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Abstract This study explores the behavioral effects of modulating CaMKII-positive (CaMKII+) neurons in the posterior hypothalamus (PH). Utilizing a chemogenetic approach in mice, we discovered that the activation of CaMKII + neurons within the PH is associated with heightened locomotor activity, reduced social interaction, and impulsive behavior unrelated to anxiety or avoidance. These observed behaviors share a significant resemblance with characteristics commonly found in attention deficit and hyperactivity disorder (ADHD). Notably, treatment with clonidine, which is frequently prescribed for ADHD, effectively reduced impulsive behaviors in our mouse model. Our findings uncover the role of the PH that has not been previously explored and suggest a possible involvement of the PH in the manifestation of ADHD-like behaviors.

Abstract Background The association between programed cell death‐ligand 1 (PD‐L1) and tumor‐infiltrating lymphocytes (TILs) in vestibular schwannoma (VS) has been investigated in a few studies. These published studies report a difference in the PD‐L1 positivity rate in malignant peripheral nerve sheath tumors. We examined PD‐L1 expression and lymphocyte infiltration in patients with VS who had undergone surgical resection and investigated the association between PD‐L1 expression and clinicopathological features. Methods The expression of PD‐L1, CD8, and Ki‐67 in 40 VS tissue specimens was investigated using immunohistochemistry, and a clinical review of the patients was performed. Results Of the 40 VS samples, 23 (57.5%) were positive for PD‐L1 and 22 (55%) were positive for CD8. No significant differences in age, tumor size, pure‐tone audiometry, speech discrimination, or Ki‐67 expression were observed between patients in the PD‐L1‐positive and PD‐L1‐negative groups. A higher level of CD8‐positive cell infiltration was observed in PD‐L1‐positive tumors than in PD‐L1‐negative tumors. Conclusion We demonstrated that PD‐L1 was expressed in VS tissues. Although no correlation was identified between clinical characteristics and PD‐L1 expression, the association between PD‐L1 and CD8 was confirmed. Thus, additional research on targeting PD‐L1 is necessary to improve immunotherapy for VS in the future.

Abstract Background Glioblastoma (GBM) is the most aggressive type of brain tumor with heterogeneity and strong invasive ability. Treatment of GBM has not improved significantly despite the progress of immunotherapy and classical therapy. Epidermal growth factor receptor variant III (EGFRvIII), one of GBM-associated mutants, is regarded as an ideal therapeutic target in EGFRvIII-expressed GBM patients because it is a tumor-specific receptor expressed only in tumors. Flagellin B (FlaB) originated from Vibrio vulnificus, is known as a strong adjuvant that enhances innate and adaptive immunity in various vaccine models. This study investigated whether FlaB synergistically could enhance the anti-tumor effect of EGFRvIII peptide (PEGFRvIII). Methods EGFRvIII-GL261/Fluc cells were used for glioblastoma-bearing mouse brain model. Cell-bearing mice were inoculated with PBS, FlaB alone, PEGFRvIII alone, and PEGFRvIII plus FlaB. Tumor growth based on MRI and the survival rate was investigated. T cell population was examined by flow cytometry analysis. Both cleaved caspase-3 and CD8 + lymphocytes were shown by immunohistochemistry (IHC) staining. Results The PEGFRvIII plus FlaB group showed delayed tumor growth and increased survival rate when compared to other treatment groups. As evidence of apoptosis, cleaved caspase-3 expression and DNA disruption were more increased in the PEGFRvIII plus FlaB group than in other groups. In addition, the PEGFRvIII plus FlaB group showed more increased CD8 + T cells and decreased Treg cells than other treatment groups in the brain. Conclusions FlaB can enhance the anti-tumor effect of PEGFRvIII by increasing CD8 + T cell response in a mouse brain GBM model.

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro. The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγnull mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo. As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC597-104 and EphA2682-689) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells’ distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8+ T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo. In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Intracranial sarcoma is an uncommon aggressive cancer with a poor prognosis and a high recurrence rate. Although postoperative adjuvant radiotherapy (RT) is the most recommended treatment strategy, it does not significantly improve survival rates. In this study, we used an attenuated Salmonella typhimurium strain engineered to secrete Vibrio vulnificus flagellin B (SLpFlaB) as an immunotherapy to assist with the antitumor effects of RT on intracranial sarcoma. In vitro, the expression of γH2AX and cleaved caspase-3 was analyzed by Western blot. In vivo detection of SLpFlaB colonization time in tumors was measured using an in vivo imaging system (IVIS). Tumor growth delay and elimination were demonstrated in an intracranial mouse model, and the distribution of macrophages, M1 macrophages, and CD8+ cells after treatment was measured using FACS analysis. Our findings in vitro suggest that combination therapy increases S-180 radiosensitivity, the expression of DNA double-strand breaks, and programmed cell death. In vivo, combination treatment causes intracranial sarcoma to be eliminated without tumor recurrence and redistribution of immune cells in the brain, with data showing the enhanced migration and infiltration of CD8+ T cells and macrophages, and an increased proportion of M1 macrophage polarization. Compared to RT alone, the combination therapy enhanced the radiosensitivity of S-180 cells, promoted the recruitment of immune cells at the tumor site, and prevented tumor recurrence. This combination therapy may provide a new strategy for treating intracranial sarcomas.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Recent clinical trials utilizing antigen-pulsed dendritic cells (DCs) have demonstrated increased survival of vaccinated cancer patients. Besides, the cytoplasmic transduction peptide (CTP) not only has an excellent transcellular efficiency but also shows a strong tendency to remain in the cytoplasm after transduction, without migrating into the nucleus. In this study, we investigated the effectiveness of immunotherapy against malignant gliomas using DCs pulsed with CTP-fused protein antigens combined with programmed cell death protein 1 blockade (anti-PD1). The expression of tumor associated antigen (WT1 and BIRC5) and PDL1 on glioblastoma (GBM) target cells was confirmed by western blot. The effect of CTP-fused protein antigens on mature DCs (VaxDCs) was determined. The immunophenotypes of VaxDCs pulsed with CTP-fused protein antigens was confirmed by flow cytometry and the cytokine production levels of T helper polarization were measured by enzyme-linked immunosorbent (ELISA) assay. The IFN-γ-enzyme linked immunospot and lactate dehydrogenase release assays were performed to estimate the cytotoxic activity of antigen-specific cytotoxic T lymphocytes (CTLs), stimulated by VaxDCs pulsed with CTP-fused protein antigens and anti-PD1, against malignant glioma cells expressing target antigens. VaxDCs pulsed with CTP-fused protein antigens showed enhanced expression of major histocompatibility complex (MHC) and co-stimulatory markers of DCs and resulted in Th1 cytokine polarization. The increase in the number of IFN-γ+ effector T cells paralleled with the enhanced percent specific lysis of GBM targets cells by antigen-specific CTLs. Our study suggested that using CTP-fused protein antigens for DC vaccine preparation along with PD1 blockade could be an effective immunotherapy strategy for GBM.

Recent development in nanofabrication technology has enabled the fabrication of plasmonic nanoapertures that can provide strong field concentrations beyond the diffraction limit. Further utilization of plasmonic nanoaperture requires the broadband tuning of the operating wavelength and precise control of aperture geometry. Here, we present a novel plasmonic coaxial aperture that can support resonant extraordinary optical transmission (EOT) with a peak transmittance of ~10% and a wide tuning range over a few hundred nanometers. Because of the shadow deposition process, we could precisely control the gap size of the coaxial aperture down to the sub–10-nm scale. The plasmonic resonance of the SiNx/Au disk at the center of the coaxial aperture efficiently funnels the incident light into the sub–10-nm gap and allows strong electric field confinement for efficient second harmonic generation (SHG), as well as EOT. In addition to the experiment, we theoretically investigated the modal properties of the plasmonic coaxial aperture depending on the structural parameters and correlation between EOT and SHG through finite-difference time-domain simulations. We believe that our plasmonic coaxial apertures, which are readily fabricated by the nanoimprinting process, can be a versatile, practical platform for enhanced light–matter interaction and its nonlinear optical applications.

Plasmacytoma in the sellar region is an extremely rare occurrence. Sellar plasmacytoma is often difficult to differentiate from pituitary tumors both clinically and radiologically. The occurrence of cranial nerve palsy, the preservation of pituitary hormone function, the presence of sellar floor destruction, and better contrast enhancement are regarded as the differentiating factors between sellar plasmacytoma and pituitary tumors. We recommend adding the massive bleeding properties of sellar plasmacytoma as another characteristic which differentiates it from a pituitary tumor.

Abstract Background Understanding the global impact of medulloblastoma on health related quality of life (HRQL) is critical to characterizing the broad impact of this disease and realizing the benefits of modern treatments. We evaluated HRQL in an international cohort of pediatric medulloblastoma patients. Methods Seventy‐six patients were selected from 10 sites across North America, Europe, and Asia, who participated in the Medulloblastoma Advanced Genomics International Consortium (MAGIC). The Health Utilities Index (HUI) was administered to patients and/or parents at each site. Responses were used to determine overall HRQL and attributes (ie specific subdomains). The impact of various demographic and medical variables on HRQL was considered—including molecular subgroup. Results The majority of patients reported having moderate or severe overall burden of morbidity for both the HUI2 and HUI3 (HUI2 = 60%; HUI3 = 72.1%) when proxy‐assessed. Self‐care in the HUI2 was rated as higher (ie better outcome) for patients from Western versus Eastern sites, P = .02. Patients with nonmetastatic status had higher values (ie better outcomes) for the HUI3 hearing, HUI3 pain, and HUI2 pain, all P

Abstract 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.

Glioblastoma, the most common aggressive cancer, has a poor prognosis. Among the current standard treatment strategies, radiation therapy is the most commonly recommended. However, it is often unsuccessful at completely eliminating the cancer from the brain. A combination of radiation with other treatment methods should therefore be considered. It has been reported that radiotherapy in combination with immunotherapy might show a synergistic effect; however, this still needs to be investigated. In the current study, a “branched multipeptide and peptide adjuvants [such as pan DR epitope (PADRE) and polyinosinic-polycytidylic acid—stabilized with polylysine and carboxymethylcellulose—(poly-ICLC)],” namely vaccine and anti-PD1, were used as components of immunotherapy to assist in the anti-tumor effects of radiotherapy against glioblastomas. With regard to experimental design, immunological characterization of GL261 cells was performed and the effects of radiation on this cell line were also evaluated. An intracranial GL261 mouse glioma model was established, and therapeutic effects were observed based on tumor size and survival time. The distribution of effector immune cells in the spleen, based on cytotoxic T lymphocyte (CTL) and natural killer (NK) cell function, was determined. The pro-inflammatory and anti-inflammatory cytokine production from re-stimulated splenocytes and single tumor cells were also evaluated. As GL261 cells demonstrated both immunological characteristics and radiation sensitivity, they were found to be promising candidates for testing this combination treatment. Combinatorial treatment with radiation, vaccine, and anti-PD1 prolonged mouse survival by delaying tumor growth. Although this combination treatment led to an increase in the functional activity of both CTLs and NK cells, as evidenced by the increased percentage of these cells in the spleen, there was a greater shift toward CTL rather than NK cell activity. Moreover, the released cytokines from re-stimulated splenocytes and single tumor cells also showed a shift toward the pro-inflammatory response. This study suggests that immunotherapy comprising a branched multipeptide plus PADRE, poly-ICLC, and anti-PD1 could potentially enhance the anti-tumor effects of radiotherapy in a glioblastoma mouse model.

Summary: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Abstract Background The CD133 transmembrane protein is a well-recognized stem cell marker that has been used to isolate putative cancer stem cell populations from gastric cancers (GCs). However, the molecular features or biomarkers underlying CD133 are largely unknown in GCs. Methods We performed gene expression profiling of CD133+ and CD133- cells sorted by flow cytometry from three GC cell lines to identify the CD133 expression signatures of GC. The CD133 expression signatures were investigated across publicly available expression profiles of multiple tumor types including GC and also for their relationship with patient survival. Results The CD133 signature genes defined as 177 upregulated genes and 129 downregulated genes in CD133+ cells compared to CD133- cells were enriched with genes involving the cell cycle and cytoskeleton, implying that cancer stem cells with unlimited self-renewal play cancer-initiating roles. The CD133 expression signatures in GC expression profiles were positively correlated with those of brain tumors expressing CD133 and human embryonic stem cells, emphasizing the transcriptional similarities across stem cell-related expression signatures. We also found that these stem cell expression signatures were inversely correlated with those representing tumor infiltrating immune and stromal cells. Additionally, high CD133 expression signatures were found in intestinal subtypes and low tumor stage GCs as well as in those with microsatellite instabilities and high mutation burdens. As examined across 20 additional tumor types, both the expression signatures representing CD133 and stromal cells were unfavorable prognostic features; however, their impact were variable across tumor types. Conclusions The transcriptional activities of CD133 and those of stromal cells representing the activity of stem cells and level of epithelial-to-mesenchymal transition, respectively, may be inversely correlated with each other across multiple tumor types including GC. This relationship may be a confounding factor and should therefore be considered when evaluating the clinical relevance of stem cell-related markers.

Gastritis is a common disease worldwide that is caused by various causes such as eating habits, smoking, severe stress, and heavy drinking, as well as Helicobacter pylori infections and non-steroidal anti-inflammatory drugs. Cinnamomum cassia is a tropical aromatic evergreen tree commonly used as a natural medicine in Asia and as a functional food ingredient. Studies have reported this species’ anti-obesity, anti-diabetic, and cardiovascular disease suppression effects. We evaluated the potential effects of C. cassia using non-steroidal anti-inflammatory drugs (NSAIDs), ethanol (EtOH), and ethanol/hydrochloric acid (HCl)-induced gastric mucosal injury models. C. cassia extracts reduced the area of gastric mucosa injury caused by indomethacin, NSAID, EtOH, and EtOH/HCl. We also applied a network pharmacology-based approach to identify the active compounds, potential targets, and pharmacological mechanisms of C. cassia against gastritis. Through a network pharmacology analysis, 10 key components were predicted as anti-gastritis effect-related compounds of C. cassia among 51 expected active compounds. The NF-κB signaling pathway, a widely known inflammatory response mechanism, comprised a major signaling pathway within the network pharmacology analysis. These results suggest that the anti-gastritis activities of C. cassia may be induced via the anti-inflammatory effects of key components, which suppress the inflammation-related genes and signaling pathways identified in this study.

Cinnamomum cassia is a natural product found in plants that has been used as a folk remedy for inflammation. In this study, we investigated the mechanism underlying the anti-inflammatory and antioxidant properties of C. cassia extract (ECC) in lipopolysaccharide (LPS)-induced murine RAW 264.7 cells, in comparison with 4-hydroxycinnamaldehyde, a C. cassia extract component. ECC and 4-hydroxycinnamaldehyde inhibited the production of nitrite oxide in a dose-dependent manner and did not show any change in cellular toxicity when treated with the same dose as that used in the nitrite assay. Moreover, they attenuated ROS accumulation after lipopolysaccharide (LPS) stimulation. ECC and 4-hydroxycinnamaldehyde decreased the mRNA and protein expression levels of inflammatory mediators (iNOS and COX-2) and cytokines such as TNF and IL-6. We also found that ECC and 4-hydroxycinnamaldehyde mitigated the phosphorylation of ERK, JNK, and transcription factors, such as NF-κB and STAT3, suppressing NF-κB nuclear translocation in LPS-activated macrophages. In addition, administration of ECC in a Sprague Dawley rat model of acute gastric injury caused by indomethacin significantly increased the gastric mucus volume. Analysis of serum and tissue levels of inflammatory mediators revealed a significant decrease in serum PGE2 and myeloperoxidase levels and a reduction in gastric iNOS, COX-2, and p65 protein levels. Collectively, these results suggest that ECC has antioxidant and anti-inflammatory effects and is a potential candidate for curing gastritis.

The medial habenula (MHb) plays an important role in nicotine-related behaviors, such as aversion and withdrawal. The MHb is composed of distinct subregions with unique neurotransmitter expression and neuronal connectivity. Here, we showed that nicotine and substance P (SP) differentially regulate neuronal excitability in subdivisions of the MHb (ventrolateral division, MHbVL; dorsal division; MHbD and superior division: MHbS). Nicotine remarkably increased spontaneous neuronal firing in the MHbVL and MHbD, but not in the MHbS, which was consistent with different magnitudes of whole-cell inward currents evoked by nicotine in each subdivision. Meanwhile, SP enhanced neuronal excitability in the MHbVL and MHbS. Although the MHbD is composed of SP-expressing neurons, they did not respond to SP. Neurons in the MHbVL increased their firing in response to bath-applied nicotine, which was attenuated by neurokinin receptor antagonists. Furthermore, nicotine addiction and withdrawal attenuated and augmented excitatory SP effects in the MHbVL, respectively. On the whole, we suggest that MHb-involving nicotine-related behaviors might be associated with SP signaling in MHb subdivisions.

Abstract Background Epithelial-mesenchymal transition (EMT), principally involving an E-cadherin to N-cadherin shift, linked to tumor invasion or metastasis, and therapeutic resistance in various human cancer. A growing body of recent evidence has supported the hypothesis that EMT play a crucial role in the invasive phenotype of gliomas. To evaluate the prognostic connotation of EMT traits in glioma, expression of E-cadherin and N-cadherin was explored in a large series of glioma patients in relation to patient survival rate. Methods Expressions of E- and N-cadherin were examined using immunohistochemical analysis in 92 glioma cases diagnosed at our hospital. These markers expressions were also explored in 21 cases of fresh frozen glioma samples and in glioma cell lines by Western blot analysis. Results Expression of E-cadherin was observed in eight cases (8.7%) with weak staining intensity in the majority of the immunoreactive cases (7/8). Expression of N-cadherin was identified in 81 cases (88.0%) with high expression in 64 cases (69.5%). Fresh frozen tissue samples and glioma cell lines showed similar results by Western blot analysis. There was no significant difference in either overall survival (OS) or progression-free survival (PFS) according to E-cadherin expression (P > 0.05). Although the OS rates were not affected by N-cadherin expression levels (P = 0.138), PFS increased in the low N-cadherin expression group with marginal significance (P = 0.058). The survival gains based on N-cadherin expression levels were significantly augmented in a larger series of publicly available REMBRANDT data (P

Abstract Background Tumor to normal tissue ratio (T/N ratio) on 11C-methionine (11C-MET) positron emission tomography/computed tomography (PET/CT) is affected by variable factors. We investigated whether T/N ratio cutoff values corrected according to metabolic tumor volume (MTV) could improve the diagnostic performance of 11C-MET PET/CT for diagnosis of recurrence in patients with metastatic brain tumor. Forty-eight patients with metastatic brain tumors underwent 11C-MET PET/CT for differential diagnosis between recurrence and radiation necrosis after gamma knife radiosurgery (GKR). Both T/N ratio and MTV were estimated in each lesion on 11C-MET PET/CT. The lesions were classified into three groups based on MTV criteria (≤ 0.5 cm3; > 0.5, ≤ 4.0 cm3; and > 4.0 cm3). The optimal cutoff values of the T/N ratio from receiver operating characteristic (ROC) curve were determined in each group (MTV-corrected) as well as total lesions (non-corrected). Finally, diagnostic performance of 11C-MET PET/CT was compared with the MTV-corrected cutoff values. Results Among 77 lesions, 51 were diagnosed with recurrence. The mean T/N ratio was 2.25 (± 1.12) for recurrent lesions and 1.44 (± 0.22) for radiation necrosis (P 4.0 cm3). In small-sized lesions (MTV ≤ 0.5 cm3), MTV-corrected cutoff values (1.23) could maintain favorable diagnostic performance with sensitivity, specificity, and diagnostic accuracy (70.0, 80.0, and 73.3%, respectively), compared to non-corrected cutoff values. Conclusions MTV-corrected cutoff values of T/N ratio could maintain the diagnostic performance of 11C-MET PET/CT in small sized, metastatic brain tumors. We expect our results to contribute to reproducible and standardized interpretation of 11C-MET PET/CT.

Purpose The purpose of this study was to evaluate the usefulness of MR imaging and to describe the MR imaging findings of pregnancy-associated breast cancer. Materials and Methods From 2006 to 2013, MR images of 23 patients with pregnancy-associated breast cancer were retrospectively evaluated. MR images were reviewed to evaluate lesion detection and imaging findings of pregnancy-associated breast cancer. MR images were analyzed by using the Breast Imaging Reporting and Data System and an additional MR-detected lesion with no mammographic or sonographic abnormality was determined. Results MR imaging depicted breast cancer in all patients, even in marked background parenchymal enhancement. Pregnancy-associated breast cancer was seen as a mass in 20 patients and as non-mass enhancement with segmental distribution in 3 patients. The most common features of the masses were irregular shape (85%), non-circumscribed margin (85%), and heterogeneous enhancement (60%). An additional site of cancer was detected with MR imaging in 5 patients (21.7%) and the type of surgery was changed. Conclusion Pregnancy-associated breast cancer was usually seen as an irregular mass with heterogeneous enhancement on MR images. Although these findings were not specific, MR imaging was useful in evaluating the disease extent of pregnancy-associated breast cancer.

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.”

To advance our understanding of pathological features associated with Alzheimer’s disease (AD), chemical tools with distinct specificity towards AD targets would be valuable. Here the authors used a structure-mechanism-based design strategy to obtain small molecules as chemical regulators for distinct pathological factors linked to AD pathology.

Postoperative complications after brain tumor surgery occur occasionally and it is important for clinicians to know how to properly manage each complication. Here, we described a rare case of late-onset, subdural fluid collection localized at the resection cavity that caused motor weakness after convexity meningioma resection, requiring differentiation from an abscess, to help clinicians determine treatment strategies. A 58-year-old right-handed female was admitted to the hospital with a headache and posterior neck pain. Brain computed tomography (CT) scans and magnetic resonance (MR) images showed a homogeneously enhanced, calcified, and multi-lobulated mass adjacent to the right motor strip without perilesional edema. The patient underwent surgery without incident or residual deficit and was discharged from the hospital in good condition. Six weeks after surgery, the patient complained of left arm monoparesis without infection-related symptoms. Brain imaging studies showed a localized fluid collection in the resection cavity with an enhanced margin and perilesional edema. Diffusion restriction was not detected. After three months of conservative treatment without surgery or antibiotics, she recovered from the neurologic deficits, and brain imaging studies showed the spontaneous regression of the fluid collection and perilesional edema. Late-onset, localized fluid collection at the resection cavity, which is similar to an abscess, could occur three to eight weeks after meningioma resection. When there are predisposing factors, including blood components and hemostatic materials in the surgical cavity, it is important for clinicians to understand this type of complication and choose conservative management as a feasible strategy.

Cough and phlegm frequently occur in respiratory diseases like upper respiratory tract infections, acute bronchitis, and chronic obstructive pulmonary diseases. To relieve these symptoms and diseases, various ingredients are being used despite the debates on their clinical efficacy. We aimed to investigate the effects of the extract CKD-497, composed of Atractylodis Rhizoma Alba and Fructus Schisandrae, in relieving cough and facilitating expectoration of phlegm. CKD-497 was found to inhibit inflammatory mediators such as interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) in lipopolysaccharide (LPS)-treated mouse macrophages and transient receptor potential cation channel 1 (TRPV-1)-overexpressed human bronchial epithelial cells stimulated by capsaicin. CKD-497 decreased the viscosity of the mucin solution. During in vivo experiments, CKD-497 reduced coughing numbers and increased expectoration of phlegm via mucociliary clearance enhancement. Collectively, these data suggest that CKD-497 possesses potential for cough and phlegm expectoration treatment.

This study compared the contents of prosapogenin depending on the extracting conditions of Red ginseng to provide basic information for developing Red ginseng-based functional foods. The content of ginsenoside Rg3 reached their maximum value at 24 h of extraction, followed by 36 h and 72 h of extraction at 100°C.