bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mental Health Stigma in Department of Defense Policies: Analysis, Recommendations, and Outcomes
Authors: Campbell Marjorie , Auchterlonie Jennifer L , Andris Zoe , Cooper Denise C , Hoyt Tim 
Published: November 2021

ABSTRACT

Introduction
Mental health stigma is one of the most frequently reported barriers to mental health help-seeking in the military. Previous research has identified that stigma-increasing language in the United States military policies was a potential deterrent to treatment-seeking. In response to a 2016 Government Accountability Office report recommendation, the current study conducted a comprehensive review of Department of Defense and military service-specific policies to identify stigmatizing language provisions and recommend appropriate language changes.

Methods
This review of policies comprised three sequential phases. First, a key-term search strategy was conducted on mental health (Phase 1) and substance misuse policies (Phase 2) to identify language that may contribute to stigma. Recommended language changes were identified, and the results of each phase were briefed to service-level Directors of Psychological Health. Approximately three years after initial identification, all mental health policies from Phase 1 for which language change recommendations had been made were examined to determine whether or not recommended changes had been incorporated (Phase 3).

Results
Out of 285 mental health and substance misuse policies, 191 (67%) contained potentially stigmatizing language. Subsequent review of implementation showed that partial or full recommended language changes had been made in 58.9% of 129 mental health-related policies that had been re-issued.

Conclusions
This collaborative effort to identify and modify potentially stigmatizing language contributed to a substantial reduction in problematic policies across the military services. Future efforts should focus on reviewing new and re-issued policies to ensure that stigma-increasing language is not present as part of routine issuance. These efforts are part of ongoing work to address the association that language and terminology have on stigma and barriers to care.
Literature Review of Sex Differences in mTBI
Authors: Haynes Nicole , Goodwin Tress 
Published: November 2021

ABSTRACTIntroductionTraumatic brain injury (TBI) remains a significant source of morbidity worldwide and is of particular concern for the military. Scientific literature examining sex differences in TBI is highly contradictory with some reporting better outcomes in men, others reporting better outcomes in women, and others reporting mixed results or no difference. While the exact cause is currently debated, the existence of such differences has important implications for surveillance techniques, treatment options, and management of long-term consequences. As the number of women within the U.S. military ranks increases and with the opening of combat roles to women in 2013, increased awareness of probable sex differences regarding TBI responses will enable better standard of care.Materials and MethodsUsing the PubMed database, a keyword search using gender, “sex factors”, “sex dependent”, “gender disparity”, TBI, “traumatic brain injury”, mTBI (mild TBI), and “cranial trauma” was used to identify articles of interest. Results were filtered for written in the last 5 years, English, and free full text. References of relevant articles were cross-checked for additional publications. Articles familiar to the authors were also included.ResultsWe review literature that includes analysis of age as an interaction in TBI, hypothesized mechanisms to explain variations in outcomes between men and women, and the need for inclusion of sex as a criterion in future studies.ConclusionsEmerging studies underscore the complexity of interpreting sex differences in TBI. The long-held belief that women have a neuroprotective advantage compared to men based on higher levels of sex hormones is being re-evaluated. Past conclusions have relied extensively on clinical studies that include a disproportionate number of men or do not stratify results based on sex. While sex hormones may be neuroprotective, underlying mechanisms are far from clarified. Future TBI studies must include women and gonadal hormone levels should be measured to address potential variables. Given the significant number of TBIs within the military, an improved understanding of TBI pathophysiology and outcomes is important considerations for mission success and servicemember longevity.
EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA
Authors: Yamazawa Erika , Tanaka Shota , Nagae Genta , Umeda Takayoshi , Hana Taijun , Kim Phyo , Higuchi Fumi , Takami Toshihiro , Nakanishi Yuta , Takai Keisuke , Komori Takashi , Takami Hirokazu , Nomura Masashi , Mukasa Akitake , Takayanagi Shunsaku , Ishii Kazuhiko , Imai Hideaki , Matsuura Reiko , Koike Tsukasa , Kushihara Yoshihiro , Nambu Shohei , Kugasawa Kazuha , Aburatani Hiroyuki , Saito Nobuhito 
Published: November 2021

Abstract

BACKGROUND
Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases.

MATERIALS AND METHODS
We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups.

RESULTS
Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups.

CONCLUSION
Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.
BIOM-01. MTH1 EXPRESSION IS UPREGULATED IN BRAIN METASTASES OF MALIGNANT MELANOMA
Authors: Timmer Marco , Timmer Marco , Kuhl Saskia , Goldbrunner Roland 
Published: November 2021

Abstract
MuT Homolog1 (MTH1) is an enzyme involved in DNA repair in normal cells and is often up-regulated in cancer cells. The enzyme catalyses the hydrolysis of oxidised dNTPs, to prevent their incorporation into DNA or RNA, resulting in mutations or cell damage/death. Cancer cells can have a high concentration of ROS, due to defective redox regulation. This results in the damage of DNA and oxidises free dNTPS, which in turn leads to mutations in DNA replication or cell death. The quantification of MTH1 expression was done by Western Blot analysis. 16 tumours were obtained during neurosurgery, 8 metastatic and 8 recurrent tumours of the same patient, and immediately frozen using liquid nitrogen. The proteins were extracted using RIPA lysis buffer. Western Blot was performed and detection followed via peroxidase linked secondary antibodies. MTH1 expression was shown to be up-regulated in brain metastases (1,442+/-0,6374) versus normal brain tissue (0,4133+/-0,277). However, in the recurrent tumour of the brain metastases, MTH1 was not expressed in a significantly higher amount compared the control tissue and less than in the brain metastases (0,6941+/-0,4146). The high expression of MTH1 in cerebral metastases presents a therapeutic target for MTH1-inhibitors, provided these are able to cross the blood brain barrier. Comparison to the primary melanoma tumour would be useful in showing significant differences of the metastases. Lower levels of MTH1 in recurrent brain metastases may suggest dedifferentiation from the original metastases. It may present a target for specific treatment of brain metastases of melanoma.
BIOM-02. LEPTOMENINGEAL DISEASE SECONDARY TO MELANOMA: UPDATES ON THE VALIDITY OF THE VERIDEX CELLSEARCH SYSTEM
Authors: Pina yolanda , Mokhtari Sepideh , Kim Youngchul , Evernden Brittany , Tran Nam , Smalley Inna , Khushalani Nikhil , Law Vincent , Puskas John , Caseres Gisela , Vogelbaum Michael , Smalley Keiran , Peguero Edwin , Forsyth Peter 
Published: November 2021

Abstract

BACKGROUND
Leptomeningeal disease (LMD) is devastating with a median survival of 8-10 weeks without treatment. LMD affects approximately 5% to 25% of melanoma patients. Its pathophysiology remains unknown and effective treatments are virtually non-existent. The primary aim of this study was to evaluate the validity of Veridex CellSearch® System (VCS) compared to Gold Standard test (i.e., CSF cytology).

MATERIALS AND METHODS
A retrospective chart review was performed of subjects with suspected LMD from melanoma enrolled in the MCC 19332/19648 at Moffitt Cancer Center. Patients underwent standard of care with different treatments as deemed appropriate by treating physician. CSF samples were obtained from lumbar punctures, surgeries, and Ommaya reservoir. CSF was evaluated for quantification of CSF circulating tumor cells (CTCs) with the Veridex CellSearch® System (VCS).

RESULTS
Forty-eight patients were identified with melanoma as primary tumor, ages 29-80. Twenty-seven had LMD (median age 62) with median KPS 70. N=19 (70%) were diagnosed radiographically and n=5 (19%) with CSF cytology; n=14 (54%) had positive cytology on first LP. From 24 patients with LMD who underwent VCS, n=22 (92% patients had positive CSF CTCs. Number of CTCs/mL CSF was significantly higher in patients with LMD versus in patients without LMD (mean SD 227.6 vs. 0.07, p &lt; 0.001). VCS sensitivity and specificity was analyzed. AUC was 0.515, with TPR 0.250 and FPR 0.286. CSF analysis and treatments were described. The median survival of those with LMD was 2.7 months.

CONCLUSION
These results indicate the potential value of the VCS as an additional tool to the gold standard in the diagnosis of LMD in patients with high suspicion of the disease. Future directions involve doing prospective studies to further validate this method, and to better understand this patient population to enhance diagnostic tools and management of LMD.
BIOM-11. THE PROGNOSTIC VALUE OF ROUTINE AND SPECIALIZED BLOOD TESTING IN GLIOBLASTOMA: A SYSTEMATIC REVIEW
Authors: van der Boog Arthur , Cialdella Fia , Bruil Danique , Smitt Karlijn , de Vos Filip , Verhoeff Joost 
Published: November 2021

Abstract

BACKGROUND
A combination of clinical characteristics, radiological findings and tissue markers is used in the assessment of glioblastoma prognosis and prediction of treatment response. The value of routine blood tests as a tool of prognosis has been a subject of debate. In addition to increased complication rate in subsequent resections and radiological uncertainty in treatment monitoring, there is a need to monitor tumor markers in a minimally invasive manner, as molecular characterization becomes more important in the management of glioblastoma. The objective of this review is to evaluate the prognostic value of any blood marker during the course of disease and treatment in glioblastoma.

METHODS
We researched Pubmed and Embase for clinical studies including cohort studies and randomized controlled trials that included at least 10 adult patients and blood testing during course of disease. We extracted data on clinically relevant endpoints, i.e. overall survival (OS) or progression-free survival (PFS), in accordance with the PRISMA statements.

RESULTS
The search strategy yielded 6389 unique articles, of which 150 met the inclusion criteria. 37 studies found an association between survival outcomes and pre-operative markers including complete blood count (erythrocytes and leukocytes with differentiation characteristics), inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), coagulability markers (prothrombin time, activated partial thromboplastin time and D-dimer), albumin, lactate dehydrogenase and glucose. Furthermore, 10 studies reported a correlation between changes in platelets, erythrocytes and leukocytes during course of disease and treatment and OS. Finally, serum and plasma levels of markers including various proteins, microRNAs and microvesicles were associated with PFS and OS.

CONCLUSION
The results of this study suggest that routine and specialized blood tests provide additive information on OS and PFS in glioblastoma. These promising findings highlight the need for further investigation of blood testing for biomarker evaluation.
BIOM-21. THE SIGNIFICANCE OF TERT PROMOTER MUTATIONS, TELOMERE LENGTH AND MGMT PROMOTER METHYLATION IN NEWLY DIAGNOSED AND RECURRENT IDH-WILDTYPE GLIOBLASTOMA (GBM): A LARGE MONO-INSTITUTIONAL STUDY
Authors: Lombardi Giuseppe , Giunco Silvia , Cavallin Francesco , Angelini Chiara , Caccese Mario , Cerretti Giulia , De Bonis Pasquale , De Rossi Anita , Zagonel Vittorina 
Published: November 2021

Abstract

BACKGROUND
the significance of TERT promoter mutations, telomere length and their interactions with MGMT methylation status in patients with IDH-wildtype GBM patients remain unclear. We performed a monoinstitutional study to better investigate their impact and their interaction on clinical outcomes.

METHODS
TERTmutations (C228T and C250T), relative telomere length (RTL) and MGMT methylation were assessed in 278 newly-diagnosed and in 65 recurrent IDH-wildtype GBM PTS which were treated from Dec2016 to Jan2020. We explored association between gene characteristics and neuroradiological response, PFS, OS. Telomere length was measured by monochrome multiplex PCR and RTL values were calculated as a telomere/single-copy gene ratio.

RESULTS
characteristics of newly diagnosed GBM PTS were: median age 63 ys, ECOG PS0-1 in 71% of PTS, radical surgery in 38%, 78% received radiation therapy plus TMZ, MGMTmet in 53%, TERT promoter was mutated in 80% (75% C228T, 25% C250T), median RTL was 1.57 (range 0.4-11.37). ORR was reported in 15% of PTS, medianOS was 15 ms (95% CI 13-18 ms), medianPFS was 8 ms (95% CI 7-9 ms). At multivariable analysis, TERT mutations and RTL were not associated with clinical outcomes; about OS, TERT mutations and RTL reported a HR of 1.05 (95% CI 0.64-1.64) and 0.99 (95% CI 0.89-1.10), respectively; MGMTmet tumors showed significant improved PFS and OS with a HR of 0.54(95% CI 0.40-0.71) and 0.47 (95% CI 0.34-0.64), respectively. All interactions among MGMT-status, TERT-mutation status and RTL were not statistically significant. Characteristics of recurrent GBM PTS were: median age 55 ys, ECOG PS0-1 in 60% of PTS, MGMTmet in 37%, TERT mutations in 75% (75% C228T, 25% C250T), RTL was 1.67 (range 0.68-8.87). At multivariable analysis, only MGMTmet tumors resulted significantly associated to prolonged OS(HR0.16;95%CI0.07-0.40). No gene interaction was significant.

CONCLUSIONS
we analyzed the impact of TERT mutations, RTL and MGMT in newly diagnosed and recurrent IDH-wildtype GBM PTS. TERT status and RTL were not associated with clinical outcomes. MGMT was the only prognostic factor. No significant interaction was demonstrated between TERT mutations, RTL and MGMT
BIOM-42. IMMUNOHISTOCHEMICAL ASSESSMENT OF MEMBRANOUS SOMATOSTATIN TYPE 2A RECEPTOR (SST2A) EXPRESSION ACROSS HIGH-RISK PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Lazow Margot , Trout Andrew , Fuller Christine , Reuss Jaime , Turpin Brian , Stanek Joseph , Szabo Sara , Salloum Ralph 
Published: November 2021

Abstract

INTRODUCTION
77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A.

METHODS
SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (&lt; 10%), 2 (10-50%), 3 (51-80%), or 4 (&gt;80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12).

RESULTS
A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033).

CONCLUSIONS
High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.
CBIO-24. NF2 LOSS-OF-FUNCTION COOPERATES WITH HYPOXIA TO DRIVE RADIATION RESISTANCE IN GRADE 2 MENINGIOMAS
Authors: Patel Bhuvic , Mahlokozera Tatenda , Lu Hsiang-Chih , Yang Alicia , Mao Diane , Sinha Namita , Dahiya Sonika , Petti Allegra , Patel Akash , Kim Albert 
Published: November 2021

Abstract
World health organization grade 2 meningiomas (G2M) are associated with an aggressive natural history characterized by frequent recurrence, resistance to radiation therapy (RT), and poor survival. We and others have shown that intratumoral necrosis is an independent predictor of disease progression in G2Ms treated with RT, suggesting that necrosis is a histopathological biomarker of radiation resistance. However, the mechanisms of radiation resistance in G2M remain unclear and treatment of radioresistant G2M is challenging. We performed genetic sequencing and histopathological analysis of 121 G2Ms and found that NF2 mutations are associated with intratumoral necrosis. To further investigate the relationship between NF2 loss-of-function, necrosis, and radiation resistance, we developed an in vitro model system using the IOMM-Lee meningioma cell line. In clonogenic survival assays, we found that NF2 knockdown under normoxia had little to no effect on radiation resistance compared to control. However, in the setting of hypoxia, NF2 knockdown significantly increased radiation resistance by maintaining cellular proliferation without impacting cell death. To understand the molecular basis of NF2 loss-of-function on radiation resistance, we performed bulk RNA sequencing of cells in our in vitro hypoxia/RT model and 10 patient G2Ms (5 necrotic and 5 non-necrotic tumors). GO and KEGG pathway analysis of the in vitro dataset revealed that NF2 deficiency triggers upregulation of pathways involved in DNA damage repair and cellular proliferation. Integration of differentially expressed genes between the in vitro NF2 loss-of-function model and necrotic patient tumors identified shared upregulation of S100A4, which promotes cell cycle progression, and downregulation of WNK2, a cell proliferation inhibitor. Together, these results suggest NF2 loss-of-function in the setting of hypoxia confers radiation resistance through a transcriptional program that promotes proliferation and DNA repair.
RADT-01. COMPARATIVE STUDY OF LOCAL CONTROL FOR BRAIN METASTASIS BETWEEN PRE-FRAME AND POST-FRAME MRI METHODS OF GAMMA KNIFE STEREOTACTIC RADIOSURGERY
Authors: Hori Yusuki , Felton Peter , Atik Ahmet , Wei Wei , Mohammadi Alireza , Angelov Lilyana , Yu Jennifer , Murphy Erin , Chao Samuel , Suh John , Barnett Gene 
Published: November 2021

Abstract

INTRODUCTION
Gamma Knife radiosurgery (GKRS) is an established treatment modality in the management of brain metastasis (BM). The standard treatment flow includes frame placement followed by obtaining a post-frame MRI for planning. However, there has been a shift in practice towards using the pre-frame MRI method. It shortens the frame-wearing time while improving quality of imaging/targeting by decreasing artifacts by screws. However, no previous studies have compared the GKRS outcome between the pre- and post-frame MRI methods.

METHODS
134 patients (61 pre-frame and 73 post-frame) with 307 BMs treated with first time GKRS were reviewed retrospectively. We defined local failure (LF) as ≥ 20% increase in maximum diameter (RECIST criteria). Kaplan-Meier and Gray’s method were used to estimate and compare cumulative incidence rate of LF between the groups; multivariable analysis for time-to-local failure (TTLF) was performed using Cox frailty model. The number of lesions was intrinsically modeled in frailty model.

RESULTS
There was no significant difference between the groups for background variables including age, gender, primary cancer, performance status, and number of lesions. Post-frame group had significantly smaller tumors at baseline (p=0.004). The cumulative incidence rates of LF for pre- vs post-frame groups were 1.6% vs 5.5% at 6 month, 6.9% vs 9.9% at 12 month, and 10.4% vs 17.4% at 24 month, respectively, without significant differences (p=0.84). Using multivariate frailty Cox model adjusting for age, gender, and lesion size, extracranial metastasis (HR 4.13, 95%CI 1.48‒11.57, p=0.007) was the significant prognostic factor for TTLF, while the frame type was not significant (p=0.46).

CONCLUSIONS
This is the first report comparing the GKRS outcome of pre- and post-frame MRI methods. The results indicated that pre-frame MRI method conveys a comparable local control for BM while maintaining practical benefits such as shortened frame-wearing time, less-artifact imaging, and longer preparation time available for planning.