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Background aims Tracking administered natural killer (NK) cells in vivo is critical for developing an effective NK cell-based immunotherapy against human hepatocellular carcinoma (HCC). Here the authors established a new molecular imaging using ex vivo-activated NK cells and investigated real-time biodistribution of administered NK cells during HCC progression. Methods Ex vivo-expanded NK cells from healthy donors were labeled with a near-infrared lipophilic cytoplasmic dye, and their proliferation, surface receptor expression and cytotoxicity activity were evaluated. Human HCC HepG2 cells were implanted into the livers of NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NSG) mice. The authors administered 1,1’-dioctadecyltetramethyl indotricarbocyanine iodide (DiR)-labeled NK cells intravenously to non-tumor-bearing and intrahepatic HCC tumor-bearing NSG mice. Fluorescent imaging was performed using a fluorescence-labeled organism bioimaging instrument. Single cell suspensions from the resected organs were analyzed using flow cytometry. Results The fluorescent DiR dye was nontoxic and did not affect the proliferation or surface receptor expression levels of the NK cells, even at high doses. The administered DiR-labeled NK cells immediately migrated to the lungs of the non-tumor-bearing NSG mice, with increased NK cell signals evident in the liver and spleen after 4 h. NK cells migrated to the intrahepatic tumor-bearing livers of both early- and late-stage HCC mice within 1 h of injection. In early-stage intrahepatic tumor-bearing mice, the fluorescence signal increased in the liver until 48 h post-injection and decreased 7 days after NK injection. In late-stage HCC, the NK cell fluorescence signal was the highest in the liver for 7 days after NK injection and persisted for 14 days. The purity of long-term persistent CD45+CD56+CD3− NK cells was highest in early- and late-stage HepG2-bearing liver compared with normal liver 2 weeks after NK injection, whereas highest purity was still observed in the lungs of non-tumor-bearing mice. In addition, Ki-67 expression was detected in migrated human NK cells in the liver and lung up to 72 h after administration. With HepG2 tumor progression, NK cells reduced the expression of NKp30 and NKG2D. Conclusions Administered NK cells were successfully tracked in vivo by labeling the NK cells with near-infrared DiR dye. Highly expanded, activated NK cells migrated rapidly to the tumor-bearing liver, where they persisted for 14 days after administration, with high purity of CD45+CD56+CD3− NK cells. Liver biodistribution and persistence of administered NK cells showed significantly different accumulation patterns during HCC progression.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ(null) (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.

Galectin 3-binding protein (LGALS3BP, also known as 90K) is a multifunctional glycoprotein involved in immunity and cancer. However, its precise role in colon inflammation and tumorigenesis remains unclear. Here, we showed that Lgals3bp−/− mice were highly susceptible to colitis and colon tumorigenesis, accompanied by the induction of inflammatory responses. In acute colitis, NF-κB was highly activated in the colon of Lgals3bp−/− mice, leading to the excessive production of pro-inflammatory cytokines, such as IL-6, TNFα, and IL-1β. Mechanistically, Lgals3bp suppressed NF-κB through the downregulation of TAK1 in colon epithelial cells. There was no significant difference in the pro-inflammatory cytokine levels between wild-type and Lgals3bp−/− mice in a chronic inflammatory state, during colon tumorigenesis. Instead, Lgals3bp−/− mice showed elevated levels of GM-CSF, compared to those in WT mice. We also found that GM-CSF promoted the accumulation of myeloid-derived suppressor cells and ultimately increased colon tumorigenesis in Lgals3bp−/− mice. Taken together, Lgals3bp plays a critical role in the suppression of colitis and colon tumorigenesis through the downregulation of the TAK1-NF-κB-cytokine axis. These findings suggest that LGALS3BP is a novel immunotherapeutic target for colon inflammation and tumorigenesis.

Backgrounds Cysteine-rich angiogenic inducer 61 (Cyr61) is emerging as an important regulator of tissue homeostasis and wound repair. We aim to explore the colonic mucosal expression of Cyr61 and analyze the association between Cyr61 expression and clinical course in patients with Crohn’s disease (CD). Methods Endoscopic samples were identified from 83 CD patients with and 372 controls by searching pathological reports. Among them, age- and sex- matched 43 of each group by a propensity score were selected to compare Cyr61 expression by immunohistochemistry (IHC). IHC scores for Cyr61 expression of CD patients were divided into tertiles to evaluate the association with clinical course. We also measured the level of mRNA for Cyr 61 and proinflammatory genes in inflamed and noninflamed colonic mucosal lesions from CD patients. Results The mean IHC scores for Cyr61 expression was higher in CD patients (86.5) than in controls (46.1, P P = 0.01). Cyr61 mRNA levels in inflamed mucosa were twofold higher than those in non-inflamed lesion (P > 0.05) and the mRNA levels of IL-6 and TLR-4 in inflamed mucosa were significantly higher than those in non-inflamed mucosa in CD patients (all P P for trend = 0.02). Compared with tertile 1 of Cyr61 expression, tertile 3 of Cyr 61 expression was associated with reduced risk of clinical recurrence (OR 0.43, 95% CI 0.20–0.92) after adjustment for age, sex and CD activity index at the time of colonoscopy in CD patients (P = 0.03). Conclusions Cyr61 mucosal expression in CD patients was inversely associated with clinical course. Future study need to be considered to evaluate whether Cyr 61 may play a role in activating inflammatory responses and contributing to wound healing and tissue repair in patients with CD.

Differentiation between radiation-induced necrosis and tumor recurrence is crucial to determine proper management strategies but continues to be one of the central challenges in neuro-oncology. We hypothesized that hyperpolarized 13C MRI, a unique technique to measure real-time in vivo metabolism, would distinguish radiation necrosis from tumor on the basis of cell-intrinsic metabolic differences. The purpose of this study was to explore the feasibility of using hyperpolarized [1-13C]pyruvate for differentiating radiation necrosis from brain tumors. Radiation necrosis was initiated by employing a CT-guided 80-Gy single-dose irradiation of a half cerebrum in mice (n = 7). Intracerebral tumor was modeled with two orthotopic mouse models: GL261 glioma (n = 6) and Lewis lung carcinoma (LLC) metastasis (n = 7). 13C 3D MR spectroscopic imaging data were acquired following hyperpolarized [1-13C]pyruvate injection approximately 89 and 14 days after treatment for irradiated and tumor-bearing mice, respectively. The ratio of lactate to pyruvate (Lac/Pyr), normalized lactate, and pyruvate in contrast-enhancing lesion was compared between the radiation-induced necrosis and brain tumors. Histopathological analysis was performed from resected brains. Conventional MRI exhibited typical radiographic features of radiation necrosis and brain tumor with large areas of contrast enhancement and T2 hyperintensity in all animals. Normalized lactate in radiation necrosis (0.10) was significantly lower than that in glioma (0.26, P = .004) and LLC metastatic tissue (0.25, P = .00007). Similarly, Lac/Pyr in radiation necrosis (0.18) was significantly lower than that in glioma (0.55, P = .00008) and LLC metastasis (0.46, P = .000008). These results were consistent with histological findings where tumor-bearing brains were highly cellular, while irradiated brains exhibited pathological markers consistent with reparative changes from radiation necrosis. Hyperpolarized 13C MR metabolic imaging of pyruvate is a noninvasive imaging method that differentiates between radiation necrosis and brain tumors, providing a groundwork for further clinical investigation and translation for the improved management of patients with brain tumors.

Purpose We investigated whether adoptive cell therapy with ex vivo–activated natural killer (NK) cells enhances the therapeutic efficacy of local tumor radiation therapy (RT) using a human triple-negative breast cancer xenograft model. Methods and Materials NK cells from healthy donors were expanded ex vivo. MDA-MB-231/Luc-GFP cells were subcutaneously implanted into the thighs of NSG mice. The animals were divided into 4 experimental groups: control, RT, NK, and RT + NK. On day 17 after tumor implantation, tumors from the RT groups were irradiated. The ex vivo–expanded NK cells were intravenously administered twice, on days 17 and 19. Primary and secondary tumors were evaluated using long-term bioluminescence imaging, and histopathology was performed on resected tumor tissue specimens. Results The luciferase signals of the primary tumors in the RT + NK group were significantly lower than those of comparably sized primary tumors in the RT group. The long-term migration and infiltration of NK cells into the primary tumor sites were significantly higher in RT + NK than in NK mice. Moreover, lymphatic metastasis to the axillary lymph nodes and liver and lung metastases were highly suppressed in the RT + NK group, as demonstrated by BLI and p53 immunohistochemistry. The long-term survival of the RT + NK group was significantly higher than that of the RT or NK groups. Conclusions Reduction in tumor burden by combining RT and systemic NK cell therapy improved the suppression of primary tumor growth, with efficient NK cell migration and penetration into the primary tumor site. Administered NK cells were maintained in the primary tissue for a significantly longer time in RT + NK group compared with NK group. Both lymphatic spread and distant metastasis to the lungs and liver were effectively suppressed by the combined therapy.

Background Primary central nervous system lymphoma (PCNSL) occurs frequently in a deep intraparenchymal location. It rarely occurs in the meninges, and bone invasion is uncommon. Case Description A 12-year-old boy was admitted to our hospital with a history of headache and seizures. Magnetic resonance imaging showed a 4-cm-sized dural-based mass with osteolytic bone change. Craniotomy and tumor removal were performed. Operative findings showed a dural-based hard tumor, including necrosis and hemorrhage, and the skull was focally destroyed by tumor cells. The tumor was completely removed. Pathologically, large atypical cells with pleomorphic nuclei and frequent mitoses were found. The tumor cells were immune-positive for CD30, epithelial cell antigen, and anaplastic lymphoma kinase. The final diagnosis was anaplastic lymphoma kinase–positive anaplastic large cell lymphoma (ALCL). There was no evidence of systemic cancer. The boy underwent chemotherapy following the Non-Hodgkin Lymphoma-Berlin-Frankfurt-Munster protocol. There was no recurrence after a 16-month chemotherapy-off period. Conclusions ALCL is not a common type of PCNSL, and central nervous system ALCL frequently involves the dura and meninges compared with PCNSL in general. However, osteolytic bone lesions are rarely seen in ALCL. This case thus represents a rare case of dural-based ALCL with bone invasion.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently established neurodegenerative disease entity. LATE neuropathological change (LATE-NC) is characterized by a TDP-43 proteinopathy that mainly involves the amygdala and medial temporal structures, with or without hippocampal sclerosis. LATE-NC is typically observed in individuals aged 80 years or older and manifests clinically as amnestic memory decline. Herein, we report a case of LATE diagnosed by brain autopsy in an 82-year-old male who had an 11-year history of memory impairment. Pathological examination revealed high Alzheimer disease neuropathological changes, as well as amygdala-predominant Lewy body pathology. In addition, immunohistochemistry for TDP-43 revealed neuronal and glial cytoplasmic inclusions in the dentate gyrus of the hippocampus, amygdala, and inferior temporal cortex. Increasing awareness of the newly defined entity LATE will enhance our understanding of the neurodegenerative processes that occur in the oldest individuals.

Background Recent evidence suggests that brain-derived neurotrophic factor (BDNF) levels and their early changes may predict antidepressant response in adults with major depressive disorder (MDD). However, in adolescents, BDNF levels in depression and their changes during antidepressant treatment are relatively unknown. We aimed to investigate whether pre-treatment BDNF levels and their early changes predict antidepressant response in depressed adolescents. Methods The study included 83 MDD adolescents and 52 healthy controls aged 12 to 17 years. All depressed adolescents were treated with escitalopram in an 8 week, open-label trial. Depression severity and serum BDNF level at baseline, and weeks 2 and 8 were measured with the Children's Depression Rating Scale-Revised (CDRS-R) and ELISA, respectively. Results Responders showed a significant decrease in BDNF levels at week 2 but non-responders and healthy controls had no changes in BDNF levels at week 2. The early decrease (baseline – week 2) of BDNF levels predicted SSRI response with moderate sensitivity and specificity. Logistic regression analysis revealed that early BDNF decrease predicted SSRI response at week 8 after controlling for other demographic and clinical variables. Limitations The follow-up duration of the study was limited in 8 weeks. It remains possible that serum BDNF levels would have changed with longer treatment. Conclusions This is the first longitudinal study to investigate the effect of antidepressants on BDNF levels in adolescents with MDD. Our findings suggest that a decrease of serum BDNF levels in early phase of SSRI treatment may be associated later SSRI response in adolescents with MDD.

Background Idiopathic hypertrophic pachymeningitis (IHP) is a rare clinical disease characterized by inflammatory fibrosis, which causes diffuse thickening of the dura mater. The inflammatory fibrosis will be locally invasive in nature but will be characterized by a benign histological appearance, known as an inflammatory pseudotumor. We present the case of a patient with an infiltrative lesion involving the right frontal convexity diagnosed as IHP, which had been suspected to be a malignant tumor or high-grade meningioma from the preoperative radiological findings. Case Description A 59-year-old man was admitted to our hospital because of a temporary loss of consciousness. Contrast-enhanced magnetic resonance imaging (MRI) of the brain showed a 30-mm × 12-mm mass located in the right frontal convexity. The lesion had an isointensity to high-intensity signal with moderate periregional edema on T2-weighted MRI, and homogeneous enhancement, including a necrotic portion with a long dural tail along the right frontal convexity, after contrast-enhanced MRI. Thus, our preliminary diagnosis was high-grade meningioma or a malignant tumor. We decided to surgically remove the tumor. Intraoperatively, the lesion appeared as a dural-based yellowish mass with partial infiltration of the cortex. Histopathological examination of the lesion revealed thickened meninges with marked fibroinflammatory changes. The inflammatory changes extended into the underlying brain parenchyma and were centered in the perivascular spaces. The lesion showed abundant lymphoplasmacytic infiltration with fibrosis. Immunohistochemistry revealed mixed T and B lymphocytes and plasma cells. Only a small number of IgG4-positive cells were identified. From these findings, we finally concluded that the diagnosis was IHP. The patient did not receive any further steroid therapy, because the patient had no evidence of systemic autoimmune disease. A follow-up brain MRI scan was performed 6 month after surgery, which revealed no recurrence of the lesion. Conclusions Surgical treatment can be the first treatment option when the lesion is not localized to a critical portion of the brain. Thus, it might be possible to arrive at a definitive diagnosis histologically and determine additional treatment strategies. Also, if the surgeons are confident that the IHP has been removed completely, additional steroid therapy might not be necessary.

Background Epstein-Barr virus (EBV)–positive diffuse large B-cell lymphoma (DLBCL) in an immunocompromised patient with organ transplantation demonstrated unusual brain magnetic resonance imaging (MRI) findings. Recognition of EBV-positive DLBCL by radiologists on MRI may prevent unnecessary neurosurgical resection, and it could be important to obtain viable cells for accurate diagnosis on stereotactic biopsy because of extensive necrosis. Case Description A 62-year-old woman presented to the emergency department with left hemiparesis grade III and dysarthria lasting for 3 weeks. She underwent kidney transplantation in 2007 and was taking immunosuppressants and had hypothyroidism. Brain MRI showed a 3.8-cm peripheral enhancing lesion with extensive central necrosis in association with marked perilesional edema. The irregular ringlike enhancing lesion showed diffusion restriction and mildly increased regional cerebral blood volume in the rim portion of the mass. 11C-Methionine positron emission tomography revealed slightly increased uptake in the peripheral lesion. The provisional diagnosis was a high-grade glioma. Stereotactic multiple biopsies were performed for the central necrotic area and peripheral enhancing lesion. The nonenhancing areas showed only necrotic material, without viable cells, and the enhancing portion showed viable cells for an accurate diagnosis in a frozen biopsy specimen. The pathologic diagnosis was EBV-positive DLBCL with extensive necrosis. Positron emission tomography of the chest, abdomen, pelvis, and neck soft tissues ruled out systemic diseases. She underwent whole-brain radiotherapy at a dose of 30.6 Gy. Eight months later, her neurologic symptoms had improved, with a stable brain lesion and improved perilesional edema. Conclusions We report an immunocompromised patient with EBV-positive DLBCL, which showed atypical MRI findings, including extensive necrosis. Multiple biopsies were required for final diagnosis.

Medulloblastoma with extensive nodularity (MBEN) is a rare histological subtype of medulloblastomas in very young children. It is characterized by an aggressive grape-like appearance and favorable outcomes. Herein, we report the case of a nine-month-old patient with MBEN, associated with an activated sonic hedgehog (SHH), with rare multimodal magnetic resonance imaging (MRI) features. Conventional MRI findings indicated the dense homogeneous enhancement of a large unusual gyriform mass in the cerebellar vermis and both cerebellar hemispheres. The mass showed restricted diffusion on diffusion-weighted images, low concentrations of taurine on MR spectroscopy, and a relatively low cerebral blood volume on dynamic susceptibility contrast (DSC) MR perfusion image. The patient underwent partial tumor resection, chemotherapy, and autologous blood stem cell transplantation. After treatment, the lesion rapidly regressed in the serial follow-up imaging without recurrence.

Objectives: Evidence suggests that emotion regulation difficulty may play an important role in the association between life stress, sleep disturbance and depressive symptoms. We proposed two models depicting the possible moderating roles of prefrontal cortex activation during emotion regulation in the associations among these variables and tested them. We hypothesized that (1) the association between stress and sleep disturbance would differ across prefrontal cortex activation during emotion regulation (moderation model) and (2) the indirect effects of stress on depressive symptoms through sleep disturbance would depend on prefrontal cortex activation during emotion regulation (moderated mediation model). Methods: Forty-eight healthy adults without sleep disorders based on nocturnal polysomnography participated in this study. They received functional magnetic resonance imaging scans while performing an emotion regulation task. They also completed questionnaires assessing life stress, sleep disturbance and depressive symptoms. The proposed models were tested using the PROCESS macro for SPSS. Results: As hypothesized, there was a significant moderating effect of prefrontal cortex activation during emotion regulation on the association between life stress and sleep disturbance. Furthermore, right lateral prefrontal cortex activation had a moderating role in the indirect effect of life stress on depressive symptoms through sleep disturbance. Conclusion: These findings highlight the important role of prefrontal cortex function during emotion regulation in the associations between stress, sleep disturbance and depressive symptoms. Increasing lateral prefrontal cortex recruitment when regulating the emotional response to negative life events may be critical for the prevention and intervention of depression as well as sleep problems.

A close link has been established between self-harm and suicide risk in adolescents, and increasing attention is given to social media as possibly involved in this relationship. It is important to identify indicators of suicidality (i.e., suicide ideation or attempt) including aspects related to contagion in online and offline social networks and explore the role of social media in the relationship between social circumstances and suicidality in young adolescents with self-harm. This study explored characteristics of Korean adolescents with a recent history of self-harm and identified how behavioral and social features explain lifetime suicidality with emphasis on the impact of social media. Data came from a nationwide online survey among sixth- to ninth-graders with self-harm during the past 12 months (n = 906). We used χ2 tests of independence to explore potential concomitants of lifetime suicidality and employed a multivariate logistic regression model to examine the relationship between the explanatory variables and suicidality. Sensitivity analyses were performed with lifetime suicide attempt in place of lifetime suicidality. 33.9% (n = 306) and 71.2% (n = 642) reported to have started self-harm by the time they were fourth- and six-graders, respectively; 44.3% (n = 400) reported that they have friends who self-harm. Having endorsed moderate/severe forms and multiple forms of self-harm (OR 5.36, p < 0.001; OR 3.13, p < 0.001), having engaged in self-harm for two years or more (OR 2.42, p = 0.001), having friends who self-harm (OR 1.92, p = 0.013), and having been bullied at school were associated with an increased odds of lifetime suicidality (OR 2.08, p = 0.004). Notably, having posted content about one’s self-harm on social media during the past 12 months was associated with an increased odds of lifetime suicidality (OR 3.15, p < 0.001), whereas having seen related content in the same period was not. Sensitivity analyses yielded similar results with lifetime suicide attempt, supporting our findings from the logistic regression. The current study suggests that self-harm may be prevalent from early adolescence in South Korea with assortative gathering. The relationship of vulnerable adolescents’ social circumstances to suicide risk may be compounded by the role of social media. As the role of social media can be linked to both risk (i.e., contagion) and benefit (i.e., social connection and support), pre-existing vulnerabilities alongside SH and what online communication centers on should be a focus of clinical attention.

Due to the progressive aging of Korean society and the introduction of brain banks to the Korean medical system, the possibility that pathologists will have access to healthy elderly brains has increased. The histopathological analysis of an elderly brain from a subject with relatively well-preserved cognition is quite different from that of a brain from a demented subject. Additionally, the histology of elderly brains differs from that of young brains. This brief review discusses primary age-related tauopathy; this term was coined to describe elderly brains with Alzheimer’s diseasetype neurofibrillary tangles mainly confined to medial temporal structures, and no β-amyloid pathology.

Purpose This study is to report clinical outcomes of salvage concurrent chemo-radiation therapy (CCRT) in treating patients with loco-regional recurrence (LRR) following initial complete resection of non-small cell lung cancer. Materials and Methods Between February 2004 and December 2016, 127 patients underwent salvage CCRT for LRR. The median radiation therapy (RT) dose was 66 Gy and clinical target volume was to cover recurrent lesion with margin without elective inclusion of regional lymphatics. Majority of patients (94.5%) received weekly platinum-based doublet chemotherapy during RT course. Results The median follow-up time from the start of CCRT was 25 months. The median survival duration was 49 months, and overall survival (OS) rates at 2 and 5 years were 72.9% and 43.9%. The 2- and 5-year rates of in-field failure-free survival, distant metastasis free survival, and progression free survival were 82.4% and 73.8%, 50.4% and 39.9%, and 34.6% and 22.3%, respectively. Grade ≥ 3 radiation-related esophagitis and pneumonitis occurred in 14 (11.0%) and six patients (4.7%), respectively. On both univariate and multivariate analysis, higher biologically equivalent dose (BED10) (≥ 79.2 Gy10 vs. < 79.2 Gy10; hazard ratio [HR], 0.431), smaller CTV (≤ 80 cm3 vs. > 80 cm3; HR, 0.403), and longer disease-free interval (> 1 year vs. ≤ 1 year; HR, 0.489) were significantly favorable factors for OS. Conclusion The current study has demonstrated that high dose salvage CCRT focused to the involved lesion only was highly effective and safe. In particular, higher BED10, smaller CTV, and longer disease-free interval were favorable factors for improved survival.

BACKGROUND: Refugees commonly experience difficulties with emotional processing, such as alexithymia, due to stressful or traumatic experiences. However, the functional connectivity of the amygdala, which is central to emotional processing, has yet to be assessed in refugees. Thus, the present study investigated resting-state functional connectivity of the amygdala and its association with emotional processing in North Korean (NK) refugees. METHODS: This study included 45 NK refugees and 40 native South Koreans (SK). All participants were administered the Toronto Alexithymia Scale (TAS), Beck Depression Inventory (BDI), and Clinical-administered PTSD Scale (CAPS), and differences between NK refugees and native SK in terms of resting-state functional connectivity of the amygdala were assessed. Additionally, the association between the strength of amygdala connectivity and the TAS score was examined. RESULTS: Resting-state connectivity values from the left amygdala to the bilateral dorsolateral prefrontal cortex (dlPFC) and dorsal anterior cingulate cortex (dACC) were higher in NK refugees than in native SK. Additionally, the strength of connectivity between the left amygdala and right dlPFC was positively associated with TAS score after controlling for the number of traumatic experiences and BDI and CAPS scores. CONCLUSIONS: The present study found that NK refugees exhibited heightened frontal-amygdala connectivity, and that this connectivity was correlated with alexithymia. The present results suggest that increased frontal-amygdala connectivity in refugees may represent frontal downregulation of the amygdala, which in turn may produce alexithymia as a compensatory mechanism to avoid experiencing negative feelings. FUNDING: This research was supported by the Brain Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT & Future Planning (No.2016M3C7A1904338) and National Research Foundation of Korea (NRF) grant funded by the Korean government (No. 2016R1A2B4011561). DECLARATION OF INTERESTS: The authors declare that they have no conflict of interest including relevant financial interests, activities, relationships, and affiliations. ETHICS APPROVAL STATEMENT: The research protocol of the present study was approved by the Institutional Review Board of Seoul National University Hospital and all participants provided written informed consent after receiving a comprehensive written and verbal description of the study.

Posttranslational modifications of the Forkhead family transcription factor, FOXO1, have been known to have important regulatory implications in its diverse activities. Several types of modifications of FOXO1, including acetylation, phosphorylation, and ubiquitination, have been reported. However, lysine methylation of FOXO1 has not yet been identified. Here, we reported that FOXO1 is methylated by G9a at K273 residue in vitro and in vivo. Methylation of FOXO1 by G9a increased interaction between FOXO1 and a specific E3 ligase, SKP2, and decreased FOXO1 protein stability. In addition, G9a expression was increased by insulin and resulted in insulin-mediated FOXO1 degradation by K273 methylation. Tissue array analysis indicated that G9a was overexpressed and FOXO1 levels decreased in human colon cancer. Cell proliferation assays revealed that G9a-mediated FOXO1 methylation increased colon cancer cell proliferation. Fluorescence-activated cell sorting (FACS) analysis indicated that apoptosis rates were higher in the presence of FOXO1 than in FOXO1 knock-out cells. Furthermore, we found that G9a protein levels were elevated and FOXO1 protein levels were decreased in human colon cancer patients tissue samples. Here, we report that G9a specific inhibitor, BIX-01294, can regulate cell proliferation and apoptosis by inhibiting G9a-mediated FOXO1 methylation.

Purpose The study purpose was to report failure patterns in Masaoka-Koga stage II to IV type C thymic epithelial tumor (TET) after postoperative radiation therapy (PORT) and to evaluate the suitability of PORT target volume confined to the “tumor bed only with margin.” Methods and Materials A retrospective review of 53 patients with stage II to IV type C TET was performed. The clinical outcomes, failure patterns in relation to PORT target volume, and prognostic factors were analyzed. Results During a median follow-up period of 69 months, 14 deaths and 25 recurrences were observed. The 5-year rates of overall survival, disease-specific survival, and freedom from recurrence were 81.0%, 91.5%, and 49.7%, respectively. The failure patterns in relation to PORT target volume were in-field failure in 2 patients (3.8%), marginal in 2 (3.8%), and out of field in 23 (43.4%), respectively. The most common failure site was the pleura (12 patients), followed by the lung parenchyma (8 patients). Relapse involving the regional lymph nodes was observed in 6 patients, of whom 4 had synchronous distant failure and only 2 had isolated ipsilateral supraclavicular lymph node failure. Conclusions The policy of PORT target volume confined to only the tumor bed seems reasonable in treating patients with stage II to IV type C TET. The development of a more effective systemic therapy regimen is warranted.

Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor originating from various soft tissues and meninges, which carries the NAB2-STAT6 fusion gene. Meningeal/intracranial SFT/HPCs (icSFT/HPC) have a poor clinical outcome with metastatic behavior compared to soft tissue/extracranial SFT/HPCs (exSFT/HPC), but the underlying genetic factors are unclear. Differentially expressed genes (DEGs) were analyzed by NanoString nCounter assay using RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples. Additionally, immunohistochemistry (IHC) was performed on 32 cases of exSFT/HPC, 18 cases of icSFT/HPC, and additional recurrent or metastatic cases to verify the findings. Pathway analysis revealed that the WNT signaling pathway was enriched in exSFT/HPC. Analysis of DEGs showed that expression of WNT5A was lower and that of MMP9 was higher in icSFT/HPC than in exSFT/HPC (p = 0.008 and p = 0.035, respectively). IHC showed that WNT5A and CD34 expression was high in exSFT/HPC (p &lt, 0.001, both), while that of MMP9 was high in icSFT/HPC (p = 0.001). Expression of CLDN5 in tumoral vessels was locally decreased in icSFT/HPC (p &lt, 0.001). The results suggested that decreased WNT5A expression, together with increased MMP9 expression, in icSFT/HPC, may affect vascular tightness and prompt tumor cells to metastasize extracranially.

We report a rare case that was initially diagnosed as an inflammatory lesion and ultimately confirmed as primary central nervous system lymphoma (PCNSL) in an immunocompetent patient who was not treated with corticosteroid prior to the initial biopsy. A 70-year-old female patient presented with numbness in the left side of face, arm, and leg. Brain magnetic resonance imaging (MRI) revealed a lesion with intense gadolinium (Gd)-enhancement in the ventral portion of the midbrain. A stereotactic biopsy demonstrated mixed T-cell and B-cell infiltrating inflammatory lesions without demyelination. Three months after postoperative treatment with steroid, the lesion markedly decreased on follow-up MRI. Twenty-six months after the initial attack, she complained of dysarthria and urinary incontinence. Repetitive MRI showed a lesion with homogeneous enhancement, extensively involving the bilateral cerebral hemisphere, corpus callosum, and the right middle cerebellar peduncle. The confirmed diagnosis was diffuse large B-cell lymphoma on the second biopsy. Despite our best efforts, she died 38 months after disease onset. Based on review of the literature and our case, preceding inflammatory lesions are not always demyelinating and T-cell dominant inflammatory lesions. When the initial biopsy reveals an inflammatory lesion in an old-aged patient, the clinician should keep in mind the development of PCNSL and perform close clinical and radiological observations for a timely diagnosis.

Objective: The effects of selective serotonin reuptake inhibitor (SSRI) on deficits in attention and executive function in adolescents with major depressive disorder (MDD) are relatively unknown. W...

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is a myositis-specific marker detected in clinically amyopathic dermatomyositis (DM). DM with anti-MDA5 antibody can be accompanied by rapidly progressive interstitial lung disease (RP-ILD) and other autoimmune disorders. Until now, only one case of neuromyelitis optica (NMO) with anti-MDA5-positive DM has been reported worldwide, in which the patient achieved a favorable outcome with intensive immunotherapy. We report a case of NMO in a patient with anti-MDA5-positive DM complicated by ILD and rheumatoid arthritis. Our patient experienced a fulminant course of NMO, rather than RP-ILD, in the presence of hyperferritinemia, which resulted in profound neurological sequelae despite immunotherapy including rituximab.

The molecular profile of cholangiocarcinoma (CC) remains elusive. The prognostic value of isocitrate dehydrogenase (IDH) mutations in CC is controversial, and there have been few relevant studies in Asian populations. In the present study, we investigated the frequency and prognostic significance of IDH mutations in Korean patients with CC. CC specimens were collected from patients who underwent surgical liver resection between 2004 and 2019. Clinical and pathological data were retrospectively reviewed from medical records. Mutational IDH profiling was performed by peptide nucleic acid-mediated PCR clamping in 206 surgical specimens; IDH-mutant samples were confirmed by next-generation sequencing (NGS). Of the 195 patients with CC, six (3.13%) were found to exhibit IDH1 (n = 5) or IDH2 (n = 1) mutations. Among patients with IDH1 mutations, four had R132C (c.394C>T) and one had R132G (c.394C>G) mutations. One patient had R172W (c.514A>T) mutations in IDH2. All IDH-mutant samples were of intrahepatic origin, and patients with IDH mutations had physiological to low serum levels of carbohydrate antigen 19-9 (CA19-9). No association between IDH mutation status and long-term survival outcomes was observed. The frequency of IDH mutations was considerably lower than the 10–20% reported in previous studies. The frequency and pattern of IDH mutations in CC are likely to vary among patients with different ethnicities. These findings suggest that characterization of the oncogenic mutation profile in different populations is of high clinical importance.

BackgroundComputer-aided diagnosis on chest x-ray images using deep learning is a widely studied modality in medicine. Many studies are based on public datasets, such as the National Institutes of Health (NIH) dataset and the Stanford CheXpert dataset. However, these datasets are preprocessed by classical natural language processing, which may cause a certain extent of label errors.ObjectiveThis study aimed to investigate the robustness of deep convolutional neural networks (CNNs) for binary classification of posteroanterior chest x-ray through random incorrect labeling.MethodsWe trained and validated the CNN architecture with different noise levels of labels in 3 datasets, namely, Asan Medical Center-Seoul National University Bundang Hospital (AMC-SNUBH), NIH, and CheXpert, and tested the models with each test set. Diseases of each chest x-ray in our dataset were confirmed by a thoracic radiologist using computed tomography (CT). Receiver operating characteristic (ROC) and area under the curve (AUC) were evaluated in each test. Randomly chosen chest x-rays of public datasets were evaluated by 3 physicians and 1 thoracic radiologist.ResultsIn comparison with the public datasets of NIH and CheXpert, where AUCs did not significantly drop to 16%, the AUC of the AMC-SNUBH dataset significantly decreased from 2% label noise. Evaluation of the public datasets by 3 physicians and 1 thoracic radiologist showed an accuracy of 65%-80%.ConclusionsThe deep learning–based computer-aided diagnosis model is sensitive to label noise, and computer-aided diagnosis with inaccurate labels is not credible. Furthermore, open datasets such as NIH and CheXpert need to be distilled before being used for deep learning–based computer-aided diagnosis.

Literature suggests that neurobiological factors such as brain structure play an important role in linking social stress with depression in adolescence. We aimed to examine the role of subcortical volumetric alteration in the association between peer problems as one type of social stress and adolescent depression. We hypothesized that there would be indirect effects of peer problems on adolescent depression through subcortical volumetric alteration. Seventy eight adolescents with major depressive disorder (MDD) (age mean [SD] = 14.9 ± 1.5, 56 girls) and 47 healthy controls [14.3 ± 1.4, 26 girls]) participated in this study. High-resolution structural T1 images were collected using the Siemens 3T MR scanner. Subcortical volumes were segmented using the Freesurfer 6.0 package. Peer problems were assessed using the Peer-Victimization Scale and the Bullying-Behavior Scale. There was a significant indirect effect of peer problems on adolescent depression through nucleus accumbens (NAcc) volume alteration, but not through the amygdala and hippocampal volumes. This result supported our model, which stated that peer problems have indirect effects through subcortical volumetric alteration (i.e., increased NAcc volume) on adolescent depression. Our finding suggests that altered NAcc volume may serve as a pathway, through which peer problems as one type of social stressor contribute to adolescent depression.

Rationale: Bevacizumab has shown good efficacy in radiation necrosis (RN) following gamma knife radiosurgery (GKRS) and associated peritumoral edema. However, few studies have reported bevacizumab failure. Moreover, the pathologic transformation of benign meningioma following GKRS has never been reported. Patients concerns: A 41-year-old man was admitted with focal seizure on the right arm. Diagnoses: Magnetic resonance imaging (MRI) demonstrated a 4.7 cm-sized convexity meningioma involving left motor cortex. Interventions: Subtotally resected tumor was confirmed as a meningothelial meningioma and subsequently treated by GKRS. During 4-year follow-up after GKRS, seizure and hemiparesis had persisted with progressively worsened peritumoral edema regardless of steroid and bevacizumab treatment. Radical debulking of tumor was achieved and immunohistopathological examination revealed angiomatous meningioma with necrotic core presenting scanty VEGF expression. Outcomes: A follow-up MRI at 4 months after debulking surgery showed a marked reduction of peritumoral edema with improvement of symptoms. Lessons: This is the first report of pathologically confirmed angiomatous transformation following GKRS. Although the pathogenesis is not fully understood, this rare pathologic transformation may be closely related to RN. Also, if bevacizumab is resistant, debulking surgery for reducing tumor burden could be an effective treatment option to control the RN.

We investigated the ability of machine-learning classifiers on radiomics from pre-treatment multiparametric magnetic resonance imaging (MRI) to accurately predict human papillomavirus (HPV) status in patients with oropharyngeal squamous cell carcinoma (OPSCC). This retrospective study collected data of 60 patients (48 HPV-positive and 12 HPV-negative) with newly diagnosed histopathologically proved OPSCC, who underwent head and neck MRIs consisting of axial T1WI, T2WI, CE-T1WI, and apparent diffusion coefficient (ADC) maps from diffusion-weighted imaging (DWI). The median age was 59 years (the range being 35 to 85 years), and 83.3% of patients were male. The imaging data were randomised into a training set (32 HPV-positive and 8 HPV-negative OPSCC) and a test set (16 HPV-positive and 4 HPV-negative OPSCC) in each fold. 1618 quantitative features were extracted from manually delineated regions-of-interest of primary tumour and one definite lymph node in each sequence. After feature selection by using the least absolute shrinkage and selection operator (LASSO), three different machine-learning classifiers (logistic regression, random forest, and XG boost) were trained and compared in the setting of various combinations between four sequences. The highest diagnostic accuracies were achieved when using all sequences, and the difference was significant only when the combination did not include the ADC map. Using all sequences, logistic regression and the random forest classifier yielded higher accuracy compared with the that of the XG boost classifier, with mean area under curve (AUC) values of 0.77, 0.76, and 0.71, respectively. The machine-learning classifier of non-invasive and quantitative radiomics signature could guide the classification of the HPV status.

Background The aim of this study was to examine the psychometric properties of the Korean version of Screen for Child Anxiety Related Emotional Disorders (SCARED) on a sample of Korean youths and to examine the cross-cultural differences in adolescents’ anxiety. Methods Our study included 147 adolescents (ages 12–17, 92 girls), 93 with major depressive disorder and 54 as controls. Participants were evaluated using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), SCARED, Child Behavior Checklist (CBCL), Disruptive Behavioral Disorder Scale (DBD) and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). Pearson’s r and Cronbach’s α values of the SCARED were calculated, and exploratory factor analysis was conducted. Results The Korean SCARED scores were correlated with the total anxiety scores of K-SADS-PL (r = 0.74) and the CBCL anxious/depressed subscale scores (r = 0.35). Results showed a five-factor structure with good internal consistency, in which some items were loaded on different factors compared to previous studies. Conclusions The Korean SCARED demonstrated promising psychometric properties, and could be a valid scale for screening anxiety symptoms in primary care. The fact that different items comprised the factors may reflect the cultural difference between United States and Korea in experiencing anxiety.

Segmentation is fundamental to medical image analysis. Recent advances in fully convolutional networks has enabled automatic segmentation; however, high labeling efforts and difficulty in acquiring sufficient and high-quality training data is still a challenge. In this study, a cascaded 3D U-Net with active learning to increase training efficiency with exceedingly limited data and reduce labeling efforts is proposed. Abdominal computed tomography images of 50 kidneys were used for training. In stage I, 20 kidneys with renal cell carcinoma and four substructures were used for training by manually labelling ground truths. In stage II, 20 kidneys from the previous stage and 20 newly added kidneys were used with convolutional neural net (CNN)-corrected labelling for the newly added data. Similarly, in stage III, 50 kidneys were used. The Dice similarity coefficient was increased with the completion of each stage, and shows superior performance when compared with a recent segmentation network based on 3D U-Net. The labeling time for CNN-corrected segmentation was reduced by more than half compared to that in manual segmentation. Active learning was therefore concluded to be capable of reducing labeling efforts through CNN-corrected segmentation and increase training efficiency by iterative learning with limited data.

Background The incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression. Case presentation We report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year-old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt’s lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti-cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi’s sarcoma was diagnosed in his right thigh. He underwent radiation therapy. Conclusion These findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers.

Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy.

Perineural invasion (PNI) has emerged as an important factor related to colorectal cancer spread; however, the impact of neoadjuvant chemoradiotherapy (nCRT) on PNI remains unclear. Herein, we investigated the prognostic value of PNI, along with lymphovascular invasion (LVI), in rectal cancer patients treated with nCRT. This single-center observational study of pathologic variables, including PNI and LVI, analyzed 1411 invasive rectal cancer patients (965 and 446 patients treated with primary resection and nCRT, respectively). The overall detection rates of LVI and PNI were 16.7 and 28.8%, respectively. The incidence of LVI was significantly lower in patients treated with nCRT (8.1 vs. 20.6%, P

Backgound In this study, we report a case of solitary Langerhans cell histiocytosis (LCH) without skull or systemic lesions including reviewing the initial magnetic resonance (MR) findings of cerebral LCH. Case Description A 36-year-old male patient presented with generalized tonic-clonic type seizure. Brain MR imaging showed a 3-cm mass lesion involving the right frontal lobe. It showed isointensity on T1-weighted images and hyperintensity on T2-weighted images. After gadolinium enhancement, the mass showed heterogeneous enhancement with perilesional edema and additional adjacent leptomeningeal enhancement. Special MR techniques focused on the enhanced lesion showed increased cerebral blood volume on perfusion images, no diffusion restriction on diffusion-weighted images, and a necrotic spectrum on MR spectroscopy. At surgery, we found a yellow mass and yellow tissue debris in the sulci adjacent to the mass and removed them. The final histopathologic diagnosis was LCH in the frontal lobe. The patient underwent scheduled adjuvant chemotherapy with cytarabine for 6 months and has been regularly followed up without any neurologic problem for 3 years. Conclusions In conclusion, additional sulcal enhancement around the mass lesion might be a clue MR imaging feature of intracerebral LCH, and special MR imaging techniques such as perfusion imaging, diffusion-weighted imaging, and MR spectroscopy could be helpful in differential diagnosis.

Purpose This study was conducted to compare clinical outcomes and treatment-related toxicities after stereotactic body radiation therapy (SBRT) with two different dose regimens for small hepatocellular carcinomas (HCC) ≤3 cm in size. Materials and. Methods We retrospectively reviewed 44 patients with liver-confined HCC treated between 2009 and 2014 with SBRT. Total doses of 45 Gy (n = 10) or 60 Gy (n = 34) in 3 fractions were prescribed to the 95% isodose line covering 95% of the planning target volume. Rates of local control (LC), intrahepatic failure-free survival (IHFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Results Median follow-up was 29 months (range, 8 to 64 months). Rates at 1 and 3 years were 97.7% and 95.0% for LC, 97.7% and 80.7% for OS, 76% and 40.5% for IHFFS, and 87.3% and 79.5% for DMFS. Five patients (11.4%) experienced degradation of albumin-bilirubin grade, 2 (4.5%) degradation of Child-Pugh score, and 4 (9.1%) grade 3 or greater laboratory abnormalities within 3 months after SBRT. No significant difference was seen in any oncological outcomes or treatment-related toxicities between the two dose regimens. Conclusions: SBRT was highly effective for local control without severe toxicities in patients with HCC smaller than 3 cm. The regimen of a total dose of 45 Gy in 3 fractions was comparable to 60 Gy in efficacy and safety of SBRT for small HCC.

Intermediate pilomyxoid tumors (IPTs) were defined by the presence of some features typical of pilomyxoid astrocytoma (PMA) in combination with features that could be considered more consistent with pilocytic astrocytoma (PA). PMA is rare in the cerebellum. And, IPT in the cerebellum is rarer than PMA. To our knowledge, only 2 reports have described IPT in the cerebellum. A 5-year-old boy had nausea and vomiting. Computed tomography revealed a large, round, low-density tumor in the cerebellar vermis area. On enhanced magnetic resonance imaging (MRI), the tumor showed inhomogeneous diffuse enhancement; the central portion showed homogenous enhancement, while the peripheral portion showed inhomogeneous enhancement. The patient underwent a midline suboccipital craniotomy, and gross total resection was performed. The tumor was gray-colored, rubbery hard, and severely hemorrhagic with a clear boundary. On pathologic examination, the combined features of both PA and PMA were retrospectively indicative of an IPT. The patient was symptom-free for 18 months, with no evidence of tumor recurrence on MRI. More observation and further studies on PMA and IPT are required to determine the most appropriate treatment for these tumors.

Background Cavernous hemangioma (CH) of the bone is a rare, benign neoplasm found usually in the vertebral body. This tumor rarely develops in the calvaria, with predilection to occur in the frontal and temporoparietal bones. Case Description A 56-year-old man with a right frontal palpable mass was admitted to our hospital. Magnetic resonance imaging (MRI) revealed a large extra-axial tumor in the right frontal bone. Intraoperatively, the bony mass involved the multilayers composed of extracranium-skull-dura-intradura-cortex. Pathologic examination revealed a typical calvarial CH penetrating dura mater. Conclusions This is the second reported case of calvarial CH with complete erosion of the dural plane and extension into subdural space. Although surgical resection is generally safe and easy, the possibility of dural invasion should be kept in mind for safe resection of calvarial CH, especially overlying the eloquent brain area.

Colorectal cancer is one of the leading causes of cancer-related deaths. Although several therapeutic management strategies are available at the early colon cancer stages, such as endoscopic mucosal or submucosal dissection, associated complications often include bleeding or bowel perforations. As an alternative approach, we investigated endoscopic non-ablative fractional laser (eNAFL) irradiation as a minimally invasive therapeutic modality for the treatment of early-stage colorectal cancer. By implanting SL4-DsRed colon cancer cells into the colons of the C57BL/6 mice, we developed an orthotopic colon tumour mouse model and demonstrated the early-stage tumour growth delay following the eNAFL irradiation. Additionally, we evaluated the temperature changes in the eNAFL-irradiated area using numerical simulations, and induced inflammation using histological analysis. Our results indicate a minimal thermal damage confined to the irradiated spot, sparing the adjacent tissue and alteration in the tumour microenvironment. eNAFL irradiation may be clinically useful as a minimally invasive therapeutic intervention at the early stage of tumourigenesis. In future, an optimal eNAFL therapeutic dose should be determined, in order to increase the efficacy of this approach.

Concerns about social status are ubiquitous during adolescence, with information about social status often conveyed in text formats. Depressed adolescents may show alterations in the functioning of neural systems supporting processing of social status information. We examined whether depressed youth exhibited altered neural activation to social status words in temporal and prefrontal cortical regions thought to be involved in social cognitive processing, and whether this response was associated with development. Forty-nine adolescents (ages 10–18; 35 female), including 20 with major depressive disorder and 29 controls, were scanned while identifying the valence of words that connoted positive and negative social status. Results indicated that depressed youth showed reduced late activation to social status (vs neutral) words in the superior temporal cortex (STC) and medial prefrontal cortex (MPFC); whereas healthy youth did not show any significant differences between word types. Depressed youth also showed reduced late activation in the dorsolateral prefrontal cortex and fusiform gyrus to negative (vs positive) social status words; whereas healthy youth showed the opposite pattern. Finally, age was positively associated with MPFC activation to social status words. Findings suggest that hypoactivation in the “social cognitive brain network” might be implicated in altered interpersonal functioning in adolescent depression. Keywords: Depression, Adolescence, Social status, Social brain, Neuroimaging

Protothecosis is an uncommon human infection caused by achlorophyllic algae of the genus Prototheca, especially P. wickerhamii. The skin is the most frequently involved organ and cases of protothecal tenosynovitis are very rare. A 71-year-old woman without prior medical history except hypertension presented with painful swelling of her right hand that did not improve despite receiving antibiotic treatment. She underwent tenosynovectomy and drainage. Histopathologic examination revealed necrotizing granulomatous inflammation and numerous spherical or morula-like organisms with a spoked wheel appearance. P. wickerhamii was identified from tissue culture. The lesion did not improve with empirical fluconazole therapy. Conventional amphotericin B was administered according to antifungal susceptibility tests and the lesion completely resolved. Protothecosis should be considered in the differential diagnosis for chronic tenosynovitis that does not respond to conventional antibacterial treatment; tissue biopsy with culture is required for diagnosis.

Background In this study, we aimed to compare repeated resection and radiation treatment, such as Gamma knife radiosurgery (GKRS) or conventional radiotherapy (RT), and investigate the factors influencing treatment outcome, including overall survival (OS), progression-free survival (PFS), and complication rates. Methods We retrospectively reviewed 67 cases of recurred intracranial meningiomas (repeated resection: 36 cases, radiation treatment: 31 cases) with 56 months of the median follow-up duration (range, 13-294 months). Results The incidence of death rate was 29.9% over follow-up period after treatment for recurred meningiomas (20/67). As independent predictable factors for OS, benign pathology [hazard ratio (HR) 0.132, 95% confidence interval (CI) 0.048-0.362, p

Background Stroke involving the cerebral white matter (WM) has increased in prevalence, but most experimental studies have focused on ischemic injury of the gray matter. This study was performed to investigate the WM in a unique rat model of photothrombotic infarct targeting the posterior limb of internal capsule (PLIC), focusing on the identification of the most vulnerable structure in WM by ischemic injury, subsequent glial reaction to the injury, and the fundamental histopathologic feature causing different neurologic outcomes. Methods Light microscopy with immunohistochemical stains and electron microscopic examinations of the lesion were performed between 3 hours and 21 days post-ischemic injury. Results Initial pathological change develops in myelinated axon, concomitantly with reactive change of astrocytes. The first pathology to present is nodular loosening to separate the myelin sheath with axonal wrinkling. Subsequent pathologies include rupture of the myelin sheath with extrusion of axonal organelles, progressive necrosis, oligodendrocyte degeneration and death, and reactive gliosis. Increase of glial fibrillary acidic protein (GFAP) immunoreactivity is an early event in the ischemic lesion. WM pathologies result in motor dysfunction. Motor function recovery after the infarct was correlated to the extent of PLIC injury proper rather than the infarct volume. Conclusions Pathologic changes indicate that the cerebral WM, independent of cortical neurons, is highly vulnerable to the effects of focal ischemia, among which myelin sheath is first damaged. Early increase of GFAP immunoreactivity indicates that astrocyte response initially begins with myelinated axonal injury, and supports the biologic role related to WM injury or plasticity. The reaction of astrocytes in the experimental model might be important for the study of pathogenesis and treatment of the WM stroke.

We report a rare case of subependymal giant cell astrocytoma (SEGA) associated with tumoral bleeding in a pediatric patient without tuberous sclerosis complex (TSC). A 10-year-old girl presented with a 2-week history of an increasingly aggravating headache. Brain magnetic resonance imaging revealed an approximately 3.6-cm, well-defined, heterogeneously enhancing mass with multistage hemorrhages on the right-sided foramen of Monro. The tumor was completely resected using a transcallosal approach. Intraoperatively, the mass presented as a gray-colored firm tumor associated with acute and subacute hemorrhages. The origin of the mass was identified as the ventricular septum adjacent to the foramen of Monro. A pathological analysis revealed pleomorphic multinucleated eosinophilic tumor cells with abundant cytoplasm. These cells showed positive staining for the glial fibrillary acidic protein and S100 protein. A diagnosis of SEGA was established. The patient recovered without any neurological symptoms. There was no evidence of TSC. The radiological follow-up showed no recurrence for 2 years. This was a case of SEGA with intratumoral hemorrhage, for which a favorable outcome was achieved, without any neurological deficit after tumoral resection.

We report a case of primary central nervous system vasculitis (PCNSV) mimicking a cortical brain tumor. A 25-year-old woman presented with a 2-week history of headache and transient right hemiparesis. Brain magnetic resonance imaging (MRI) revealed a cortical-involving lesion on the left frontal lobe. The 6-cm sized lesion showed low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. The lesion had continual linear enhancement on the subcortical white matter and leptomeninges. There was no evidence of hemorrhage on susceptibility-weighted images and no diffusion restriction on diffusion-weighted images. The regional cerebral blood volume was decreased on the MR perfusion images, and spectroscopy showed increased lactate and lipid peaks. The symptoms were aggravated by fever and seizures. Biopsy was performed to rule out tumorous or inflammatory lesions. Pathologically, lymphocytes were infiltrated on the vessels, and the arachnoid membrane was thickened with inflammatory cells. The patient did not have any underlying diseases, including immune disorders. After high-dose steroid administration, her symptoms improved. Two months later, brain MRI showed a reduction in the infiltration of the T2 hyperintensity lesion with subtle subcortical enhancement. We present a case of PCNSV involving the left frontal lobe, showing vasogenic edema, mass effect, and subcortical linear contrast enhancement without hemorrhage or infarction.

Recent research has implicated altered neural response to interpersonal feedback as an important factor in adolescent depression, with existing studies focusing on responses to feedback from virtual peers. We investigated whether depressed adolescents differed from healthy youth in neural response to social evaluative feedback from mothers. During neuroimaging, twenty adolescents in a current episode of major depressive disorder (MDD) and 28 healthy controls listened to previously recorded audio clips of their own mothers’ praise, criticism and neutral comments. Whole-brain voxelwise analyses revealed that MDD youth, unlike controls, exhibited increased neural response to critical relative to neutral clips in the parahippocampal gyrus, an area involved in episodic memory encoding and retrieval. Depressed adolescents also showed a blunted response to maternal praise clips relative to neutral clips in the parahippocampal gyrus, as well as areas involved in reward and self-referential processing (i.e. ventromedial prefrontal cortex, precuneus, and thalamus/caudate). Findings suggest that maternal criticism may be more strongly encoded or more strongly activated during memory retrieval related to previous autobiographical instances of negative feedback from mothers in depressed youth compared to healthy youth. Furthermore, depressed adolescents may fail to process the reward value and self-relevance of maternal praise.

Diaschisis has been described as functional depression distant to the lesion. A variety of neuroscientific approaches have been used to investigate the mechanisms underlying diaschisis. However, few studies have examined the pathological changes in diaschisis at ultrastructural level. Here, we used a rat model of capsular infarct that consistently produces diaschisis in ipsilesional and contralesional motor and sensory cortices. To verify the occurrence of diaschisis and monitor time-dependent changes in diaschisis, we performed longitudinal 2-deoxy-2-[18F]-fluoro-d-glucose microPET (FDG-microPET) study. We also used light and electron microscopy to identify the microscopic and ultrastructural changes at the diaschisis site at 7, 14, and 21 days after capsular infarct modeling (CIM). FDG-microPET showed the occurrence of diaschisis after CIM. Light microscopic examinations revealed no significant histopathological changes at the diaschisis site except a mild degree of reactive astrogliosis. However, electron microscopy revealed swollen, hydropic degeneration of axial dendrites and axodendritic synapses, although the neuronal soma (including nuclear chromatin and cytoplasmic organelles) and myelinated axons were relatively well preserved up to 21 days after injury. Furthermore, number of axodendritic synapses was significantly decreased after CIM. These data indicate that a circumscribed subcortical white-matter lesion produces ultrastructural pathological changes related to the pathogenesis of diaschisis.

Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported. The reported two cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence. The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding "farewell to oligoastrocytoma."

The receptor tyrosine kinase, recepteur d'origine nantais (RON), is known to be associated with the progression, metastasis, and prognosis of various types of cancers. Nevertheless, the role of RON in human oral squamous cell carcinoma (OSCC) is unclear. This study evaluated whether RON affects oncogenic behavior, oncogenic signaling pathways, and clinical outcomes, including survival, in human OSCC. Reverse transcription‑PCR, quantitative PCR, western blotting and immunohistochemical staining were used to determine mRNA and protein expression levels of RON. Cell invasion, migration and apoptosis assays were used to assess the functional effects of small interfering RNA‑mediated knockdown of RON or snail family transcriptional repressor 2 (SLUG). RON knockdown suppressed tumor cell invasion and migration and enhanced apoptosis in human OSCC cells. RON knockdown also decreased the phosphorylation of MAPK signaling proteins, such as ERK1/2, JNK and p38. In addition, RON knockdown suppressed the expression of the epithelial mesenchymal transition (EMT)‑related transcription factor, SLUG. SLUG knockdown blocked the enhancement of cell invasion and migration induced by macrophage‑stimulation protein (MSP)‑mediated RON activation in OSCC cells. The cell morphology was changed to spindle‑like shape under MSP‑mediated RON activation in OSCC cells. RON was overexpressed in both fresh and paraffin‑embedded human OSCC tissues. Taken together, these results indicate that RON contributed to tumor progression by regulating the EMT‑related factor, SLUG, and the MAPK pathway in OSCC. This study may provide a theoretical basis for the application of RON‑targeting agents, currently being studied in various cancer fields, for the treatment of OSCC.

Background Caveolin-1 (Cav-1) plays an important role in the development of various human cancers. We investigated the relationship between Cav-1 expression and non-small cell lung cancer (NSCLC) progression in the context of brain metastasis (BM). Methods Cav-1 expression was investigated in a series of 102 BM samples and 49 paired primary NSCLC samples, as well as 162 unpaired primary NSCLC samples with (63 cases) or without (99 cases) metastasis to distant organs. Human lung cancer cell lines were used for in vitro functional analysis. Results High Cav-1 expression in tumor cells was observed in 52% (38/73) of squamous cell carcinomas (SQCs) and 33% (45/138) of non-SQCs. In SQC, high Cav-1 expression was increased after BM in both paired and unpaired samples of lung primary tumors and BM (53% vs. 84% in paired samples, P = 0.034; 52% vs. 78% in unpaired samples, P = 0.020). Although the difference in median overall survival in patients NSCLC was not statistically significant, high Cav-1 expression in tumor cells (P = 0.005, hazard ratio 1.715, 95% confidence index 1.175–2.502) was independent prognostic factors of overall survival on multivariate Cox regression analyses, in addition to the presence of BM and non-SQC type. In vitro assays revealed that Cav-1 knockdown inhibited the invasion and migration of lung cancer cells. Genetic modulation of Cav-1 was consistently associated with SNAIL up- and down-regulation. These findings were supported by increased SNAIL and Cav-1 expression in BM samples of SQC. Conclusions Cav-1 plays an important role in the BM of NSCLC, especially in SQC. The mechanism may be linked to SNAIL regulation. Electronic supplementary material The online version of this article (10.1186/s12935-019-0892-0) contains supplementary material, which is available to authorized users.

A 36-year-old man presented with a subcutaneous nodule on the right upper arm. A small nodule had developed 8 years earlier, and grew in size, accompanied by a tingling sensation and numbness. In addition, he had a bluish irregular patch on the right hand since birth, which crossed from the palm to the dorsal hand. Skin biopsies from the hand showed a heavily pigmented melanocyte proliferation in the dermis with perieccrine, perivascular, and perineural involvement, and a diagnosis of congenital plaque-type blue nevus was made. The tumor on the arm was located closely along the median nerve, and was observed as a large black pedunculated round tumor. Histopathologically, the tumor on the arm consisted of densely packed tissue with nevoid cells without atypia in the larger nodular part, and heavily pigmented spindle and epithelioid melanocytes in the slender stalk area, which was diagnosed as cellular blue nevus with pigmented epithelioid melanocytoma-like pattern. Next-generation sequencing revealed GNAQ mutations in the hand lesion, and in the lesions on the arm. This case suggests that the areas of skin following the same neural distribution of a congenital plaque-type blue nevus on the extremities should be followed up for secondary changes.