SEGA-like circumscribed astrocytoma in a non-NF1 patient, harboring molecular profile of GBM. A case report.

Subependymal giant cell astrocytoma (SEGA) is a low-grade periventricular tumor that is closely associated with tuberous sclerosis complex (TSC). SEGA typically arises during the first two decades of life and rarely arises after the age of 20-25 years. Nevertheless, it has also been reported that glioma histologically resembling SEGA, so-called SEGA-like astrocytoma, can arise in neurofibromatosis type 1 (NF1) patients, even in the elderly. Herein, we report a case of SEGA-like circumscribed astrocytoma arising in the lateral ventricle of a 75-year-old woman. Whole-exome sequencing revealed a somatic variant of NF1. Methylation array analysis led to a diagnosis of "methylation class glioblastoma, IDH-wildtype, mesenchymal-type (GBM, MES)" with a high calibrated score (0.99). EGFR amplification, CDKN2A/B homozygous deletion, chromosomal +7/-10 alterations, and TERT promoter mutation, typical molecular abnormalities usually found in GBM, were also observed. While most reported cases of SEGA-like astrocytoma have arisen in NF1 patients, the patient was neither TSC nor NF1. Near total removal was accomplished with endoscopic cylinder surgery. At the 36-month follow-up, there was no tumor recurrence without adjuvant therapies. This clinical behavior did not match GBM. SEGA-like astrocytoma of the elderly is rare, and this is the oldest case reported so far. In addition, high-grade molecular features found in circumscribed tumor remain unclear. Further investigations among larger series are needed for clarifying the underlying molecular mechanisms.

DNA methylation array analysis for diffuse leptomeningeal glioneuronal tumor with conspicuous hypothalamic mass. A case report.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare glioneuronal neoplasm newly included in the 2016 World Health Organization Classification of Tumors of the Central Nervous System. Owing to the wide spectrum of its histopathological and radiological features, accurate diagnosis can be challenging. Recently, molecular testing including DNA methylation array has been introduced with the possibility of improving diagnostic accuracy and contributing to the subtyping especially for brain tumors with ambiguous histology. Two molecularly distinct subtypes of DLGNT have been reported: methylation class-1 (MC-1) with an indolent clinical course and MC-2, the latter aggressive. Herein, we report a case of a 14-year-old girl with a conspicuous hypothalamic mass lesion and diffuse leptomeningeal enhancement on magnetic resonance imaging. Biopsy specimens obtained from the hypothalamic lesion endoscopically were mainly composed of oligodendrocyte-like cells. However, it was difficult to make a definite diagnosis from these non-specific histological findings. Thus, DNA methylation array analysis was performed additionally by using formalin-fixed, paraffin-embedded tissue, resulting in a diagnosis of "MC-1 subtype of DLGNT" with a high calibrated score (0.99). Consequently, she was treated conservatively, with neither progression of the tumor nor aggravation of symptoms for the next 12 months. It was concluded that DNA methylation array analysis for DLGNT, a rare glioneuronal tumor, could be a powerful tool not only for accurate diagnosis but also decision-making in selecting the best treatment.

Primary central nervous system lymphomas with massive intratumoral hemorrhage: Clinical, radiological, pathological, and molecular features of six cases.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

DNA methylation accumulation in gastric mucosa adjacent to cancer after Helicobacter pylori eradication.

Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication.

An epilepsy-associated glioneuronal tumor with mixed morphology harboring FGFR1 mutation.

Glioneuronal tumor (GNT) is a rare central nervous system neoplasm composed of glial and neuronal components. Making the specific diagnosis of GNT can be challenging due to histopathological and genetical similarities among some GNTs and low-grade gliomas. We report a case of GNT with rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, and pilocytic astrocytoma-like morphology harboring FGFR1 mutation. A 16-year-old female presented with absence seizures. Magnetic resonance imaging revealed a right temporal lobe mass with multinodular enhancement by gadolinium administration. The tumor was mostly composed of oligodendrocyte-like cells (OLCs) with variable perinuclear haloes. Abundant Rosenthal fibers and eosinophilic granular bodies were identified. Neither mitotic figures nor areas of necrosis were seen. Focal neurocytic rosette features, involving ring-like arrays of OLCs around eosinophilic cores, were observed. Direct sequencing showed a missense mutation in FGFR1 K656E, whereas FGFR1 N546K, PIK3CA, and BRAF V600E were intact. KIAA1549-BRAF fusion was not detected by fluorescence in situ hybridization analysis.

A case of high-grade astrocytoma with BRAF and ATRX mutations following a long-standing course over two decades.

Pediatric high-grade gliomas are rare and occasionally hard to classify. These tumors often feature a well-demarcated histology and are expected to have a better outcome than ordinary diffuse high-grade gliomas in adults. We herein report a case of circumscribed high-grade glioma that showed a distinct molecular profile and followed an excellent course for 26 years. The patient, a 3-year-old boy at onset, presented with a contrast-enhancing mass in the right temporal lobe and underwent resection. Histologically, the tumor mainly consisted of compact bundles of GFAP-positive spindle cells. With its malignant features including brisk mitotic activity and pseudopallisading necrosis, a diagnosis of high-grade astrocytoma was made and adjuvant chemoradiotherapy was administered. After a disease-free period of two decades, the tumor recurred locally. The resected tumor was histologically identical to the primary tumor and additionally contained pleomorphic cells, but lacked eosinophilic granular bodies and reticulin networks. The primary and recurrent tumors both harbored the BRAF V600E mutation, and the recurrent tumor was immunonegative for ATRX. Combined BRAF and ATRX mutations are rare in gliomas, with only a pediatric case of glioblastoma being reported in the literature. However, our case cannot be regarded as glioblastoma because of its well-demarcated histology and excellent course. The distinction of either a diffuse or localized nature in gliomas is important, particularly in children, for predicting prognoses and selecting adjuvant therapies that consequently affect life-long health care. The present case provides novel insights into pediatric high-grade astrocytomas.

Dentatorubral-pallidoluysian atrophy (DRPLA) with a small ganglioglioma component containing neurofibrillary tangles and polyglutamine aggregation.

Dentatorubral-pallidoluysian atrophy (DRPLA), one of the polyglutamine diseases, has not been reported in combination with ganglioglioma (GG). Herein, we report an autopsy case of a 72-year-old man with DRPLA with a small GG component harboring neurofibrillary tangles (NFTs) and polyglutamine aggregates. NFTs, cytoplasmic accumulations of hyper-phosphorylated tau, are mainly observed in Alzheimer's disease (AD) and other tau-associated neurodegenerative disorders. NFTs can also be present in normal aging, and are occasionally observed in low-grade central nervous system (CNS) neoplasms such as GG. In the present case, whole brain examination demonstrated widespread deposition of polyglutamine aggregates, including GG, whereas NFTs were restricted to the GG component. In addition, no other AD or aging-related neuropathological structures were detected throughout the CNS. These findings may provide us with clues to elucidate the pathogenetic mechanisms that neuronal neoplasms may have to develop NFTs regardless of aging, and that polyglutamine may accumulate in neoplastic neurons in polyglutamine disease.

Younger and Sicker: Comparing Micronesians to Other Ethnicities in Hawaii.

OBJECTIVES: We compared the age at admission and the severity of illness of hospitalized Micronesians with 3 other racial/ethnic groups in Hawaii. METHODS: With Hawaii Health Information Corporation inpatient data, we determined the age at admission and the severity of illness for 162,152 adult, non-pregnancy-related hospital discharges in Hawaii from 2010 to 2012. We performed multivariable linear regression analyses within major disease categories by racial/ethnic group. We created disease categories with all patient refined-diagnosis related groups. RESULTS: Hospitalized Micronesians were significantly younger at admission than were comparison racial/ethnic groups across all patient refined-diagnosis related group categories. The severity of illness for Micronesians was significantly higher than was that of all comparison racial/ethnic groups for cardiac and infectious diseases, higher than was that of Whites and Japanese for cancer and endocrine hospitalizations, and higher than was that of Native Hawaiians for substance abuse hospitalizations. CONCLUSIONS: Micronesians were hospitalized significantly younger and often sicker than were comparison populations. Our results will be useful to researchers, state governments, and hospitals, providers, and health systems for this vulnerable group.

Hypothalamic hamartoma with neurofibrillary tangles.

Hypothalamic hamartomas are rare tumors that typically present in childhood, often with gelastic seizures, precocious puberty, or as a manifestation of Pallister-Hall syndrome. Neurofibrillary tangles are cytoplasmic aggregates of hyperphosphorylated tau that are best recognized in Alzheimer disease, other tau-associated neurodegenerative diseases, or as part of aging, but occasionally may be seen in low-grade neoplasms with a ganglion cell component as gangliocytoma or ganglioglioma. Herein, we report a case of hypothalamic hamartoma with neurofibrillary tangles.

Snapshots of a protein folding intermediate.

We have investigated the folding dynamics of Thermus thermophilus cytochrome c(552) by time-resolved fluorescence energy transfer between the heme and each of seven site-specific fluorescent probes. We have found both an equilibrium unfolding intermediate and a distinct refolding intermediate from kinetics studies. Depending on the protein region monitored, we observed either two-state or three-state denaturation transitions. The unfolding intermediate associated with three-state folding exhibited native contacts in ß-sheet and C-terminal helix regions. We probed the formation of a refolding intermediate by time-resolved fluorescence energy transfer between residue 110 and the heme using a continuous flow mixer. The intermediate ensemble, a heterogeneous mixture of compact and extended polypeptides, forms in a millisecond, substantially slower than the ∼100-µs formation of a burst-phase intermediate in cytochrome c. The surprising finding is that, unlike for cytochrome c, there is an observable folding intermediate, but no microsecond burst phase in the folding kinetics of the structurally related thermostable protein.

Effect of US health policies on health care access for Marshallese migrants.

The Republic of the Marshall Islands is a sovereign nation previously under the administrative control of the United States. Since 1986, the Compacts of Free Association (COFA) between the Republic of the Marshall Islands and the United States allows Marshall Islands citizens to freely enter, lawfully reside, and work in the United States, and provides the United States exclusive military control of the region. When the COFA was signed, COFA migrants were eligible for Medicaid and other safety net programs. However, these migrants were excluded from benefits as a consequence of the Personal Responsibility and Work Opportunity Reconciliation Act. Currently, COFA migrants have limited access to health care benefits in the United States, which perpetuates health inequalities.

Use of tenofovir disoproxil fumarate in highly viremic, hepatitis B mono-infected pregnant women.

BACKGROUND: Antiviral therapy in addition to immunoprophylaxis at birth has been shown to further reduce perinatal transmission of hepatitis B virus (HBV) in highly viremic women. AIMS: The aim of this study was to describe the use of tenofovir disoproxil fumarate (TDF) prophylaxis to reduce maternal HBV DNA levels and potentially vertical transmission in highly viremic women. METHODS: After receiving IRB approval, we performed a retrospective chart review of mothers positive for hepatitis B surface antigen (HBsAg) who delivered between 2009 and 2012. We identified women with HBV DNA levels ≥6 log copies/mL who were treated with TDF in pregnancy. RESULTS: There were 22 women identified. The majority were of Micronesian ethnicity. All were negative for hepatitis C antibody and HIV infection. The median gestational age of TDF initiation was 31 weeks with a median duration of treatment of 45 days. There was a reduction in median HBV DNA levels from baseline 9.0 ± 2.0 to 5.4 ± 1.1 log copies/mL after treatment. There were five (22.7 %) preterm deliveries and five (22.7 %) cesarean deliveries. All infants received immunoprophylaxis at birth. Postnatal HBsAg testing at 9-12 months was available for 13 infants, 12 of which were negative. There was one case of perinatal transmission. CONCLUSIONS: This is the second published case series to date on the use of TDF prophylaxis in HBV mono-infected, highly viremic mothers. This series suggests the use of TDF in pregnancy reduces maternal HBV DNA levels and is well tolerated.

Chromogenic in situ hybridization reveals specific expression pattern of long non-coding RNA DRAIC in formalin-fixed paraffin-embedded specimen.

Long non-coding RNA (lncRNA) plays an important role in the regulation of gene expression in normal and cancer cells. We previously discovered a novel tumor-suppressive lncRNA, DRAIC, in prostate cancer cells. Subsequent studies have demonstrated that DRAIC is dysregulated in various malignancies and exhibits a tumor-suppressive or pro-oncogenic function. However, details regarding its expression pattern in normal and cancerous tissues remain largely unknown. In this study, we performed chromogenic in situ hybridization (CISH) using RNAscope technology to assess DRAIC expression in formalin-fixed paraffin-embedded (FFPE) specimens. In the neuroendocrine-differentiated cancer cell line VMRC-LCD, CISH revealed a diffuse localization of DRAIC in the cytoplasm as well as specific accumulation in the nuclear compartment. DRAIC expression was comprehensively analyzed using tissue microarrays containing 89 normal and 155 tumor tissue samples. DRAIC was weakly expressed in normal epithelial cells of the colon, bronchiole, kidney, prostate, and testis. Conversely, DRAIC was moderately to highly expressed in some cancer tissues, including prostate adenocarcinoma, invasive ductal carcinoma of the breast, neuroendocrine carcinoma of the esophagus, lung adenocarcinoma, and small cell lung carcinoma. While DRAIC knockdown did not affect VMRC-LCD cellular viability and invasive ability, gene expression related to the neuroendocrine and cancer-related pathways was altered. Our expression analysis revealed the specific expression pattern of DRAIC in normal and cancerous FFPE tissues. The results presented here may lead to the elucidation of additional novel functions of DRAIC.

TB-free Ebeye: Results from integrated TB and noncommunicable disease case finding in Ebeye, Marshall Islands.

Background: Tuberculosis (TB) incidence rates in the Republic of the Marshall Islands are among the highest in the world, 480/100,000 in 2017. In response, the Health Ministry completed islandwide screening in Ebeye Island in 2017. Methods: Participants were interviewed to obtain TB history, exposures, and symptoms. TB assessment included chest radiography with sputum collection for GeneXpert® MTB-RIF if indicated. TB diagnosis was made by consensus of visiting TB experts. Participants were also screened for Hansen's disease (HD) and diabetes mellitus (DM). For persons aged ≥21 years, blood pressure, cholesterol, and blood glucose were assessed. Results: A total of 5,166 persons (90.0 % of target population) completed screening leading to the identification of 39 new cases of TB (755/100,000) and 14 persons with HD (270/100,000). DM was detected in 1,096 persons (27 %), including in 351 persons not previously diagnosed. The rate of hypertension was 61 % and of hypercholesterolemia was 15 %. New or prevalent TB diagnosis was associated with newly diagnosed or history of DM (aOR 4.68, 2.15-10.20). Conclusions: In Ebeye, an integrated TB screening campaign found TB, HD, DM, and hypertension. TB and DM were strongly associated.

Storylines of family medicine II: foundational building blocks-context, community and health.

Storylines of Family Medicine is a 12-part series of thematically linked mini-essays with accompanying illustrations that explore the many dimensions of family medicine, as interpreted by individual family physicians and medical educators in the USA and elsewhere around the world. In 'II: foundational building blocks-context, community and health', authors address the following themes: 'Context-grounding family medicine in time, place and being', 'Recentring community', 'Community-oriented primary care', 'Embeddedness in practice', 'The meaning of health', 'Disease, illness and sickness-core concepts', 'The biopsychosocial model', 'The biopsychosocial approach' and 'Family medicine as social medicine.' May readers grasp new implications for medical education and practice in these essays.

Influence of agent's self-disclosure on human empathy.

As AI technologies progress, social acceptance of AI agents, including intelligent virtual agents and robots, is becoming even more important for more applications of AI in human society. One way to improve the relationship between humans and anthropomorphic agents is to have humans empathize with the agents. By empathizing, humans act positively and kindly toward agents, which makes it easier for them to accept the agents. In this study, we focus on self-disclosure from agents to humans in order to increase empathy felt by humans toward anthropomorphic agents. We experimentally investigate the possibility that self-disclosure from an agent facilitates human empathy. We formulate hypotheses and experimentally analyze and discuss the conditions in which humans have more empathy toward agents. Experiments were conducted with a three-way mixed plan, and the factors were the agents' appearance (human, robot), self-disclosure (high-relevance self-disclosure, low-relevance self-disclosure, no self-disclosure), and empathy before/after a video stimulus. An analysis of variance (ANOVA) was performed using data from 918 participants. We found that the appearance factor did not have a main effect, and self-disclosure that was highly relevant to the scenario used facilitated more human empathy with a statistically significant difference. We also found that no self-disclosure suppressed empathy. These results support our hypotheses. This study reveals that self-disclosure represents an important characteristic of anthropomorphic agents which helps humans to accept them.

Three-Dimensional Amide Proton Transfer-Weighted Imaging for Differentiating between Glioblastoma, IDH-Wildtype and Primary Central Nervous System Lymphoma.

Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1-100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1-100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses.

Early detection of genotoxic hepatocarcinogens in rats using γH2AX and Ki-67: prediction by machine learning.

Direct DNA double-strand breaks result in phosphorylation of H2AX, a variant of the histone H2 protein. Phosphorylated H2AX (γH2AX) may be a potential indicator in the evaluation of genotoxicity and hepatocarcinogenicity. In this study, γH2AX and Ki-67 were detected in the short-term responses (24 h after chemical administration) to classify genotoxic hepatocarcinogens (GHs) from non-GH chemicals. One hundred and thirty-five 6-week-old Crl: CD(SD) (SPF) male rats were treated with 22 chemicals including 11 GH and 11 non-GH, sacrificed 24 h later, and immunostained with γH2AX and Ki-67. Positivity rates of these markers were measured in the 3 liver ZONEs 1-3; portal, lobular, and central venous regions. These values were input into 3 machine learning models-Naïve Bayes, Random Forest, and k-Nearest Neighbor to classify GH and non-GH using a 10-fold cross-validation method. All 11 and 10 out of 11 GH caused significant increase in γH2AX and Ki-67 levels, respectively (P < .05). Of the 3 machine learning models, Random Forest performed the best. GH were identified with 95.0% sensitivity (76/80 GH-treated rats), 90.9% specificity (50/55 non-GH-treated rats), and 90.0% overall correct response rate using γH2AX staining, and 96.2% sensitivity (77/80), 81.8% specificity (45/55), and 90.4% overall correct response rate using Ki-67 labeling. Random Forest model using γH2AX and Ki-67 could independently predict GH in the early stage with high accuracy.

Future Perspective for ALK-Positive Anaplastic Large Cell Lymphoma with Initial Central Nervous System (CNS) Involvement: Could Next-Generation ALK Inhibitors Replace Brain Radiotherapy for the Prevention of Further CNS Relapse?

Central nervous system (CNS) involvement in anaplastic large cell lymphoma (ALCL) at diagnosis is rare and leads to poor prognosis with the use of the standard ALCL99 protocol alone. CNS-directed intensive chemotherapy, such as an increased dose of intravenous MTX, increased dose of dexamethasone, intensified intrathecal therapy, and high-dose cytarabine, followed by cranial irradiation, has been shown to improve survival in this population. In this paper, the authors describe a 14-year-old male with an intracranial ALCL mass at onset who received CNS-directed chemotherapy followed by 23.4 Gy of whole-brain irradiation. After the first systemic relapse, the CNS-penetrating ALK inhibitor, alectinib, was applied; it has successfully maintained remission for 18 months without any adverse events. CNS-penetrating ALK inhibitor therapy might prevent CNS relapse in pediatric ALK-positive ALCL. Next-generation ALK inhibitors could be introduced as a promising treatment option, even for primary ALCL with CNS involvement, which could lead to the omission of cranial irradiation and avoid radiation-induced sequalae. Further evidence of CNS-penetrating ALK inhibitor combined therapy for primary ALK-positive ALCL is warranted to reduce radiation-induced sequalae in future treatments.