bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of calcium to phosphorus ratio in spot urine samples as a practical method to monitor phosphorus intake adequacy in sows
Authors: Grez-Capdeville Mariola , Crenshaw Thomas D
Published: November 2021

The objective of this study was to evaluate the reliability of using Ca to P ratio measured in spot urine samples to assess P intake adequacy in gestating and lactating sows. A total of 36 sows were fed one of six concentrations of dietary total P (0.40%, 0.48%, 0.56%, 0.64%, 0.72%, and 0.80%) from day 7.5 ± 1 after breeding until the end of lactation (day 26.6 ± 1). Dietary Ca to P ratio was maintained constant across treatments at 1.25:1. Total 24-h urine samples were collected in mid- and late gestation (days 77.1 ± 2 and 112.4 ± 1), and early and late lactation (days 4.5 ± 1 and 18.2 ± 1). In parallel to 24-h collections, spot urine samples were collected at three different times (early morning, late morning, and late afternoon) in late gestation and late lactation. Urine Ca and P concentrations were measured and Ca to P ratio was calculated. Sows were classified as P-adequate or P-deficient according to dietary P intake. Urine Ca to P ratio was greater in sows fed P-deficient diets than sows fed P-adequate diets (P < 0.001). Receiver operating characteristic (ROC) curves were used to determine the cutoff values for urine Ca to P ratio to predict P intake adequacy. Three different categories of P intake were defined according to urine Ca to P ratio: deficient, adequate, and excessive. The area under the ROC for Ca to P ratio was 0.88 (95% CI 0.81 to 0.95). Best cutoff value of urine Ca to P ratio was 1.5 (sensitivity 94% and specificity 68%) to identify sows fed P-deficient diets and 0.5 for P-excessive diets (sensitivity 82% and specificity 82%). A strong relationship between Ca to P ratio in 24-h and spot urine samples was determined (r = 0.93, P < 0.01), independent of physiological state and collection time of spot samples (adjusted-R2 = 0.86, P < 0.01). The degree of agreement between spot and 24-h urine for P intake adequacy, assessed by Cohen’s weighted kappa analysis, was substantial (0.78, 95% CI 0.69 to 0.88). We conclude that urinary Ca to P ratio provides a reliable prediction of the adequacy of P intake in reproducing sows. Urinary Ca to P ratio measurements in random spot urinary offers a practical method to determine dietary P adequacy.
Relationship between energy intake and growth performance and body composition in pigs selected for low backfat thickness
Authors: Liu Fan , Brewster Christopher J , Gilmour Samantha L , Henman David J , Smits Robert J , Luxford Brian G , Dunshea Frank R , Pluske John R , Campbell Roger G
Published: November 2021

Genetic selection of pigs over recent decades has sought to reduce carcass fat content to meet consumer demands for lean meat in many countries (e.g., Australia). Due to the impacts of genetic changes, it is unknown whether the carcass fat measures are still responsive to energy intake. Thus, the present experiment aimed to quantify the relationship between tissue composition and dietary energy intake in finisher pigs selected for low carcass backfat. Intact male and female pigs (n = 56 for each sex; Primegro Genetics, Corowa, NSW, Australia) were fed seven different amounts of an amino acid adequate wheat-based diet containing 14.3 MJ digestible energy (DE)/kg to provide the following daily DE intakes- 25.8, 29.0, 32.6, 35.3, 38.5, 41.5, and 44.2 (ad libitum) MJ DE/d for males, and 25.8, 28.9, 32.0, 35.6, 38.3, 40.9, and 44.5 (ad libitum) MJ DE/d for females between 60 and 108 kg live weight. Body composition of anesthetized pigs was measured using the dual energy X-ray absorptiometry (DXA) method when individual pigs reached 108 kg, and protein, fat, and ash deposition rates were calculated. Pigs were slaughtered on the second day post-DXA scan for carcass backfat measurement. The results showed that the carcass backfat thickness (standardized at 83.7 kg carcass) increased by 0.125 mm for every MJ increase in daily DE intake in male pigs (P = 0.004; R2 = 0.130), but carcass backfat of female pigs (standardized at 85.1 kg carcass) was not responsive to daily DE intake. Whole-body fat composition and fat deposition rate increased linearly (both P < 0.01) in male pigs but quadratically (both P < 0.01) in female pigs in response to DE intake. Every MJ increase of daily DE intake increased the rate of daily protein deposition by 3.8 g in intact male pigs (P < 0.001; R2 = 0.781) and by 2.5 g in female pigs (P < 0.001; R2 = 0.643). In conclusion, the selection for low backfat thickness over the last two decades has altered the response of fat deposition and backfat thickness to energy intake, particularly in female pigs. Despite this change, the linear relationship between DE intake and protein deposition rate was maintained in these modern genetics.
Physical Rehabilitation and Mental Health Care After Burn Injury: A Multinational Study
Authors: Kazis Lewis E , Sager Alan , Bailey Hannah M , Vasudevan Ananya , Garrity Brigid , Tompkins Ronald G
Published: November 2021

While remarkable improvements have been made to acute hospital burn care in recent decades, it is not matched by improvements in post-acute care, including physical rehabilitation and mental health. Progress in acute hospital treatment of burn survivors now highlights the next important step—addressing care once a patient leaves intensive treatment and is discharged to the community. Long-term physical rehabilitation and mental health services are vital to improving quality of life for burn survivors. Using qualitative methods, we apply an adapted Reeve framework to assess and compare post-acute physical rehabilitation and mental health care across 13 countries on 6 continents. Twenty semistructured interviews were conducted with burn surgeons and rehabilitation specialists. One major theme that emerged was the importance of training and resources to the quality of post-acute care. This exploratory study suggests the value of investing scarce resources in a range of low-cost interventions to improve follow-up burn care. One intervention identified here is short-term training in post-acute rehabilitation and mental health to upgrade and standardize best clinical practices to address as-yet unmet post-discharge needs of burn survivors.
Most Prominent Factors Contributing to Burn Injury-Related Amputations: An Analysis of a Referral Burn Center
Authors: Gurbuz Kayhan , Demir Mete , Basaran Abdulkadir , Das Koray
Published: November 2021

Amputations are uncommon surgical procedures in patients with severe burn injuries. However, these patients often face extreme physical and psychological challenges that result in social stigmatization and inadequate rehabilitation facilities. A retrospective cohort study was designed for the patients admitted to the Burn Center of Adana City Training and Research Hospital (ACTRH). During the study period, 2007 patients aged 0.5 to 92 years were hospitalized at the burn center from January 2016 to June 2020. The incidence of amputation observed among inpatient burn injuries regardless of the etiology was 1.9%, and 87.2% were male. The univariate and multivariate logistic regression analyses were performed to detect the most prominent factors contributing to burn-related amputations. Considering the leading factors of amputations in patients with severe burns, the cause of burns appears to be one of the main factors in past research, and electrical burns were prominent in this context. Also, “the fire-flame-related burns,” “full-thickness burns,” “the presence of infection,” “male gender,” “patients within the 18 to 64 age group,” and “the burns involved 10% to < 50% of total body surface area (TBSA)” were found to be the most prominent factors of amputations among patients having severe burns. Although they are rare, amputations related to burns commonly cause a decrease in quality of life. Therefore, besides increasing occupational health and safety methods for these risk groups, especially for adults of working age; also, it is essential to increase the importance and awareness of the precautions to be taken in daily life.
A Review of the Most Impactful Published Pharmacotherapy-Pertinent Literature of 2019 and 2020 for Clinicians Caring for Patients With Thermal or Inhalation Injury
Authors: Hill David M , Boyd Allison N , Zavala Sarah , Adams Beatrice , Reger Melissa , Maynard Kaylee M , Adams Tori R , Drabick Zachary , Carter Kristen , Johnson Heather A , Alexander Kaitlin M , Smith Lisa , Frye Jared , Gayed Rita M , Quan Asia N , Walroth Todd A
Published: November 2021

Keeping abreast with current literature can be challenging, especially for practitioners caring for patients sustaining thermal or inhalation injury. Practitioners caring for patients with thermal injuries publish in a wide variety of journals, which further increases the complexity for those with resource limitations. Pharmacotherapy research continues to be a minority focus in primary literature. This review is a renewal of previous years’ work to facilitate extraction and review of the most recent pharmacotherapy-centric studies in patients with thermal and inhalation injury. Sixteen geographically dispersed, board-certified pharmacists participated in the review. A MeSH-based, filtered search returned 1536 manuscripts over the previous 2-year period. After manual review and exclusions, only 98 (6.4%) manuscripts were determined to have a potential impact on current pharmacotherapy practices and included in the review. A summary of the 10 articles that scored highest are included in the review. Nearly half of the reviewed manuscripts were assessed to lack a significant impact on current practice. Despite an increase in published literature over the previous 2-year review, the focus and quality remain unchanged. There remains a need for investment in well-designed, high impact, pharmacotherapy-pertinent research for patients sustaining thermal or inhalation injuries.
Coverage, Usage, Physical Integrity, and Bio-efficacy of Olyset Nets in the Plateau Region, South Benin Following the 2011 Nationwide Distribution
Authors: Sovi Arthur , Gnanguenon Virgile , Azondekon Roseric , Oké-Agbo Frédéric , Houevoessa Speraud , Salako Albert S , Akinro Bruno , Govoetchan Renaud , Ossé Razaki , Tokponnon Filémon , Padonou Gil G , Akogbéto Martin C
Published: November 2021

The present study investigated in 8 villages of the Plateau region the coverage, usage, physical integrity, and bio-efficacy of the Olyset nets distributed nationwide by the Benin's National Malaria Control Programme in July 2011. The questionnaire administered as well as the observations made in the households allowed estimating the coverage and usage rates of the 2011 Olyset nets. While their physical integrity was assessed through standard WHO methodology, their bio-efficacy was evaluated through gas chromatography, and WHO cone testing performed with the Kisumu susceptible strain. Mosquito collections through human landing catches (HLCs) were also performed in torn nets to assess if a loss of protection of sleepers occurred as the nets fabric integrity got more damaged. Nine months postdistribution, the coverage and usage rates of the 2011 Olyset nets were 67.4% (95% CI: 65.8–68.9) and 73.3% (95% CI: 70.7–75.8) respectively. About 28% of the 2011 Olyset nets were torn. A drastic drop of the insecticide quantity on the fibers of the nets [from 7.08 µg (95% CI: 5.74–8.42) to 0.2 µg (95% CI: 0.01–0.38)] as well as mortality rates <80% were observed with most nets evaluated. Moreover, the biting rates of An. gambiae s.l. (Diptera: Culicidae) inside torn nets increased in line with their fabric integrity loss. These data support the conclusion that future deployment of nets in the field must be strengthened by community sensitization on their correct use in order to postpone as much as possible appearance of holes and loss of insecticidal activity and encourage repairing of torn nets.
Involvement of Follicular Patency in the Ovarian Developmental Block in Virus-infected, MdSGHV, House Flies, Musca domestica (Diptera: Muscidae)
Authors: Fagan Shawheen , Ramirez Arianna , Serdy Sara , Stoffolano John G
Published: November 2021

The Musca domestica salivary gland hypertrophy virus (MdSGHV) is known to have marked effects on the female Musca domestica L. (or common house fly) reproductive system, particularly regarding the size and functionality of the ovaries. Examination of the terminal ovarian follicles can help determine if and how MdSGHV mechanistically causes the block in ovarian development. In this study, terminal ovarian follicle lengths were measured and monitored for patency using Trypan blue dye staining. We examined the effect of MdSGHV infection on female house fly ovarian follicles and attempted to rescue the diminished ovarian follicles in MdSGHV-infected house flies through the application of a hormonal treatment (i.e., methoprene). Comparison of patency in control saline-injected females, virus-injected females with no methoprene application, and virus-injected females with topical methoprene application revealed that none of the virus-infected flies showed an increase in terminal follicular length beyond stage 3 follicles (staging according to Adams 1974). Additionally, none showed evidence of patency. In control, saline-injected females, we found the threshold length of the terminal follicles for the onset of patency to be 600 µm. When examined at 48, 72, and 96 h post-eclosion, average follicle length for infected females seldom reached 250 µm and they also failed to display patency. Thus, the virus is somehow involved in shutting down the mechanism involved in follicular patency. The lack of patency in infected follicles may also be one of the determining factors preventing vertical transmission of the pathogen.
Loving Mean: Racialized Medicine and the Rise of Postwar Eugenics in Toni Morrison’sHome
Authors: Fitz Gerald James
Published: November 2021

This essay reads Toni Morrison’s Home (2012) against the backdrop of the United States’ well-documented patterns of unconstrained experimentation on racial-minority patients. The essay focuses specifically on contexts of mid-century eugenics, which exposed black Americans, often women, to nonconsensual and nontherapeutic surgical procedures. I argue that Home is not only informed by these traumatic histories of medical violence but is also able to construct an ethics of care out of them through the imperative of loving mean–a de-idealized love concerned less with sympathy than with survival. In so doing, the novel advances intersubjective forms of healing that challenge the systemic roots of reproductive racism and make possible the potential for meaningful recovery from both physical and historical trauma.
The Effect of Preoperative Behavioral Intervention on Pain, Anxiety, Opioid Use, and Function in Patients Undergoing Total Knee Arthroplasty: A Randomized Controlled Study
Authors: Meyer Vanessa M , Beydoun Hind A , Gyenai Leonora , Goble Nicole M , Hunter Michelle M , McGill Robert J
Published: November 2021

Objective

To evaluate the efficacy of preoperative cognitive-behavioral psychoeducation (CBE) for improved pain, anxiety, opioid use, and postoperative function in total knee arthroplasty (TKA) patients.

Methods

A randomized controlled trial was conducted among 36 military health system beneficiaries attending preoperative education for TKA. The standard of care (SOC) group (n = 18) received information on home safety, rehabilitation, postoperative precautions, and pain management. In addition, the occupational therapy led CBE group (n = 16) received information on principles of holistic wellness (healing process, effects of stress on healing, heart-rate control through diaphragmatic breathing, anti-inflammatory nutrition, goal setting, and mental imagery). Outcomes of interest: knee active range of motion, pain (Defense and Veterans Pain Rating Scale), opioid medication use, heart-rate coherence (emwave2), anxiety (Generalized Anxiety Disorder Scale), and function (Knee Outcome Survey Activities of Daily Living [KOS-ADL], modified Functional Independence Measure, and Global Rate of Change).

Results

The CBE group demonstrated significantly greater decline in pain overall, with activity, and during sleep in relation to the SOC group when comparing visit 1 to visit 5. Opioid medication use was significantly lower for CBE versus SOC. Postoperative General Anxiety Disorder-7 scores decreased significantly among CBE participants with similar increase in high heart rate coherence. Function significantly improved postoperatively based on KOS-ADL and Global Rate of Change scores. Twice as many CBE participants had same-day discharge compared to SOC participants and most CBE participants continued with healthy lifestyle recommendations at the 3-month follow-up.

Conclusion

A cognitive-behavioral approach to preoperative education may improve postoperative pain, anxiety, and function while decreasing opioid use among TKA patients. Findings from this pilot study support further research to examine similar interventions among distinct surgical populations and encourage further evaluation on the effects of CBE to enhance health and healthcare delivery.
Development of a Risk Prediction Model for Assessing Dental Readiness in the Canadian Armed Forces
Authors: Batsos Constantine , Boyes Randy , McIsaac Michael , Webber Colleen , Mahar Alyson
Published: November 2021

Introduction

The establishment and sustainment of a high state of dental readiness in the Canadian Armed Forces (CAF) are the primary missions of the Royal Canadian Dental Corps. The objective of this study was to develop a risk prediction tool to estimate dental readiness in active CAF personnel.

Materials and Methods

The prediction model was developed to predict the classification of non-deployable (yes/no) within 12 months (primary) and 18 months (secondary) using both dental history data (including dental attendance, restorations, root canals, and third molar status) and demographic information. Two cohorts were used for development: a recruit cohort who enrolled between April 2016 and March 2017 and a longer-serving member (LSM) cohort who had their recall dental exam between May 2014 and October 2014. Each group was followed until April 26, 2018. Elastic net logistic regression models were used to create the models. Model performance was evaluated using area under the curve, F1, and the Brier score.

Results

The recruit cohort included 2,828 individuals and the LSM cohort included 2,398 individuals. Overall, the classification of non-deployable occurred in 5.1% of the study population within 12 months and 9.6% of the population within 18 months. The models predicted the outcome with an area under the receiver operating curve of 0.77 in recruits and 0.70 in LSMs.

Conclusion

The prediction model shows potential but its performance and usability could be further improved through the consistent collection of high quality, discretely entered, epidemiological data following standardized diagnostic terminology and coding. A recalibrated and automated version of this model could assist in decision making, resource allocation, and the enhancement of military dental readiness.
Post-Traumatic Stress Disorder Treatment Outcomes in Military Clinics
Authors: Mclay Robert , Fesperman Susan , Webb-Murphy Jennifer , Delaney Eileen , Ram Vasudha , Nebeker Bonnie , Burce Cleo Mae
Published: November 2021

Introduction

Despite a wide literature describing the impact of PTSD on military personnel, there is limited information concerning the results of PTSD treatment within military clinics mental health. Having such information is essential for making predictions about service members’ chances of recovery, choosing best treatments, and for understanding if new interventions improve upon the standard of care.

Materials and Methods

We reviewed data from the Psychological Health Pathways (PHP) database. Psychological Health Pathways is a standardized battery of demographics and psychometric outcome measures, including measurement of PTSD symptom severity, that is collected in military mental health clinics. We examined changes in PTSD symptom severity scores over time and developed logistic regression models to predict who responded to treatment, showed clinical success, or improved to the point that they could likely stay in the military.

Results

After about 10 weeks in mental health clinics, severity scores for PTSD, sleep, depression, resilience, and disability all improved significantly. Of 681 patients tracked, 38% had clinically significant reductions on the PTSD Checklist (PCL) (i.e., “treatment response”), 28% no longer met criteria for PTSD on the PCL, and 23% did both (i.e., “clinical treatment success”). For the ultimate end point of “military treatment success,” defined as meeting criteria for both clinical treatment success and reporting that their work-related disability was mild or better, 12.8% of patients succeeded. Depression scores were the most powerful predictor of treatment failure.

Conclusions

Recovery from PTSD is possible during military service, but it is less likely in individuals with certain negative prognostic factors, most notably severe depression.
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

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

Introduction

Traumatic 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 Methods

Using 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.

Results

We 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.

Conclusions

Emerging 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

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

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

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 < 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

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

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

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 (< 10%), 2 (10-50%), 3 (51-80%), or 4 (>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

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

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.
RADT-14. TOWARDS IMAGE-GUIDED MODELING OF PATIENT-SPECIFIC RHENIUM-186 NANOLIPOSOME DISTRIBUTION VIA CONVECTION-ENHANCED DELIVERY FOR GLIOBLASTOMA MULTIFORME
Authors: Wu Chengyue , Hormuth David , Christenson Chase , Abdelmalik Michael , Phillips William , Hughes Thomas , Brenner Andrew , Yankeelov Thomas
Published: November 2021

Convection-enhanced delivery (CED) of Rhenium-186 nanoliposomes (RNL) is a promising approach to provide precise delivery of large, localized doses of radiation with the goal of extending overall survival for patients with recurrent GBM. A central component of successful CED, is achieving optimal catheter placement for delivery of the therapy. While surgical planning software exists for this purpose, current approaches are designed for small molecules and therefore are not appropriate for larger particles like RNL. To address this concern, we have developed a mathematical model to predict the distribution of RNL via CED on a patient-specific basis. The model is defined on the 3D brain domain which consists of 1) pressure and flow fields generated by accounting for catheter infusion, flow through brain, and fluid loss into capillaries, and 2) the transport of RNL governed by an advection-diffusion equation. We utilize pre-operative MRI to assign patient-specific tissue geometry and properties (e.g., diffusivity, conductivity), and calibrate the model with SPECT measurements within 24 h post the RNL delivery. This model is implemented on one patient enrolled in NCT01906385. The accuracy of model calibration and prediction is evaluated by the Dice score and concordance correlation coefficient (CCC) between modeled and measured distributions of RNL. Our model calibration achieves Dice scores of 0.80, 0.81, 0.69 and CCC of 0.92, 0.93, 0.73 for RNL distributions at the mid-delivery, end of delivery, and 24 h after the delivery, respectively. Long-term model prediction achieves Dice scores of 0.69 and 0.52 at 144 h and 196 h after the delivery, respectively, and CCC of 0.57 and 0.31. Preliminary results demonstrate a proof-of-concept for a patient-specific model to predict the spatiotemporally-resolved distribution of nanoparticles. Ongoing efforts focus on improving our model by accounting backflow and angle of catheter placement, and applying to more patients. Funding: NIH R01CA235800, CPRIT RR160005.