Inter-Rater Reliability and Correlation of L1 Hounsfield Unit Measurements with DXA Scores.

INTRODUCTION: While prior studies have generally reported rigorous protocols using prespecified CT scanner settings for HU measurements, the present study sought to report on the correlation between DXA and HUs recorded using several CT scanners with varying sequences, simulating measurements performed in "real-world" hospital and Emergency Department (ED) settings. METHODOLOGY: Six raters performed HU measurements of trabecular bone at the L1 vertebral body for forty consecutive patients on Phillips and General Electric (GE) abdominal CT scans obtained between 2017 and 2021. Inter-rater reliability of the HU measurements and their correlations with recorded DXA-based bone assessments were determined. Correlation coefficients were calculated for the HU measurements between scanner vendors as well as for the CT HUs with each DXA measurement. RESULTS: The ICC for L1 HUs read on the Phillips and GE scanners were 0.85 and 0.82, respectively, indicating excellent agreement. The correlation coefficient for the mean HUs on the Phillips and GE scanners was 0.92, also indicating excellent correlation. For both scanner vendors, the HU values most closely correlated with the total femur and femoral neck T-scores. CONCLUSIONS: HU values recorded on a Phillips and GE scanner both demonstrated excellent inter-rater reliability. Correlations were strongest between L1 HU values and total femur DXA T-scores. Readily available abdominal CT image data across multiple hospital settings can be utilized by providers of varying level of imaging interpretation expertise to determine vertebral body Hounsfield units that may help identify osteoporosis risk without additional radiation exposure or cost.

Clinical advances in oncolytic virotherapy for pediatric brain tumors.

Malignant brain tumors constitute nearly one-third of cancer diagnoses in children and have recently surpassed hematologic malignancies as the most lethal neoplasm in the pediatric population. Outcomes for children with brain tumors are unacceptably poor and current standards of care-surgical resection, chemotherapy, and radiation-are associated with significant long-term morbidity. Oncolytic virotherapy has emerged as a promising immunotherapy for the treatment of brain tumors. While the majority of brain tumor clinical trials utilizing oncolytic virotherapy have been in adults, five viruses are being tested in pediatric brain tumor clinical trials: herpes simplex virus (G207), reovirus (pelareorep/Reolysin), measles virus (MV-NIS), poliovirus (PVSRIPO), and adenovirus (DNX-2401, AloCELYVIR). Herein, we review past and current pediatric immunovirotherapy brain tumor trials including the relevant preclinical and clinical research that contributed to their development. We describe mechanisms by which the viruses may overcome barriers in treating pediatric brain tumors, examine challenges associated with achieving effective, durable responses, highlight unique aspects and successes of the trials, and discuss future directions of immunovirotherapy research for the treatment of pediatric brain tumors.

Evaluation of immunologic parameters in canine glioma patients treated with an oncolytic herpes virus.

Aim: To molecularly characterize the tumor microenvironment and evaluate immunologic parameters in canine glioma patients before and after treatment with oncolytic human IL-12-expressing herpes simplex virus (M032) and in treatment naïve canine gliomas. Methods: We assessed pet dogs with sporadically occurring gliomas enrolled in Stage 1 of a veterinary clinical trial that was designed to establish the safety of intratumoral oncoviral therapy with M032, a genetically modified oncolytic herpes simplex virus. Specimens from dogs in the trial and dogs not enrolled in the trial were evaluated with immunohistochemistry, NanoString, Luminex cytokine profiling, and multi-parameter flow cytometry. Results: Treatment-naive canine glioma microenvironment had enrichment of Iba1 positive macrophages and minimal numbers of T and B cells, consistent with previous studies identifying these tumors as immunologically "cold". NanoString mRNA profiling revealed enrichment for tumor intrinsic pathways consistent with suppression of tumor-specific immunity and support of tumor progression. Oncolytic viral treatment induced an intratumoral mRNA transcription signature of tumor-specific immune responses in 83% (5/6) of canine glioma patients. Changes included mRNA signatures corresponding with interferon signaling, lymphoid and myeloid cell activation, recruitment, and T and B cell immunity. Multiplexed protein analysis identified a subset of oligodendroglioma subjects with increased concentrations of IL-2, IL-7, IL-6, IL-10, IL-15, TNFα, GM-CSF between 14 and 28 days after treatment, with evidence of CD4+ T cell activation and modulation of IL-4 and IFNγ production in CD4+ and CD8+ T cells isolated from peripheral blood. Conclusion: These findings indicate that M032 modulates the tumor-immune microenvironment in the canine glioma model.

The One Health Consortium: Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Combination With a Checkpoint Inhibitor in Canine Patients With Sporadic High Grade Gliomas.

As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct "head-to-head" comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that "toggle" TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.

Impact of exercise on bone mineral density, fall prevention, and vertebral fragility fractures in postmenopausal osteoporotic women.

Osteoporosis is the most prevalent bone disease worldwide and predisposes affected individuals to fragility fractures. Exercise has been shown to have multiple health benefits in post-menopausal osteoporotic women, but often recommendations regarding the benefits of specific exercise types are vague. Improving bone mineral density (BMD) is an essential component in any program to prevent osteoporotic vertebral fractures. The objective of this report is to briefly review the current understanding on the impact of exercise on BMD in postmenopausal women as it pertains to fragility fractures. Broad categories of exercises include aerobic, resistance, stretching, and balance. Tai Chi, Yoga, and Pilates are a heterogeneous group of specific exercise modalities that can span multiple categories. Current literature suggests that only resistance type exercises have a convincing impact on BMD. Core-strengthening exercises and attention to posture/balance can help mitigate falls. A number of barriers affect patient compliance and accessibility to exercise. In summary, exercise should be included in any multi-modality osteoporosis treatment plan with the goal of sustained exercise throughout life. If possible, osteoporotic women should be on a resistance-based regimen incorporating weight-bearing exercises, and also target posture and balance. Healthcare providers and educators should have resources readily available for patients.

Repeat gamma knife stereotactic radiosurgery in the treatment of trigeminal neuralgia: A single-center experience and focused review of the literature.

OBJECTIVES: Repeat Gamma Knife stereotactic radiosurgery (GKSR) for refractory trigeminal neuralgia (TGN) is an increasingly common practice. Prior studies have reported varying success rates and incidence of trigeminal nerve dysfunction following repeated GKSR. We report treatment outcomes and toxicity in patients following repeat GKSR for TGN at the University of Alabama at Birmingham (UAB) with a focused review of the literature. METHODS: We retrospectively reviewed medical records of 55 TGN patients re-treated with radiosurgery using the Leksell Gamma Knife® at the University of Alabama at Birmingham between 1996 and 2012. Outcomes were defined using the Modified Marseille Scale. Demographics, prior treatments and symptom duration were correlated with outcomes. RESULTS: Eighteen patients (33%) achieved Marseille Class I or II, 14 (25%) Class III or IV, and 23 (42%) Class V at a mean follow-up of 14.4 months. Twenty-five patients (45%) developed new trigeminal nerve dysfunction after re-treatment. Of these, four (16%) did not develop dysfunction until subsequent microvascular decompression (MVD) for inadequate symptom relief. CONCLUSIONS: Although more than half of the patients undergoing repeat GKSR for refractory TGN maintained excellent or good outcomes (Marseille classes I-IV) at an average follow-up of 14.4 months, neither age, gender, nor pre-treatment duration of symptoms or interval between treatments had a statistically significant effect on outcomes. Following repeat GKSR, patients have increased risk for new-onset trigeminal nerve dysfunction and those undergoing MVD after repeat GKSR may have an increased risk for new-onset trigeminal nerve dysfunction.

Prospective and Multicenter Evaluation of Outcomes for Quality of Life and Activities of Daily Living for Balloon Kyphoplasty in the Treatment of Vertebral Compression Fractures: The EVOLVE Trial.

BACKGROUND: Osteoporotic and neoplastic vertebral compression fractures (VCF) are common and painful, threatening quality of life and increasing risk of morbidity and mortality. Balloon kyphoplasty is a percutaneous option for treating painful cancer- and osteoporosis-related VCFs, supported by 2 randomized trials demonstrating efficacy benefits of BKP over nonsurgical care. OBJECTIVE: To investigate 12-mo disability, quality of life, and safety outcomes specifically in a Medicare-eligible population, representing characteristic patients seen in routine clinical practice. METHODS: A total of 354 patients with painful VCFs were enrolled at 24 US sites with 350 undergoing kyphoplasty. Four coprimary endpoints-Numerical Rating Scale (NRS) back pain, Oswestry Disability Index (ODI), Short Form-36 Questionnaire Physical Component Summary (SF-36v2 PCS), EuroQol-5-Domain (EQ-5D)-were evaluated for statistically significant improvement 3 mo after kyphoplasty. Data were collected at baseline, 7 d, and 1, 3, 6, and 12 mo (www.clinicaltrials.gov registration NCT01871519). RESULTS: At the 3-mo primary endpoint, NRS improved from 8.7 to 2.7 and ODI improved from 63.4 to 27.1; SF-36 PCS was 24.2 at baseline improving to 36.6, and EQ-5D improved from 0.383 to 0.746 (P < .001 for each). These outcomes were statistically significant at every follow-up time point. Five device-/procedure-related adverse events, intraoperative asymptomatic balloon rupture, rib pain, and aspiration pneumonia, and a new VCF 25 d postprocedure, and myocardial infarction 105 d postprocedure were reported and each resolved with proper treatment. CONCLUSION: This large, prospective, clinical study demonstrates that kyphoplasty is a safe, effective, and durable procedure for treating patients with painful VCF due to osteoporosis or cancer.

The incarceration of individuals with severe mental disorders.

This study examines the extent to which severely mentally disabled (SMD) patients in one county mental health system were incarcerated in the local jail and examines characteristics of a sample (N = 30) of such individuals. We found that in the study year, 7.9% of known SMD patients had at least one incarceration in the county jail. Diagnoses were predominantly in the schizophrenia spectrum with 70% also actively abusing substances at the time of incarceration. The majority of crimes were non-violent and substance abuse related. Half of the sample was judged to be candidates for diversion programs. Our findings are consistent with recent literature confirming that substance abusing SMD individuals are at high risk of incarceration and could benefit from integrated mental health and substance abuse treatment.

Changes in antibody and complement production in Xenopus laevis during postmetamorphic development revealed in a primary in vivo or in vitro antibody response.

Xenopus laevis (G-line) mounts a primary plaque forming cell (PFC) response either in vivo or in vitro following challenge with foreign erythrocytes. Methods are described for generating and assaying the response, which specify criteria such as antigen dose, antigen choice, response kinetics, and complement source. The results suggest that at the peak of the primary response (approximately day 6), animals of different ages produce predominantly different 'classes' of antibody which display markedly different complement-fixing characteristics. Antibodies produced by larvae and 4-month-old postmetamorphic animals appear here to be unable to fix either guinea pig complement (GPC') or adult Xenopus complement, but can readily fix complement from 6-month-old Xenopus. The proportion of spleen PFC's producing antibody capable of fixing GPC' progressively increases from about six months to 18 months of age. Possible explanations for such ontogenetic changes are discussed.