evaluate practical training and improve education on clinical trial and research. This survey was based on the results of questionnaire before and after the practical training undertaken by 240 pharmaceutical students (Kanto region; 1 university, Tokai region; 2 university, Kinki region; 9 university) at Mie University Hospital between 2011 and 2022. In the questionnaire before practical training, lectures in university (n=219, 91%) were the main source of information on clinical trials and research. Fifty-two students (22%) correctly answered the contents of phase 1-4 trials. As an occupation that can perform clinical research coordinator (CRC)'s work, only 7 students (3%) answered that "all medical and non-medical professionals" can perform the CRC's duties. Regarding the understanding of terms related to clinical trials and research, more than 90% of the students understood the meaning of "subjects," "informed consent," and "placebo" even before practical training. Otherwise, even after practical training, students' understanding of "reimbursement," "follow-up period," "audit," or "direct access" was less than 80%. Practical training improved the understanding of terms such as clinical trial (Wilcoxon signed-rank test, p<0.001), clinical research phase 1-4 trials (Wilcoxon signed-rank test, p<0.001), interest in clinical trials and research (McNemar-Bowker test, p<0.001), and understanding of CRC's work (McNemar-Bowker test, p<0.001). We will improve the content of practical training and bequeath the knowledge and importance of drug discovery and development to the next generation.

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ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)-infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1-uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1-infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7-) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1-infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.

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Sturge-Weber syndrome (SWS) is a neurocutaneous syndrome with vascular lesions of the cerebral meninges, port wine spots on the face, and glaucoma of the eyes; it is a congenital, non-genetic disease whose etiology and mechanisms are unknown. In this report, we describe a rare case of SWS with unilateral large odontogenic tumors in the maxilla and mandible. The histopathological diagnosis of the maxillary bone lesion on biopsy was juvenile psammomatoid ossifying fibroma, which is considered a type of ossifying fibroma of craniofacial bone origin. However, the final pathological diagnosis of the excision was cemento-ossifying fibroma derived from periodontal ligament cells, and we discuss the histopathology in detail. In addition, the mandibular lesion was one of the largest odontomas reported to date. Furthermore, in this case, we suggest the possibility that the maxillary and mandibular bone lesions are not separate lesions, but a series of lesions related to SWS.

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Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

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BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

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Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.

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Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin ß2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

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This clinical image presents a report on the diagnosis and treatment of anti-NMDAR encephalitis, a rare disease. This report emphasizes the importance of a differential diagnosis for acute psychiatric symptoms. Accurate and timely diagnosis is critical for the selection and implementation of treatment and for optimal patient outcomes.

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Objectives Patients with hematological cancer receiving chemotherapy have a high risk of thiamine deficiency due to accelerated thiamine usage by tumor cells. Mild or severe thiamine deficiency can lead to varying degrees of neurological symptoms. We evaluated the relationship between thiamine deficiency and neurological symptoms, including mild or nonspecific symptoms, and the influence of chemotherapy on thiamine serum levels in patients with hematological cancer receiving chemotherapy. Materials and Methods We retrospectively identified 42 patients diagnosed with hematological cancer at our hospital, using electronic medical records collected from March 2019 to March 2020. We evaluated the risk factors associated with neurological symptoms (mild-to-severe cognitive impairment, attention impairment, and mood or emotional disorder), the relationship between the presence of neurological symptoms and thiamine serum levels, and changes in thiamine serum levels after chemotherapy. Results Thiamine deficiency was significantly associated with neurological symptoms. The thiamine serum levels in the group with neurological symptoms were significantly lower than those in the group without neurological symptoms. The Wilcoxon rank-sum test showed that thiamine serum levels after chemotherapy were significantly lower than those before administration of chemotherapy. Conclusion Thiamine serum levels in patients with hematological cancer may be used as a reference to maintain neurological status during chemotherapy.

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BACKGROUND: Although rare, several immune-related adverse effects can be life-threatening. Here, we describe a metastatic gastric cancer patient presenting with nivolumab-related myasthenia gravis and myocarditis, a previously unreported adverse effect of gastric cancer treatment. CASE PRESENTATION: A 66-year-old man with metastatic gastric cancer visited the emergency department because of dizziness after the first dose of nivolumab. Diagnoses of nivolumab-related myasthenia gravis and myocarditis were established. Myocardial biopsy results and anti-acetylcholine receptor antibody positivity confirmed the diagnoses. Despite plasma exchange and intravenous methylprednisolone and immunoglobulin administration, the patient's general condition gradually worsened, and he died. CONCLUSIONS: Strict monitoring for cardiac and neuromuscular symptoms after nivolumab administration is necessary to rapidly treat these adverse effects.

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BACKGROUND: Clinical evidence of thiamine-related neuropsychiatric symptoms, including the initial stage, is limited because serum thiamine levels tend to be evaluated only for patients who develop severe neuropsychiatric symptoms suspected to be related to severe thiamine deficiency. This study aimed to evaluate the relationship between thiamine decline and neuropsychiatric symptoms, including initial symptoms, and the effect of chemotherapy on serum thiamine levels in gastrointestinal and hematological cancer patients receiving chemotherapy. METHOD: We retrospectively identified 87 patients who were diagnosed with gastrointestinal and hematological cancers at our hospital. We evaluated the risk factors associated with neuropsychiatric symptoms, including initial symptoms (neuropsychiatric symptoms), the relationship between the presence of neuropsychiatric symptoms and serum thiamine levels, and changes in serum thiamine levels after chemotherapy. RESULTS: Logistic regression analysis identified thiamine decline as a significant factor associated with neuropsychiatric symptoms (p < 0.001, odds ratio = 0.040, 95% confidence interval [CI]: 0.010-0.163). The Mann-Whitney U test showed that patients with neuropsychiatric symptoms had significantly lower serum thiamine levels (19.5 ± 5.4 ng/mL, n = 39) than patients without neuropsychiatric symptoms (31.9 ± 14.2 ng/mL, n = 48) (p = 0.001). In hematological cancer patients, serum thiamine levels gradually declined after chemotherapy, with the lowest levels at 5-8 weeks (23.5 ± 7.6 ng/mL, P = 0.035 vs. 0 weeks, Wilcoxon rank sum test). CONCLUSION: Our study showed that a decrease in serum thiamine levels can be a risk factor for neuropsychiatric symptoms, and chemotherapy can lead to a decrease in serum thiamine levels.

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Less than half of the cases of autoimmune encephalitis have brain MRI abnormalities; however, some patterns of MRI findings help diagnosis. Usually, DWI and FLAIR images reveal hyperintensity lesions in the cortical or subcortical regions or the cerebellum and/or the brainstem. Hyperintensity lesions in the limbic cortex on DWI suggest NMDAR encephalitis. RA or polychondritis-related meningitis show bright dot or linear signals on the convexities on DWI. Area postrema syndrome is a typical form of neuromyelitis optica. These conditions need to be diagnosed promptly for effective treatment.

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Sporadic Creutzfeldt-Jacob disease(sCJD)is a prion disease presenting with subacute or rapidly progressive dementia with a poor prognosis. Asymmetrical cortical lesions with thalamic involvement are found in sCJD cases, which is similar distribution to status epileptics, but the lesions are not observed in the limbic systems, and they rarely occur in the precentral gyrus. Characteristically, hyperintense abnormal findings are more prominent on DWI than on FLAIR and T2WI. 19.9% of CJD is genetic CJD(gCJD), and CJD with a mutation of codon 180 from valine to isoleucine(V180I)accounts for 40% of gCJD in Japan. Patients with this type of gCJD rarely have a family history because of the low penetration rate. The age of onset is usually later, and its clinical symptoms deteriorate more slowly than sCJD. DWI shows abnormal cortical hyperintense signals(cortical ribboning).

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Mild encephalitis/encephalopathy with a reversible splenial lesion(MERS)is a clinically and radiologically benign condition that has been described within the past two decades. MRI findings include isolated symmetrical ovoid lesions of the splenium with a high-intensity signal on DWI and decreased apparent diffusion coefficient. These findings have been associated with viral infections, epilepsy, antiepileptic drug usage, and metabolic disturbances, among others. These conditions may present with severe clinical features, such as consciousness disturbance or cytokine storm; however, patients usually recover completely with optimal treatment. Some pathological conditions with splenic lesions, such as Marchiafava-Bignami disease, may be irreversible. Therefore, diseases with splenic lesions require careful attention.

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Neuronal intranuclear inclusion disease(NIID)is a progressive neurodegenerative condition characterized by eosinophilic hyaline intranuclear inclusions in neuronal and other somatic cells. Since 2011, when skin biopsy was proven to be a diagnostic tool, the incidence of NIID has been increasing. Its symptoms include dementia, muscle weakness, and sensory or autonomic disturbance. MRI shows hyperintense lesions of the subcortical white matter, especially on the U-fiber. These findings persist and continue to worsen for years.

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