[A case of Seizure-related 6 homolog like 2 (Sez6l2) antibody-associated autoimmune cerebellar ataxia].

A 35-year-old male patient had been repeatedly involved in car accidents since the age of 34 years, had difficulty in tidying his room, and developed speech and gait disorders. At the first examination, he had a hypophonia and poor gait, but he could talk and walk by himself. His Mini-Mental State Examination (MMSE) score was 23 and mild cognitive impairment was observed. Three months later, neurological findings showed subacute progression to loss of speech, and poor right dominant diadochokinesia and finger tapping, poor finger-nose test and heel-knee test, and loss of ability to stand and walk. Cerebellar atrophy was observed on head MRI, and the patient was positive for Seizure-related 6 homolog like 2 (Sez6l2) antibody, leading to a diagnosis of Sez6l2 antibody-associated autoimmune cerebellar ataxia. Immunotherapy halted the progression of symptoms, and the patient showed slight improvement. Sez6l2 antibody measurement and immunotherapy were considered necessary for subacute progressive cerebellar ataxia of unknown cause.

The Characteristics of magnetic resonance imaging and immunohistochemical findings in de-differentiated liposarcoma.

PURPOSE: Radiological imaging in Dedifferentiated liposarcoma (DDLPS) often shows the coexistence of fatty and non-fatty solid components; however, it has been shown that when fatty components were not identified on magnetic resonance imaging (MRI), the diagnosis of DDLPS would not have been diagnosed if immunohistochemical (IHC) staining had not been performed. The aim of this study was to investigate the pattern of MRI and relationship between MRI and IHC findings in DDLPS. METHODS: We retrospectively reviewed the cases of 25 patients with DDLPS. To identify the MRI spectrum of DDLPS, tumors were classified into the following four categories based on MRI findings: I = a well-defined fatty mass and juxtaposed well-defined non-fatty mass, II = a non-fatty component within a predominantly fatty mass, III = a focal fatty component within a large non-fatty mass, and IV = a non-fatty mass with atypical MRI findings. IHC staining for CDK4, MDM2, and p16 were evaluated. RESULTS: Category IV tumor was the most common tumor in this population. Of the 22 patients who underwent IHC staining, MDM2, CDK4, and p16 were positive in 21, 20, and 19 patients, respectively. MDM2 was positive in all 11 patients with category IV tumors; CDK4 and p 16 were positive in 10 and eight patients, respectively. There was no difference of survival between the patients with category I, II and III and category IV. CONCLUSIONS: DDLPS without fatty components on MRI scans was mostly found. We recommend IHC staining to screen for DDLPS even if the tumors in STS cases have a non-fatty component.

Do coagulation or fibrinolysis reflect the disease condition in patients with soft tissue sarcoma?

BACKGROUND: Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs. METHODS: TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated. RESULTS: The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14). CONCLUSION: Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.

Radiodynamic therapy with acridine orange local administration as a new treatment option for primary and secondary bone tumours.

AIMS: Acridine orange (AO) demonstrates several biological activities. When exposed to low doses of X-ray radiation, AO increases the production of reactive radicals (radiodynamic therapy (AO-RDT)). We elucidated the efficacy of AO-RDT in breast and prostate cancer cell lines, which are likely to develop bone metastases. METHODS: We used the mouse osteosarcoma cell line LM8, the human breast cancer cell line MDA-MB-231, and the human prostate cancer cell line PC-3. Cultured cells were exposed to AO and radiation at various concentrations followed by various doses of irradiation. The cell viability was then measured. In vivo, each cell was inoculated subcutaneously into the backs of mice. In the AO-RDT group, AO (1.0 µg) was locally administered subcutaneously around the tumour followed by 5 Gy of irradiation. In the radiation group, 5 Gy of irradiation alone was administered after macroscopic tumour formation. The mice were killed on the 14th day after treatment. The change in tumour volume by AO-RDT was primarily evaluated. RESULTS: The viability of LM8, MDA-MB-231, and PC-3 cells strongly decreased at AO concentration of 1.0 µg/ml and a radiation dose of 5 Gy. In xenograft mouse model, the AO-RDT also showed a strong cytocidal effect on tumour at the backside in osteosarcoma, breast cancer, and prostate cancer. AO-RDT treatment was more effective for tumour control than radiotherapy in breast cancer. CONCLUSION: AO-RDT was effective in preventing the proliferation of osteosarcoma, breast cancer, and prostate cancer cell lines in vitro. The reduction in tumour volume by AO-RDT was also confirmed in vivo.Cite this article: Bone Joint Res 2022;11(10):685-692.

The role of soluble CD80 in patients with soft tissue tumors.

BACKGROUND: Immune checkpoint protein (ICP), which is a central factor group of the immune system, has been reported to have a correlation between the degree of its expression and the prognosis of patients with malignant tumors, and many inhibitors have appeared as therapeutic targets. On the other hand, a soluble form of ICP in circulating blood induced systemic immunosuppression. In this study, we investigated the relationship between the soluble form of CD80 (sCD80) which is a ligand for the inhibitory system CTLA-4, in blood, and clinicopathological parameters in patients with soft tissue tumors. METHODS: A total of 119 patients with primary soft tissue tumors were enrolled in this study. The sCD80 levels were measured by enzyme immunoassay. RESULTS: There were no significant differences in sCD80 levels between benign (34) and soft tissue sarcoma (STS) patients (85). In STS, the high-sCD80 group had significantly lower metastasis-free survival (MS) and lower overall survival (OS) than the low-sCD80 group at 5 years using the log-rank test (OS: high > 404 pg/mL, low ≤ 404 pg/mL, MS: high > 531 pg/ml, low ≤ 531 pg/ml). On multivariate Cox proportional hazard analysis, the high-sCD80 group had significant differences in 5MS and 5OS compared to the low-sCD80 group. CONCLUSIONS: In conclusion, sCD80 may negatively affect systemic immune circumstances, in STS, and may have potential as a therapeutic target.

Compound Library Screening for Synergistic Drug Combinations: mTOR Inhibitor and Proteasome Inhibitor Effective Against Osteosarcoma Cells.

BACKGROUND/AIM: The development of new drugs is urgently needed for new treatment strategies that can improve the prognosis of osteosarcoma (OS). In this study, we attempted to identify combinations of new molecular-targeted agents for OS. MATERIALS AND METHODS: A library containing 324 compounds was used. For the first screening, MG-63 OS cells were treated with each of the compounds and cell viability was measured. After the best candidate compound was decided, the compound was included in a second screening. The combination of most effective compounds was decided. The antiproliferative effect of the combination was examined and the cell signaling mechanism was evaluated by western blot analysis. 143B OS-bearing mice were used for in vivo antitumor testing. RESULTS: In the first screening, bortezomib was chosen as the effective drug. In the second screening with bortezomib, everolimus was chosen. This combination showed a synergistic inhibitory effect on cell proliferation when compared to monotherapy with each of these drugs alone. Compared to monotherapy, the combination therapy enhanced the levels of cleaved poly (ADP-ribose) polymerase, caspase-3, caspase-8 and caspase-9, phospho-c-Jun N-terminal kinase, and P38. In contrast, the levels of c-MYC proto-oncogene bHLH transcription factor, survivin, and phospho-cyclin D1 were reduced. The combination effectively induced apoptosis and interfered with cell cycle progression. In the in vivo analysis, the combination therapy significantly inhibited tumor growth. CONCLUSION: The combination of everolimus and bortezomib demonstrated a synergistic effect against OS both in vitro and in vivo. These results indicate that this combination may be useful as a novel therapeutic strategy for OS.

GPR64, Screened from Ewing Sarcoma Cells, Is a Potential Target for Antibody-Based Therapy for Various Sarcomas.

Ewing sarcoma is an aggressive and the second most common bone tumor in adolescent and young adult patients. The 5-year survival rate is 60-70% for localized disease but 30% for patients with metastases. Here, we aimed to identify a therapeutic target for Ewing sarcoma and evaluate antibody-based therapeutic agents using in vitro and in vivo models. We identified G protein-coupled receptor 64 (GPR64) as a therapeutic target for Ewing sarcoma via next-generation RNA-sequencing. GPR64v205 mRNA was expressed in HTB166, A673, MG63, 143B, HS-Sy II, and HT1080 cell lines as well as in Ewing sarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, and synovial sarcoma tissues. GPR64 expression was observed in 62.5% of sarcoma cases and was overexpressed in 33.9% cases. GPR64-specific monoclonal antibodies were tested as near-infrared probes for in vivo imaging using subcutaneous tumor mouse xenografts. Fluorescence intensity was stronger for the AF700-labeled anti-GPR64 antibody than that for the AF700-labeled isotype control antibody. GPR64 was detected in engrafted tumors of A673, 143B, HT1080, and the epididymis but not in other resected tissues. The anti-GPR64 antibody showed excellent binding to GPR64-positive tumors but not to healthy tissues. This antibody has potential for drug delivery in the antibody-based treatment of sarcomas.

Spontaneous pneumothorax in a 17-year-old male patient with multiple exostoses: A case report and review of the literature.

BACKGROUND: Multiple exostoses generally develop in the first decade of life. They most frequently arise from the distal femur, proximal tibia, fibula, and proximal humerus. Costal exostoses are rare, contributing to 1%-2% of all exostoses in hereditary multiple exostoses (HME). They are usually asymptomatic, but a few cases have resulted in severe thoracic injuries. Pneumothorax caused by costal exostoses is rare, with only 13 previously reported cases. We report a new case of pneumothorax caused by costal exostoses. CASE SUMMARY: A 17-year-old male with HME underwent surgery for removal of exostoses around his right knee. Four months following the operation, he felt chest pain when he was playing the trumpet; however, he did not stop playing for a week. He was referred to our hospital with a chief complaint of chest pain. The computed tomography (CT) scan revealed right pneumothorax and multiple exostoses in his right ribs. The CT scan also revealed visceral pleura thickness and damaged lung tissues facing the exostosis of the seventh rib. We diagnosed that exostosis of the seventh rib induced pneumothorax. Costal exostosis resection was performed by video-assisted thoracoscopic surgery (VATS) 2 wk after the onset. The patient's postoperative course was uneventful, and there was no recurrence of pneumothorax for 2 years. CONCLUSION: Costal exostoses causing thoracic injuries should be resected regardless of age. VATS must be considered in cases with apparently benign and relatively small exostoses or HME.

Role of the Prognostic Nutritional Index in Patients With Soft-tissue Sarcoma.

BACKGROUND: This study aimed to determine whether the prognostic nutritional index (PNI) can predict the prognosis in patients with soft-tissue sarcoma (STS) before treatment and to examine whether there is an association between PNI values and clinical characteristics. PATIENTS AND METHODS: The data on 100 patients with primary STS were retrospectively reviewed. The cohort included 55 men and 45 women, with a mean age of 64 years. The mean follow-up duration was 41.7 months. RESULTS: The median PNI was 51.35. The PNI was significantly inversely associated with tumor size, tumor grade, and age. We found that the PNI was a significant prognostic marker for disease-specific and event-free survival using univariate and multivariate analyses. Patients with a low PNI had poorer disease-specific and event-free survival than those with a high PNI. CONCLUSION: These results suggest that the PNI can be used as a prognostic marker in patients with STS.

Significance of coagulation and fibrinolysis markers for benign and malignant soft tissue tumors.

BACKGROUND: The intimate relationship between coagulation and fibrinolysis in malignant tumors is a well-known phenomena, with the malignant phenotype enhancing coagulation and fibrinolysis. We hypothesized that soft tissue sarcoma (STS) affects the expression of coagulation and fibrinolysis markers, which could be used to distinguish STS from benign soft tissue tumors. We analyzed the correlations between plasma levels of D-dimer (DD), plasmin-α2 plasmin inhibitor complex (PIC), soluble fibrin (SF), and thrombin-antithrombin III complex (TAT) in benign soft tissue tumors and STS to elucidate whether these markers can be used to predict STS. METHODS: Plasma DD, PIC, SF and TAT levels in primary soft tissue tumors (benign 67, STS 68) were measured before biopsy or treatment. The marker levels were analyzed and compared to various clinicopathological parameters. RESULTS: In malignancy (STS), the average DD, PIC and SF levels were significantly higher than in benign tumors. Multivariate logistic analysis of continuous variables indicated that only PIC exhibited a significant difference (OR: 24.5, 95%CI: 3.55-170, p = 0.0012). Receiver operating characteristic curve analysis produced area under the curve values for DD: 0.691, PIC: 0.784, SF: 0.734 and TAT: 0.588. Youden's index was used to establish thresholds of 0.37 (DD), 0.80 (PIC), 0.90 (SF) and 0.82 (TAT). Threshold values for PIC and SF indicated high specificity (0.881, 0.791) and high positive predictive value (0.818, 0.745), respectively. The highest accuracy value among the markers was observed for PIC (0.704). Significant differences in multivariate analysis of binary variables were demonstrated by categorizing low and high groups based on their threshold, PIC (≥0.80) (OR: 3.36, 95%CI: 1.19-9.43, p = 0.0212) and SF (≥0.90) (OR: 2.63, 95%CI: 1.04-6.66, p = 0.0404) . CONCLUSIONS: Of the coagulation and fibrinolysis markers studied, increased PIC levels were related to STS and over 0.80 PIC was the most suitable for the prediction of STS, which, along with other diagnostic tools, represents a helpful subsidiary tool for the prediction of STS.

Prevalence of disease-causing genes in Japanese patients with BRCA1/2-wildtype hereditary breast and ovarian cancer syndrome.

Panel sequencing of susceptibility genes for hereditary breast and ovarian cancer (HBOC) syndrome has uncovered numerous germline variants; however, their pathogenic relevance and ethnic diversity remain unclear. Here, we examined the prevalence of germline variants among 568 Japanese patients with BRCA1/2-wildtype HBOC syndrome and a strong family history. Pathogenic or likely pathogenic variants were identified on 12 causal genes for 37 cases (6.5%), with recurrence for 4 SNVs/indels and 1 CNV. Comparisons with non-cancer east-Asian populations and European familial breast cancer cohorts revealed significant enrichment of PALB2, BARD1, and BLM mutations. Younger onset was associated with but not predictive of these mutations. Significant somatic loss-of-function alterations were confirmed on the wildtype alleles of genes with germline mutations, including PALB2 additional somatic truncations. This study highlights Japanese-associated germline mutations among patients with BRCA1/2 wildtype HBOC syndrome and a strong family history, and provides evidence for the medical care of this high-risk population.

[A case of Alexander disease with repeated loss of consciousness and with rapid aggravation of dysbasia by falling].

A 41-year-old woman presented with short-stepped gait from 20 years old and with repeated loss of consciousness from 21 years old. She had a deep cerebral white matter lesion on brain MRI at 34 years of age, but she did not reach a definitive diagnosis. At the age of 41, the gait disorder rapidly worsened after fall and fall-related head trauma. She had fixation nystagmus, dysphonia, speech disorder and exaggerated tendon reflexes. Her bilateral plantar reflex was positive, and she was not able to walk by herself. The brain and cervical MRI showed atrophy of the medulla and upper spinal cord and a deep cerebral white matter lesion. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. As a result, we identified a heterozygous p.R79H (c.250 G>A) missense mutation of the GFAP gene in the patient. This case suggests that loss of consciousness may be caused by autonomic disorder due to orthostatic hypotension and reflex syncope (vasovagal syncope), psychogenic non-epileptic seizures (PNES) by mental and physical stress. It is important to consider the pathophysiology and management of Alexander disease, in which the progression of gait disorder caused by pyramidal tract disorder is rapidly exacerbated by fall and head injury.

Experiences of intimate partner violence as perpetrated among Japanese university freshmen.

Objectives: To compare experiences regarding the perpetration of intimate partner violence among Japanese university freshmen between 2008 and 2014. Study design: Two-stage cross-sectional study. Methods: A self-administered questionnaire survey was completed in both 2008 and 2014 by students at the same university. Results: There were significant reductions in episodes of verbal harassment (adjusted odds ratio [AOR]: 0.601, 95% confidence interval [CI]: 0.382, 0.945, P = 0.027) that occurred when a boy/girlfriend said "you don't give me priority" to his/her partner when they did not see them (AOR: 0.450, 95%CI: 0.207, 0.979, P = 0.044), and also in instances of irritation that resulted when a boy/girlfriend disobeyed his/her partner (AOR: 0.385, 95%CI: 0.161, 0.921, P = 0.032) from 2008 to 2014. The perpetration scores were reduced from 1.87 ±â€…0.16 in 2008 to 1.41 ±â€…0.117 in 2014 (t test, P = 0.016). The perpetration scores in 2014 were significantly lower than those in 2008, regardless of gender, age, university faculty, and participation in lectures/seminars about domestic violence (DV) and/or dating DV (P = 0.030). Conclusions: Findings showed reductions in some types of harassment, as well as in perpetration scores, between 2008 and 2014 among Japanese university freshmen at the same university. However, further study is required to determine the factors related to the perpetration of harassment.

Subungual onychomycosis due to Aspergillus niger mimicking a glomus tumor: A case report.

Onychomycosis is a common nail infection caused by dermatophytes, while non-dermatophytes including Aspergillus spp. are causes of nail onychomycosis. Aspergillus niger is not common as a cause of nail onychomycosis. In the current study we present a 60-year-old woman with subungual onychomycosis due to Aspergillus niger mimicking a glomus tumor. Physical examination revealed right thumb had a black color of nail bed. Localized tenderness and severe pain were observed. However, the cold sensitivity test, Loves pin test and Hildreths test were negative. On radiograph, bone erosion was found in a part of distal phalanx at the right thumb. Magnetic resonance imaging identified a mass at the subungual space, which exhibited low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The differential diagnosis included glomus tumor and infection. The histological findings demonstrated dichotomous septate hyphae. The culture was positive for Aspergillus niger. The results suggested that when physical examination is not typical for a glomus tumor, other diseases may be considered. Additionally, frozen section diagnosis may be useful.

[A case of reversible cerebral vasoconstriction syndrome (RCVS) triggered by human placenta extract].

We present a case of a female patient with reversible cerebral vasoconstriction syndrome (RCVS) arising after receiving subcutaneous injection of human placenta extract. A 44-year-old woman started taking human placenta extract with the aim of improving her menopausal symptoms, fatigue, and beauty. However, 18 days after taking human placenta extract, she had three episodes of thunderclap headache. Repeated cranial CT did not show subarachnoid hemorrhage; CSF examination showed neither xanthochromia nor inflammation. Brain diffusion weighted and FLAIR images were normal. However, magnetic resonance angiography showed multifocal segmental stenosis of the right middle cerebral artery and bilateral anterior cerebral arteries. Follow-up angiography, which performed 12 days after the oncet of thunderclap headache, revealed almost normalized flow in all cerebral arteries; we made a diagnosis of RCVS. She has had no symptoms and signs since the third attack of headache. The only identified etiologic factor was subcutaneous injection of human placenta extract started 18 days prior to onset. This is the first report of RCVS triggered by human placenta extract.

Knowledge, experience, and potential risks of dating violence among Japanese university students: a cross-sectional study.

BACKGROUND: The Domestic Violence Prevention Act came into effect in Japan in 2001, but covers only marriage partner violence and post-divorce partner violence, and does not recognize intimate partner violence (IPV). The present study was performed to determine the experience of harassment, both toward and from an intimate partner, and recognition of harassment as IPV among Japanese university students. METHODS: A self-administered questionnaire survey regarding the experience of harassment involving an intimate partner was conducted as a cross-sectional study among freshman students in a prefectural capital city in Japan. RESULTS: A total of 274 students participated in the present study. About half of the subjects (both male and female students) had experience of at least one episode of harassment toward or had been the recipient of harassment from an intimate partner. However, the study participants did not recognize verbal harassment, controlling activities of an intimate partner, and unprotected sexual intercourse as violence. Experience of attending a lecture/seminar about domestic violence and dating violence did not contribute to appropriate help-seeking behavior. CONCLUSIONS: An educational program regarding harassment and violence prevention and appropriate help-seeking behavior should be provided in early adolescence to avoid IPV among youth.

[A late-onset case of nonconvulsive status epilepticus of generalized epilepsy].

We report a 78-year-old woman who had episodes of nonconvulsive status epilepticus (NCSE) with dizziness. At 75 years of age, she had first seizure, but was not well examined. At 78 years of age, she had brief myoclonic jerks of her arms, soon after awakening, in May. She suffered from strong dizziness and was admitted in our hospital at the end of June. The symptoms regressed with bed rest in few days and she was discharged. However, she was admitted again with dizziness in the middle of July. There were no myoclonic jerks of her arms or legs and she could converse and interact normally, but was slightly disoriented (JCS: 2). Blood test, Cerebrospinal fluid analyses and brain MRI were normal. An EEG showed frequent intermittent generalized multiple spikes and slow wave complexes and a 3-4 Hz generalized spike and slow wave complexes every 2-4 seconds during whole 20 minutes record. Intravenous injection of 5 mg diazepam terminated status immediately. Thereafter, she was treated with sodium valproate (400 mg/day). Her symptoms improved, and interictal epileptic discharges extremely decreased. Late-onset NCSE of generalized epilepsy is rare. We discussed this case as an important case for diagnosis of NCSE with subtle symptom of dizziness.

[An autopsy case of amyotrophic lateral sclerosis with ampulla cardiomyopathy].

We herein report an autopsy case of a 63-year-old man with amyotrophic lateral sclerosis (ALS) who developed "ampulla cardiomyopathy." At the age of 56, he noticed a progressive weakness in his right upper extremity. One year later, a progressive weakness of the left upper extremity began. Dropped head and progressive weakness of the lower extremities emerged at the ages of 61 and 62, respectively. Intravenous immunoglobulin and plasma-exchange therapies did not improve his weakness. At the age of 63, one month before his death, he was hospitalized due to aspiration pneumonia. A tracheostomy was performed to secure his airway. Four days after the operation, an ST elevation of his electrocardiogram was incidentally found on the ECG monitor. An echocardiogram revealed diffuse hypokinesia of the wall of the left ventricle except in the basal portion, which is the typical finding of "ampulla cardiomyopathy." Wall motion of the left ventricle improved and his circulatory condition was stabilized after treatment, but his condition thereafter worsened again and he died 3 weeks later. An autopsy examination revealed diffuse fibrosis and degeneration of the cardiomyofibers. Neuropathological examination revealed neuronal cell loss, Bunina bodies and skein-like inclusions in the hippoglossal nuclei. In the thoracic spinal cord, degenarated anterior horn cells were seen and macrophage permeation in the corticospinal tract were shown by CD68 immunostaining. Therefore, the final neuropathological diagnosis was ALS. This report is the first autopsy case of ALS complicated with "ampulla cardiomyopathy."