Experimental iodine-125 seed irradiation of intracerebral brain tumors in nude mice

<p>Abstract</p> <p>Background</p> <p>High-dose radiotherapy is standard treatment for patients with brain cancer. However, in preclinical research external beam radiotherapy is limited to heterotopic murine models– high-dose radiotherapy to the murine head is fatal due to radiation toxicity. Therefore, we developed a stereotactic brachytherapy mouse model for high-dose focal irradiation of experimental intracerebral (orthotopic) brain tumors.</p> <p>Methods</p> <p>Twenty-one nude mice received a hollow guide-screw implanted in the skull. After three weeks, 5 × 10⁵U251-NG2 human glioblastoma cells were injected. Five days later, a 2 mCi iodine-125 brachytherapy seed was inserted through the guide-screw in 11 randomly selected mice; 10 mice received a sham seed. Mice were euthanized when severe neurological or physical symptoms occurred. The cumulative irradiation dose 5 mm below the active iodine-125 seeds was 23.0 Gy after 13 weeks (BED_tumor= 30.6 Gy).</p> <p>Results</p> <p>In the sham group, 9/10 animals (90%) showed signs of lethal tumor progression within 6 weeks. In the experimental group, 2/11 mice (18%) died of tumor progression within 13 weeks. Acute side effects in terms of weight loss or neurological symptoms were not observed in the irradiated animals.</p> <p>Conclusion</p> <p>The intracerebral implantation of an iodine-125 brachytherapy seed through a stereotactic guide-screw in the skull of mice with implanted brain tumors resulted in a significantly prolonged survival, caused by high-dose irradiation of the brain tumor that is biologically comparable to high-dose fractionated radiotherapy– without fatal irradiation toxicity. This is an excellent mouse model for testing orthotopic brain tumor therapies in combination with radiation therapy.</p

Influence of severity and level of injury on the occurrence of complications during the subacute and chronic stage of traumatic spinal cord injury:a systematic review

Objective: Secondary health conditions (SHCs) are long-term complications that frequently occur due to traumatic spinal cord injury (tSCI) and can negatively affect quality of life in this patient population. This study provides an overview of the associations between the severity and level of injury and the occurrence of SHCs in tSCI. Methods: A systematic search was conducted in PubMed and Embase that retrieved 44 studies on the influence of severity and/or level of injury on the occurrence of SHCs in the subacute and chronic phase of tSCI (from 3 months after trauma). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: In the majority of studies, patients with motor-complete tSCI (American Spinal Injury Association [ASIA] Impairment Scale [AIS] grade A or B) had a significantly increased occurrence of SHCs in comparison to patients with motor-incomplete tSCI (AIS grade C or D), such as respiratory and urogenital complications, musculoskeletal disorders, pressure ulcers, and autonomic dysreflexia. In contrast, an increased prevalence of pain was seen in patients with motor-incomplete injuries. In addition, higher rates of pulmonary infections, spasticity, and autonomic dysreflexia were observed in patients with tetraplegia. Patients with paraplegia more commonly suffered from hypertension, venous thromboembolism, and pain. Conclusions: This review suggests that patients with a motor-complete tSCI have an increased risk of developing SHCs during the subacute and chronic stage of tSCI in comparison with patients with motor-incomplete tSCI. Future studies should examine whether systematic monitoring during rehabilitation and the subacute and chronic phase in patients with motor-complete tSCI could lead to early detection and potential prevention of SHCs in this population

Spatial concordance of DNA methylation classification in diffuse glioma.

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. RESULTS: Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. CONCLUSION: Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists

Clinical, radiologic, pathologic, and molecular characteristics of long-term survivors of diffuse intrinsic pontine glioma (DIPG): a collaborative report from the International and European Society for Pediatric Oncology DIPG registries

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of &lt; 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age &lt; 3 or &gt; 10 years (11% v 3% and 33% v 23%, respectively; P &lt; .001) and with longer symptom duration ( P &lt; .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002). Conclusion We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

A patient with an odontoid fracture and atrophy of the tongue: a case report and systematic review of the literature

BACKGROUND: Traumatic hypoglossal nerve palsy is a rare entity and has rarely been described in association with an odontoid fracture. CASE DESCRIPTION: We present a patient with a posttraumatic odontoid fracture who developed selective weakness of his arms and a unilateral hypoglossal nerve palsy. A systematic review of the literature is presented, and hypothetical causes for the injury are discussed. CONCLUSION: Bell's cruciate paralysis and central cord syndrome are probably expressions of the same mechanism rather than 2 separate entities based on a preferential damage of pyramidal crossing arm fibers. C2 fractures with concomitant lower cranial nerve injury are relatively rare and have a reasonably good outcome, especially when unilateral

Experimentally induced autonomic neuropathy: Beneficial effect of a systemic ACTH4-9 analogue on oculomotor nerve regeneration

While the regenerating capacity of peripheral nerves has been the subject of intensive study, little is known about the regenerative capacity of the autonomic nervous system. Using an animal model, where the pupil diameter of the eye in the rat serves as a parameter of autonomic function, we studied whether systemic treatment with the neuropeptide Org 2766, a synthetic ACTH4-9, analogue, facilitates the functional recovery of parasympathetic nerve fibres after transection, and after a crush lesion of the oculomotor nerve. By simply photographing the rat's pupil under standardised conditions, we show that sectioning the oculomotor nerve leads to an immediate mydriasis, followed by spontaneous regeneration in 30 days. Systemic treatment with an ACTH4-9 analogue had no effect on the rate or quality of recovery. However, systemic treatment with an ACTH4-9 analogue after a crush lesion of the oculomotor nerve (spontaneous regeneration time 16 days) did enhance the speed of recovery of the parasympathetic nerve fibres in the oculomotor nerve, especially in the initial stages of regeneration. We conclude that the animal model used in this study is valuable for studying the regenerative capacity of the autonomic nervous system and the influence of neurotrophic peptides on autonomic neuropathies. Evidence is presented that synthetic ACTH4-9 analogue exerts beneficial neurotrophic effects, not only in peripheral sensorimotor neuropathies but also in autonomic neuropathies

Deep learning-based preoperative predictive analytics for patient-reported outcomes following lumbar diskectomy: feasibility of center-specific modeling

Background Context: There is considerable variability in patient-reported outcome measures following surgery for lumbar disk herniation. Individualized prediction tools that are derived from center- or even surgeon-specific data could provide valuable insights for shared decision-making. Purpose: To evaluate the feasibility of deriving robust deep learning-based predictive analytics from single-center, single-surgeon data. Study Design: Derivation of predictive models from a prospective registry. Patient Sample: Patients who underwent single-level tubular microdiskectomy for lumbar disk herniation. Outcome Measures: Numeric rating scales for leg and back pain severity and Oswestry Disability Index scores at 12 months postoperatively. Methods: Data were derived from a prospective registry. We trained deep neural network-based and logistic regression-based prediction models for patient-reported outcome measures. The primary endpoint was achievement of the minimum clinically important difference (MCID) in numeric rating scales and Oswestry Disability Index, defined as a 30% or greater improvement from baseline. Univariate predictors of MCID were also identified using conventional statistics. Results: A total of 422 patients were included (mean [SD] age: 48.5 [11.5] years; 207 [49%] female). After 1 year, 337 (80%), 219 (52%), and 337 (80%) patients reported a clinically relevant improvement in leg pain, back pain, and functional disability, respectively. The deep learning models predicted MCID with high area-under-the-curve of 0.87, 0.90, and 0.84, as well as accuracy of 85%, 87%, and 75%. The regression models provided inferior performance measures for each of the outcomes. Conclusions: Our study demonstrates that generating personalized and robust deep learning-based analytics for outcome prediction is feasible even with limited amounts of center-specific data. With prospective validation, the ability to preoperatively and reliably inform patients about the likelihood of symptom improvement could prove useful in patient counselling and shared decision-making