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Study Design: Human bone marrow stem cells (hBMSCs) and human adipose-derived stem cells (hADSCs) have demonstrated the capability to regenerate bone once they have differentiated into osteoblasts., Objective: This systematic review aimed to evaluate the in vitro osteogenic differentiation potential of these cells when seeded in a poly (lactic- co -glycolic) acid (PLGA) scaffold., Methods: A literature search of 4 databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted in January 2021 for studies evaluating the osteogenic differentiation potential of hBMSCs and hADSCs seeded in a PLGA scaffold. Only in vitro models were included. Studies in languages other than English were excluded., Results: A total of 257 studies were identified after the removal of duplicates. Seven articles fulfilled our inclusion and exclusion criteria. Four of these reviews used hADSCs and three used hBMSCs in the scaffold. Upregulation in osteogenic gene expression was seen in all the cells seeded in a 3-dimensional scaffold compared with 2-dimensional films. High angiogenic gene expression was found in hADSCs. Addition of inorganic material to the scaffold material affected cell performance., Conclusions: Viability, proliferation, and differentiation of cells strongly depend on the environment where they grow. There are several factors that can enhance the differentiation capacity of stem cells. A PLGA scaffold proved to be a biocompatible material capable of boosting the osteogenic differentiation potential and mineralization capacity in hBMSCs and hADSCs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: The vertebral column is the most common site for skeletal metastasis, often leading to debilitating pain and weakness. Metastatic cancer has unique genetic drivers that potentiate tumorigenicity. There is an unmet need for novel targeted therapy in patients with spinal metastatic disease., Methods: The authors assessed the effect of verteporfin-induced yes-associated protein (YAP) inhibition on spine metastatic cell tumorigenicity and radiation sensitivity in vitro. Animal studies used a subcutaneous xenograft mouse model to assess the use of systemic intraperitoneal verteporfin (IP-VP) and intratumoral verteporfin microparticles (IT-VP) to inhibit the tumorigenicity of lung and breast spinal metastatic tumors from primary patient-derived tissue., Results: Verteporfin led to a dose-dependent decrease in migration, clonogenicity, and cell viability via inhibition of YAP and downstream effectors cyclin D1, CTGF, TOP2A, ANDRD1, MCL-1, FOSL2, KIF14, and KIF23. This was confirmed with knockdown of YAP. Verteporfin has an additive response when combined with radiation, and knockdown of YAP rendered cells more sensitive to radiation. The addition of verteporfin to YAP knockdown cells did not significantly alter migration, clonogenicity, or cell viability. IP-VP and IT-VP led to diminished tumor growth (p < 0.0001), especially when combined with radiation (p < 0.0001). Tissue analysis revealed diminished expression of YAP (p < 0.0001), MCL-1 (p < 0.0001), and Ki-67 (p < 0.0001) in tissue from verteporfin-treated tumors compared with vehicle-treated tumors., Conclusions: This is the first study to demonstrate that verteporfin-mediated inhibition of YAP leads to diminished tumorigenicity in lung and breast spinal metastatic cancer cells. Targeting of YAP with verteporfin offers promising results that could be translated to human clinical trials.

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin's functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin's cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM.

Background and Aim: Adipose-derived mesenchymal stem cells (ADSCs) have been proven effective to prevent distal skin flap necrosis in preclinical models. However, to appropriately translate these findings to clinical trials, the effect of ADSC of human origin (hADSC) needs to be evaluated. We hypothesize that hADSC treatment is as effective as animal ADSC treatment at preventing distal skin flap necrosis in animal flap models., Methods: Three databases were inquired on August 17, 2020, to evaluate the necrotic flap area after using hADSCs in animal models of ischemic flaps. No publication status or dates were considered. Studies were included if they used hADSCs, measured the surviving or necrotic skin area of flaps, used animal models, and were in English. Studies were excluded if they did not use cells of human origin. The flap survival or necrotic area, perfusion, capillary density, vascular endothelial growth factor secretion and HIF-1α expression were extracted., Results: Ten studies met inclusion criteria. The mean absolute risk reduction (ARR) in necrotic skin area was 22.37% (95% confidence interval [CI] 16.98-27.76%, P <0.05) for flaps treated with animal ADSCs and 18.04% (95% CI 2.74-33.33%, P<0.05) for flaps treated with hADSCs. The difference between mean ARRs was not statistically significant (4.33%, 95% CI - 34.47-43.13%, P >0.05)., Conclusion: Human ADSCs prevent skin flap necrosis to the same degree as animal ADSCs in rodent and rabbit flap models., Relevance for Patients: This review found that adipose-derived stem cells of human origin are equally effective at reducing the risk of surgical flap necrosis in preclinical models of small animals as autologous animal cells. The findings in this review should encourage researchers to use human adipose-derived stem cells in animal models of ischemic flaps to accelerate their translation into clinical trials and, eventually, surgical practice. The low immunogenicity of these cells should be leveraged to gain insight into the effects of the products that will be ultimately administered to patients. Furthermore, human adipose-derived stem cells' pro-angiogenic mechanism of action sets this therapy as a promising preventive measure for flap necrosis., Competing Interests: The authors report no conflicts of interest., (Copyright: © 2022 Whioce Publishing Pte. Ltd.)

Background: Human adipose-derived stem cells (hADSCs) have gained attention lately because of their ease of harvesting and ability to be substantially multiplied in laboratory cultures. Stem cells are usually cultured under atmospheric conditions; however, preconditioning stem cells under hypoxic conditions seems beneficial., Aim: This systematic review aims to investigate the effect of hypoxia preconditioning and its impact on the proliferation and angiogenic capacity of the hADSCs., Methods: We performed a systematic review by searching PubMed, Scopus, Embase, and Google Scholar databases from all years through March 22, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Medical Subject Headings terms "adipose-derived stem cell," "Hypoxia," "cell proliferation," and "angiogenesis" guided our search. Only articles written in English using experimental models comparing a preconditioned group against a control group of hADSCs with data on proliferation and angiogenic capacity were included., Results: Our search yielded a total of 321 articles. 11 articles met our inclusion criteria and were ultimately included in this review. Two studies induced hypoxia using hypoxia-inducible factor-1 alpha stabilizing agents, while nine reached hypoxia by changing oxygen tension conditions around the cells. Four articles conducted in-vivo studies to correlate their in-vitro findings, which proved to be consistent. Although 1 article indicated cell proliferation inhibition with hypoxia preconditioning, the remaining 10 found enhanced proliferation in preconditioned groups compared to controls. All articles showed an enhanced angiogenic capacity of hADSCs after hypoxia preconditioning., Conclusion: In this review, we found evidence to support hypoxia preconditioning of hADSCs before implantation. Benefits include enhanced cell proliferation with a faster population doubling rate and increased secretion of multiple angiogenic growth factors, enhancing angiogenesis capacity., Relevance for Patients: Although regenerative therapy is a promising field of study and treatment in medicine, much is still unknown. The potential for angiogenic therapeutics with stem cells is high, but more so, if we discover ways to enhance their natural angiogenic properties. Procedures and pathologies alike require the assistance of angiogenic treatments to improve outcome, such is the case with skin grafts, muscle flaps, skin flaps, or myocardial infarction to mention a few. Enhanced angiogenic properties of stem cells may pave the way for better outcomes and results for patients., Competing Interests: The authors declare no conflict of interest, (Copyright: © Whioce Publishing Pte. Ltd.)

Background: Archeological archives report cranioplasty as 1 of the oldest surgical procedures; however, it was not until the last century that true advances have been made. Alternative approaches are necessary to achieve optimal closure of the defect with fewer adverse effects. We aim to evaluate the use of human adipose-derived stem cells (hADSCs) alone or seeded in scaffolds as the main treatment for cranial bone defects and to assess human patient outcomes., Methods: A systematic review was performed by querying PubMed, Ovid MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature databases with the MeSH terms: "adipose-derived stem cells," "cranial bone defect," "stromal vascular factor," "fat grafting," as well as synonyms in combinations determined by our search strategy. We included human models that used hADSCs as primary therapy. We excluded studies in languages other than English., Results: One hundred ninety-four studies were identified after removal of duplicates. Four articles that used hADSCs as the main therapy to treat calvarial defects in humans were included. One article applied the cell therapy alone, and 3 used β-tricalcium phosphate granules as a scaffold to seed the hADSCs., Conclusions: Bone regeneration was reached in a short and intermediate period using autologous hADSCs in humans with no major adverse effects in all 4 articles included. A long-term follow-up study (6 years) exhibited late infections and reabsorption of the β-tricalcium phosphate scaffold seeded with hADSCs., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Background: Radiation-induced skin injuries have been treated with different medical therapies and have shown diverse outcomes. We aim to evaluate the effect of adipose-derived stem cells (ADSCs) therapy on radiation-induced skin injury., Methods: We performed a review by querying PubMed, Ovid MEDLINE, and EMBASE databases from inception to April 2020 following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The MeSH terms "adipose-derived stem cells," "wound healing," "radiation," and synonyms in combinations determined our search strategy. Experimental peer-reviewed articles describing the protocol and comparing the results with controls were included. Non-English studies were excluded., Results: Our search recorded a total of 137 articles. Only 8 studies met our inclusion criteria and were included in this review. Five studies evaluated the use of ADSC alone, whereas the others evaluated the efficacy of ADSC seeded in scaffolds. Adipose-derived stem cell-based therapies, either alone or seeded in scaffolds, were shown to improve wound healing in most studies when compared with controls., Conclusions: There is evidence supporting the positive benefits from ADSC-based therapies in radiation-induced skin injury. However, further studies are needed to standardize the method of ADSC extraction, radiation-induced skin injury experimental model, and increase the time of follow-up to evaluate the results accurately., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Glioblastoma (GBM) is the most common primary brain cancer in adults where tumor cell heterogeneity and sex differences influence clinical outcomes. Here, we functionally characterize three male and three female patient-derived GBM cell lines, identify protumorigenic BTICs, and create novel male and female preclinical models of GBM. Cell lines were evaluated on the following features: proliferation, stemness, migration, tumorigenesis, clinical characteristics, and sensitivity to radiation, TMZ, rh TNFSF10 (rhTRAIL), and rh BMP4 All cell lines were classified as GBM according to epigenetic subtyping, were heterogenous and functionally distinct from one another, and re-capitulated features of the original patient tumor. In establishing male and female preclinical models, it was found that two male-derived GBM cell lines (QNS108 and QNS120) and one female-derived GBM cell line (QNS315) grew at a faster rate in female mice brains. One male-derived GBM cell line (QNS108) decreased survival in female mice in comparison with male mice. However, no survival differences were observed for mice injected with a female-derived cell line (QNS315). In summary, a panel of six GBM patient-derived cell lines were functionally characterized, and it was shown that BTIC lines can be used to construct sex-specific models with differential phenotypes for additional studies., (©2021 American Association for Cancer Research.)

The potential to differentiate into different cell lines, added to the easy and cost-effective method of extraction, makes adipose-derived stem cells (ADSCs) an object of interest in lymphedema treatment. Our study's goal was to conduct a comprehensive systematic review of the use of ADSCs in lymphatic tissue engineering and regeneration. On July 23, 2019, using PubMed/MEDLINE, Cochrane Clinical Answers, Cochrane Central Register of Controlled Trials, and Embase databases, we conducted a systematic review of published literature on the use of ADSCs in lymphatic tissue engineering and regeneration. There were no language or time frame limitations, and the following search strategy was applied: ((Adipose stem cell) OR Adipose-derived stem cell)) AND ((Lymphedema) OR Breast Cancer Lymphedema). Only original research manuscripts were included. Fourteen studies fulfilled the inclusion criteria. Eleven studies were experimental (in vitro or in vivo in animals), and only three were clinical. Publications on the topic demonstrated that ADSCs promote lymphangiogenesis, and its effect could be enhanced by modulation of vascular endothelial growth factor-C, interleukin-7, prospero homeobox protein 1, and transforming growth factor-β1. Pilot clinical studies included 11 patients with breast cancer-related lymphedema, and no significant side effects were present at 12-month follow-up. Literature on the use of ADSCs in lymphatic tissue engineering and regeneration demonstrated promising data. Clinical evidence is still in its infancy, but the scientific community agrees that ADSCs can be useful in regenerative lymphangiogenesis. Data collected in this review indicate that unprecedented advances in lymphedema treatment can be anticipated in the upcoming years.

Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival.

Objective: Evaluate a number of biomarkers that can objectively measure the wound healing process, and identify the materials that could replicate this in smart wound dressings., Method: A systematic review was conducted to establish the use of materials sensitive to biomarkers. Publications in English were included. Review articles and abstracts presented at conferences were excluded., Results: A total of 296 studies were identified, of which 19 were included. All of these were experimental studies. The articles evaluated pH, temperature, blood pressure, uric acid, and glucose. The materials used were hydrogels, fibres and conductive inks., Conclusion: The most cited biomarker was pH. Materials that evaluate biomarkers via colorimetric methods could be the most suitable to incorporate into smart wound dressings.

Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor-initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell's neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1-depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.

The complex process of wound healing can be delayed in circumstances when the natural niche is extremely altered. Adipose-derived stem cells (ADSC) seem to be a promising therapy for these type of wounds. We aim to describe the studies that used ADSC for wound healing after a full-thickness skin defect, the ADSC mechanisms of action, and the outcomes of the different ADSC therapies applied to date. We performed a review by querying PubMed database for studies that evaluated the use of ADSC for wound healing. The Mesh terms, adipose stem cells AND (skin injury OR wound healing) and synonyms were used for the search. Our search recorded 312 articles. A total of 30 articles met the inclusion criteria. All were experimental in nature. ADSC was applied directly (5 [16.7%]), in sheets (2 [6.7%]), scaffolds (14 [46.7%]), skin grafts (3 [10%]), skin flaps (1 [3.3%]), as microvesicles or exosomes (4 [13.3%]), with adhesives for wound closure (1 [3.3%]), and in a concentrated conditioned hypoxia-preconditioned medium (1 [3.3%]). Most of the studies reported a benefit of ADSC and improvement of wound healing with all types of ADSC therapy. ADSC applied along with extracellular matrix, stromal cell-derived factor (SDF-1) or keratinocytes, or ADSC seeded in scaffolds showed better outcomes in wound healing than ADSC alone. ADSC have shown to promote angiogenesis, fibroblast migration, and up-regulation of macrophages chemotaxis to enhance the wound healing process. Further studies should be conducted to assure the efficacy and safety of the different ADSC therapies.

Central nervous system (CNS) tumors are a leading source of morbidity and mortality worldwide. Today, different strategies have been developed to allow targeted and controlled drug delivery into the brain. Gene therapy is a system based on the modification of patient's cells through the introduction of genetic material to exert a specific action. Administration of the foreign genetic material can be done through viral-mediated delivery or non-viral delivery via physical or mechanical systems. For brain cancer specifically, gene therapy can overcome the actual challenge of blood brain barrier penetration, the main reason for therapeutic failure. Chitosan (CS), a natural based biodegradable polymer obtained from the exoskeleton of crustaceans such as crab, shrimp, and lobster, has been used as a delivery vehicle in several non-viral modification strategies. This cationic polysaccharide is highly suitable for gene delivery mainly due to its chemical properties, its non-toxic nature, its capacity to protect nucleic acids through the formation of complexes with the genetic material, and its ease of degradation in organic environments. Recent evidence supports the use of CS as an alternative gene delivery system for cancer treatment. This review will describe multiple studies highlighting the advantages and challenges of CS-based delivery structures for the treatment of brain tumors. Furthermore, this review will provide insight on the translational potential of various CS based-strategies in current clinical cancer studies. Specifically, CS-based nanostructures including nanocapsules, nanospheres, solid-gel formulations, and nanoemulsions, also microshperes and micelles will be evaluated., (Copyright © 2020 Lara-Velazquez, Alkharboosh, Norton, Ramirez-Loera, Freeman, Guerrero-Cazares, Forte, Quiñones-Hinojosa and Sarabia-Estrada.)

Current minimally invasive optical techniques for in vivo deep-brain imaging provide a limited resolution, field of view, and speed. These limitations prohibit direct assessment of detailed histomorphology of various deep-seated brain diseases at their native state and therefore hinder the potential clinical utilities of those techniques. Here, we report an ultracompact (580 μm in outer diameter) theranostic deep-brain microneedle combining 800-nm optical coherence tomography imaging with laser ablation. Its performance was demonstrated by in vivo ultrahigh-resolution (1.7 μm axial and 5.7 μm transverse), high-speed (20 frames per second) volumetric imaging of mouse brain microstructures and optical attenuation coefficients. Its translational potential was further demonstrated by in vivo cancer visualization (with an imaging depth of 1.23 mm) and efficient tissue ablation (with a 1448-nm continuous-wave laser at a 350-mW power) in a deep mouse brain (with an ablation depth of about 600 μm)., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background  Chronic tenosynovitis of the upper extremities caused by Mycobacterium kansasii ( M. kansasii ) is uncommon, but symptoms may overlap with other more common diseases. Late diagnosis and treatment can lead to disfiguration of structures and rupture of tendons, resulting in worse cosmetic outcomes after reconstruction. Methods  We present a clinical case and literature review of M. kansasii in patients with chronic tenosynovitis of upper extremities. PubMed was queried for cases of upper extremities tenosynovitis caused by M. kansasii . The keywords " M. kansasii ," "tenosynovitis" and synonyms were used for search in different combinations. Manuscripts, with no specific data or another condition, where the infection was not located in the upper extremities, were reviews, or not in English, were excluded from the study. Results  We described 23 reported cases of tenosynovitis of the upper extremity caused by M. kansasii . An immunosuppressed state was present in eight (34.8%) cases, and 12 (52.2%) patients received immunosuppressive treatment. A long-time period between the first appearance of symptoms and the definitive diagnosis was identified (median: 7 months, interquartile range: 9). The most frequent symptoms were local swelling (65.2%), pain (56.5%), mass effect (26%), and stiffness (13%). Tendon rupture was found in three (13%) patients as a complication of the disease. Moreover, seven (30.4%) patients underwent previous surgeries to try to relieve the symptoms before definitive diagnosis was achieved. Conclusion M. kansasii is an important differential causal pathogen for tenosynovitis of the upper extremities. Although rare, raising awareness about this infectious disease is imperative to avoid inadequate management and hazardous aesthetic sequelae., Competing Interests: Conflict of Interest The reports by A.S.P., A.S., A.J.F., B.D.R., D.B., D.J.R., M.T.H., R.S.-E. and this study were supported in part by the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, by the Mayo Clinic Center of Individualized Medicine, and by the Plastic Surgery Foundation.

Background/aim: Osteosarcoma of the upper extremities is rare, and characteristics in this location have not been described before. We aimed to analyze the characteristics and survival rate of osteosarcoma of the upper extremities., Materials and Methods: A retrospective cohort study was performed by querying the National Cancer Database. Statistical analysis was performed using a multivariate logistic regression model and Kaplan-Meier log-rank tests for survival., Results: A total of 991 patients were diagnosed with osteosarcoma of the upper extremities. Most tumors were osteogenic and osteoblastic (66.8%), larger than 8 cm (47.9%), high grade (64.3%), lymph node-negative (7.9%), and without metastasis to lungs (39.0%). Osteosarcomas of the hand and wrist were less likely to be high-grade when compared to osteosarcomas of the forearm, arm, and shoulder., Conclusion: The results of this study help us to approach patients promptly and avoid total amputation, increasing functionality and prognosis of the disease., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Female athymic nude rats ( Rattus norvegicus ; n = 45; age, 6 wk) were used in an IACUC-approved protocol to investigate mechanisms and potential treatments associated with brain, spine, and spinal cord metastases from triple negative breast cancer. The analgesic plan included the use of buprenorphine SR LAB (0.6 mg/kg; 0.11 mL/rat) subcutaneously and an oral NSAID delivered via the water. Thirty-seven rats reached the experimental end point at 3 mo after xenotransplantation and were euthanized for tissue harvest. Grossly, all 37 rats had nodules in the subcutis over the shoulders; these were identified as small, cystic structures (diameter, approximately 0.25 cm). The cysts and haired skin were submitted for LC-MS/MS (liquid chromatography-tandem mass spectrometry) and histopathology. Histologically, the cysts were lined by fibrous connective tissue mildly infiltrated by macrophages, lymphocytes, and plasma cells. Adjacent blood vessels were rimmed by a mild infiltrate of lymphocytes and plasma cells. The cysts contained variable accumulations of a light pink, proteinaceous fluid. The cause for the cysts could not be determined histologically; there was no evidence of neoplasia. LC-MS/MS analysis revealed that the cysts contained buprenorphine. We hypothesize that the lack of T cells and a cell-mediated immune response in these rats prevented the dissolution of the vehicle and absorption of the buprenorphine. The manufacturer provides a cautionary statement regarding the use of this formulation in nude mice due to skin reactions, but to our knowledge, this report is the first description of an apparent lack of absorption of the drug in immunodeficient animals.

Purpose: This study seeks to ascertain whether different primary tumor types have a propensity for brain metastases (BMs) in different cerebral vascular territories and cerebral edema., Methods: Consecutive adult patients who underwent surgical resection of a BM at a tertiary care institution between 2001 and 2011 were retrospectively reviewed. Only patients with the most common primary cancers (lung, breast, skin-melanoma, colon, and kidney) were included. Preoperative MRIs were reviewed to classify all tumors by cerebral vascular territory (anterior cerebral artery-ACA, lenticulostriate, middle cerebral artery-MCA, posterior cerebral artery-PCA, posterior fossa, and watershed), and T2-weighted FLAIR widths were measured. Chi square analyses were performed to determine differences in cerebral vascular distribution by primary tumor type, and one-way ANOVA analyses were performed to determine FLAIR signal differences., Results: 669 tumors from 388 patients were classified from lung (n = 316 BMs), breast (n = 144), melanoma (n = 119), renal (n = 47), and colon (n = 43). BMs from breast cancer were less likely to be located in PCA territory (n = 18 [13%]; χ 2  = 6.10, p = 0.01). BMs from melanoma were less likely to be located in cerebellar territory (n = 11 [9%]; χ 2  = 14.1, p < 0.001), and more likely to be located in lateral (n = 5 [4%]; χ 2  = 4.56, p = 0.03) and medial lenticulostriate territories (n = 2 [2%]; χ 2  = 6.93, p = 0.009). BMs from breast and melanoma had shorter T2-FLAIR widths, with an average [IQR] of 47.2 [19.6-69.2] mm (p = 0.01) and 41.2 [14.4-62.7] mm (p = 0.002) respectively. Conversely, BMs from renal cancer had longer T2-FLAIR widths (64.2 [43.6-80.8] mm, p = 0.002)., Conclusions: These findings suggest that different primary tumor types could have propensities for different cerebral vascular territories and cerebral edema.

Ninety percent of deaths from solid tumors have been ascribed to the invasion and metastatic dissemination of cancer cells. One of the most fundamental prerequisites of brain tumor stem cell invasion is their ability to penetrate and traverse through the basement membrane and stromal compartments displacing from their original point of origin and repopulating at a distant site and adjacent tissue. In order to propose a successful clinical strategy, the investigation of the molecular determinants of invasion must factor in measurements and predictors of the complexity of brain tumor invasion potential accounting for the physiological scenarios encountered in the tumor niche. This chapter will highlight some laboratory approaches such as: spot assay, 3D chemogradient chambers, Fluoroblok™ tumor invasion, organotypics, and 3D tumor spheroid assays that could help mitigate the investigation of a tumor stem cell's invasion capacity through restrictive 3D environments otherwise seen in vivo.

Studies have demonstrated that buprenorphine, a front line drug for veterinary analgesia, may alleviate symptoms of chronic pain. A cage side observation protocol was used to record behavioral signs in a mouse clinical trial of extended release buprenorphine. A retrospective review of the observations for signs of pain and stress revealed that mice given a fivefold overdose of buprenorphine (16.25 mg/kg) showed lethargy and facial signs associated with stress. However, similar signs were observed in the drug-free control mice as early as Day 3 of single-cage housing. This appears to be the first report of cage effects in a clinical trial for a veterinary drug.

Background Context: Metastases to the spine are a common source of severe pain in cancer patients. The secondary effects of spinal metastases include pain, bone fractures, hypercalcemia, and neurological deficits. As the disease progresses, pain severity can increase until it becomes refractory to medical treatments and leads to a decreased quality of life for patients. A key obstacle in the study of pain-induced spinal cancer is the lack of reliable and reproducible spine cancer animal models. In the present study, we developed a reproducible and reliable rat model of spinal cancer using human-derived tumor tissue to evaluate neurological decline using imaging and behavioral techniques., Purpose: The present study outlines the development and characterization of an orthotopic model of human breast cancer to the spine in immunocompromised rats., Study Design/setting: This is a basic science study., Methods: Female immunocompromised rats were randomized into three groups: tumor (n=8), RBC3 mammary adenocarcinoma tissue engrafted in the L5 vertebra body; sham (n=6), surgery performed but not tumor engrafted; and control (n=6), naive rats, no surgery performed. To evaluate the neurological impairment due to tumor invasion, functional assessment was done in all rodents at day 40 after tumor engraftment using locomotion gait analysis and pain response to a mechanical stimulus (Randall-Selitto test). Bioluminescence (BLI) was used to evaluate tumor growth in vivo and cone beam computed tomography (CBCT) was performed to evaluate bone changes due to tumor invasion. The animals were euthanized at day 45 and their spines were harvested and processed for hematoxylin and eosin (H&E) staining., Results: Tumor growth in the spine was confirmed by BLI imaging and corroborated by histological analysis. Cone beam computed tomography images were characterized by a decrease in the bone intensity in the lumbar spine consistent with tumor location on BLI. On H&E staining of tumor-engrafted animals, there was a near-complete ablation of the ventral and posterior elements of the L5 vertebra with severe tumor invasion in the bony components displacing the spinal cord. Locomotion gait analysis of tumor-engrafted rats showed a disruption in the normal gait pattern with asignificant reduction in length (p=.02), duration (p=.002), and velocity (p=.002) of right leg strides and only in duration (p=.0006) and velocity (p=.001) of left leg strides, as compared with control and sham rats. Tumor-engrafted animals were hypersensitive to pain stimulus shown as a significantly reduced response in time (p=.02) and pressure (p=.01) applied when compared with control groups., Conclusions: We developed a system for the quantitative analysis of pain and locomotion in an animal model of metastatic human breast cancer of the spine. Tumor-engrafted animals showed locomotor and sensory deficits that are in accordance with clinical manifestation in patients with spine metastasis. Pain response and locomotion gait analysis were performed during follow-up. The Randall-Selitto test was a sensitive method to evaluate pain in the rat's spine. We present a model for the study of bone-associated cancer pain secondary to cancer metastasis to the spine, as well as for the study of new therapies and treatments to lessen pain from metastatic cancer to the neuroaxis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Spinal cord injury (SCI) causes debilitating neurological dysfunction and has been observed in warfighters injured in IED blasts. Clinical benefit of SCI treatment remains elusive and better large animal models are needed to assess treatment options. Here, we describe a controlled electromagnetic spinal cord impactor for use in large animal models of SCI., Methods: A custom spinal cord impactor and platform were fabricated for large animals (e.g., pig, sheep, dog, etc.). Impacts were generated by a voice coil actuator; force and displacement were measured with a load cell and potentiometer respectively. Labview (National Instruments, Austin, TX) software was used to control the impact cycle and import force and displacement data. Software finite impulse response (FIR) filtering was employed for all input data. Silicon tubing was used a surrogate for spinal cord in order to test the device; repeated impacts were performed at 15, 25, and 40 Newtons., Results: Repeated impacts demonstrated predictable results at each target force. The average duration of impact was 71.2 ±6.1ms. At a target force of 40N, the output force was 41.5 ±0.7N. With a target of 25N, the output force was 23.5 ±0.6N; a target of 15Newtons revealed an output force of 15.2 ±1.4N. The calculated acceleration range was 12.5-21.2m/s 2 ., Conclusions: This custom spinal cord impactor reliably delivers precise impacts to the spinal cord and will be utilized in future research to study acute traumatic SCI in a large animal., (Published by Elsevier Ltd.)

OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100β, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma-engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

There is a need for enabling non-viral nanobiotechnology to allow safe and effective gene therapy and cell therapy, which can be utilized to treat devastating diseases such as brain cancer. Human adipose-derived mesenchymal stem cells (hAMSCs) display high anti-glioma tropism and represent a promising delivery vehicle for targeted brain tumor therapy. In this study, we demonstrate that non-viral, biodegradable polymeric nanoparticles (NPs) can be used to engineer hAMSCs with higher efficacy (75% of cells) than leading commercially available reagents and high cell viability. To accomplish this, we engineered a poly(beta-amino ester) (PBAE) polymer structure to transfect hAMSCs with significantly higher efficacy than Lipofectamine™ 2000. We then assessed the ability of NP-engineered hAMSCs to deliver bone morphogenetic protein 4 (BMP4), which has been shown to have a novel therapeutic effect by targeting human brain tumor initiating cells (BTIC), a source of cancer recurrence, in a human primary malignant glioma model. We demonstrated that hAMSCs genetically engineered with polymeric nanoparticles containing BMP4 plasmid DNA (BMP4/NP-hAMSCs) secrete BMP4 growth factor while maintaining their multipotency and preserving their migration and invasion capacities. We also showed that this approach can overcome a central challenge for brain therapeutics, overcoming the blood brain barrier, by demonstrating that NP-engineered hAMSCs can migrate to the brain and penetrate the brain tumor after both intranasal and systemic intravenous administration. Critically, athymic rats bearing human primary BTIC-derived tumors and treated intranasally with BMP4/NP-hAMSCs showed significantly improved survival compared to those treated with control GFP/NP-hAMCSs. This study demonstrates that synthetic polymeric nanoparticles are a safe and effective approach for stem cell-based cancer-targeting therapies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Metastases to the spine from non-hepatocellular carcinomas, such as cholangiocarcinoma and angiosarcoma, occur rarely. With improvements in oncologic care, the number of patients diagnosed with metastatic cancer is expected to increase. We performed a systematic review of the literature to assess the clinical presentation, treatment, outcome and survival of patients diagnosed with non-hepatocellular carcinoma spinal metastasis using PubMed, Embase, CINAHL, Cochrane Library and Web of Science. We identified 19 cases of spinal metastases from non-hepatocellular carcinomas that fit our pre-specified criteria. The mean age at presentation was 62.3years and cholangiocarcinoma was the most common subtype. Patients frequently presented with pain, weakness or paraparesis and at the time of diagnosis, most of them had multi-level involvement of the spine. A majority of patients with spinal metastasis were treated either with radiation or chemotherapy or received no treatment. A minority of the reports included information on survival, which revealed a median survival of 1.5months following diagnosis of the spinal metastasis. Although there is a paucity of published literature on non-hepatocellular carcinoma spinal metastasis, this systematic review provides descriptive clinical characteristics of these patients., (Published by Elsevier Ltd.)

Brainstem gliomas comprise 10-20% of all pediatric central nervous system (CNS) tumors and diffuse intrinsic pontine gliomas (DIPGs) account for the majority of these lesions. DIPG is a rapidly progressive disease with almost universally fatal outcomes and a median survival less than 12 months. Current standard-of-care treatment for DIPG includes radiation therapy, but its long-term survival effects are still under debate. Clinical trials investigating the efficacy of systemic administration of various therapeutic agents have been associated with disappointing outcomes. Recent efforts have focused on improvements in chemotherapeutic agents employed and in methods of localized and targeted drug delivery. This review provides an update on current preclinical and clinical studies investigating treatment options for brainstem gliomas., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Extended-release buprenorphine is an effective analgesic in laboratory animals, and its safety has been established in mice but not in rats. The authors used a target animal safety trial to evaluate the safety of extended-release buprenorphine in rats. Fischer 344 rats received post-surgical subcutaneous injections of 1.3 mg, 3.9 mg or 6.5 mg buprenorphine per kg body weight (two times, six times or ten times the intended dose, respectively), and their body weight, clinical signs and symptoms, clinical pathology and histopathology were monitored for 4 d. Body weight was not significantly different in rats that received buprenorphine compared with control rats. Signs of nausea-related behavior were observed in 25% of the rats treated with buprenorphine. Clinical pathology results for all rats were normal, and gross and microscopic histopathology examinations identified no substantial abnormalities, suggesting that this behavior was of minor consequence. Other adverse events previously reported to occur with opiate therapy, including weight loss and dermal lesions at drug injection sites, were not observed in this study. The results of this study show that post-surgical administration of an extended-release buprenorphine product is safe in Fischer 344 rats and does not necessarily cause substantial adverse effects, confirming that opiate therapy is a viable choice in laboratory animal medicine.

Study Design Retrospective study. Objective Our objective was to identify preoperative prognostic factors associated with survival in patients with spinal metastasis from lung carcinoma. Methods A retrospective analysis of 26 patients diagnosed with lung carcinoma metastatic to the spinal column was performed to determine factors associated with survival. We used 3 months survival as the clinical cutoff for whether surgical intervention should be performed. We analyzed patients who survived less than 3 months compared with those who survived more than 3 months. Demographic, preoperative, operative, and postoperative factors including functional scores were collected for analysis. Results The median survival for all patients in our study was 3.5 months. We found a statistically significant difference between the group that survived less than 3 months and the group that survived greater than 3 months in terms of extrathoracic metastasis, visceral metastasis, and average postoperative modified Rankin score. Conclusion Determining which patients with lung cancer spinal metastases will benefit from surgical intervention is often dictated by the patient's predicted life expectancy. Factors associated with poorer prognosis include age, functional status, visceral metastases, and extrathoracic metastases. Although the prognosis for patients with lung cancer spinal metastases is poor, some patients may experience long-term benefit from surgical intervention.

Purpose: Renal cell carcinoma (RCC) is an aggressive disease that metastasizes to the spine often requiring surgery. However, selecting the appropriate surgical intervention can be challenging. The Tokuhashi scoring system can be used to predict survival and inform the surgical strategy. We set out to determine the Tokuhashi score for patients with RCC spine metastases and compare expected and observed survival., Methods: Records were reviewed for all patients who underwent surgery for spinal metastases at a single institution from January 2000 to December 2011 to determine the Tokuhashi score and survival. Kaplan-Meier estimates and log-rank test for univariate analysis were performed with R version 2.15.12 (R Foundation, 2012)., Results: Thirty patients underwent 40 spinal operations for metastatic RCC. Median survival was 11.4 months. Preoperative Tokuhashi scores were: 12-15, 15 patients; 9-11, seven patients; 0-8, eight patients. Median survival was 32.9, 11.7, and 5.4 months, respectively. Bone (p=0.01) and visceral metastases (p=0.005), and KPS (p=0.002) significantly affected survival. Tokuhashi score predicted survival (p=0.016); survival differed between the high and low score groups (p=0.006)., Conclusions: RCC is an aggressive disease with short life expectancy when metastatic to the spine. However, patients with low systemic disease burden and solitary spinal metastases can have long survival and benefit from excisional surgery. Tokuhashi score can be useful in selecting surgical intervention in patients with RCC spinal metastases, and may be more relevant than in other cancers with spinal metastases.

Object: Transection of peripheral nerves produces loss of sensory and/or motor function. After complete nerve cutting, the distal and proximal segment ends retract, but if both ends are bridged with unaltered chitosan, progesterone-impregnated chitosan, or silicone tubes, an axonal repair process begins. Progesterone promotes nerve repair and has neuroprotective effects thwarting regulation of neuron survival, inflammation, and edema. It also modulates aberrant axonal sprouting and demyelination. The authors compared the efficacy of nerve recovery after implantation of progesterone-loaded chitosan, unaltered chitosan, or silicone tubes after sciatic nerve transection in rats., Methods: After surgical removal of a 5-mm segment of the proximal sciatic nerve, rats were implanted with progesterone-loaded chitosan, unaltered chitosan, or silicone tubes in the transected nerve for evaluating progesterone and chitosan effects on sciatic nerve repair and ipsilateral hindlimb kinematic function, as well as on gastrocnemius electro-myographic responses. In some experiments, tube implantation was performed 90 minutes after nerve transection., Results: At 90 days after sciatic nerve transection and tube implantation, rats with progesterone-loaded chitosan tubes showed knee angular displacement recovery and better outcomes for step length, velocity of locomotion, and normal hindlimb raising above the ground. In contrast, rats with chitosan-only tubes showed reduced normal raising and pendulum-like hindlimb movements. Aberrant fibers coming from the tibial nerve innervated the gastrocnemius muscle, producing electromyographic responses. Electrical responses in the gastrocnemius muscle produced by sciatic nerve stimulation occurred only when the distal nerve segment was stimulated; they were absent when the proximal or intratubular segment was stimulated. A clear sciatic nerve morphology with some myelinated fiber fascicles appeared in the tube section in rats with progesterone-impregnated chitosan tubes. Some gastrocnemius efferent fibers were partially repaired 90 days after nerve resection. The better outcome in knee angle displacement may be partially attributable to the aberrant neuromuscular synaptic effects, since nerve conduction in the gastrocnemius muscle could be blocked in the progesterone-impregnated chitosan tubes. In addition, in the region of the gap produced by the nerve resection, the number of axons and amount of myelination were reduced in the sciatic nerve implanted with chitosan, progesterone-loaded chitosan, and silicone tubes. At 180 days after sciatic nerve sectioning, the knee kinematic function recovered to a level observed in control rats of a similar age. In rats with progesterone-loaded chitosan tubes, stimulation of the proximal and intratubular sciatic nerve segments produced an electromyographic response. The axon morphology of the proximal and intratubular segments of the sciatic nerve resembled that of the contralateral nontransected nerve., Conclusions: Progesterone-impregnated chitosan tubes produced aberrant innervation of the gastrocnemius muscle, which allowed partial recovery of gait locomotion and could be adequate for reinnervating synergistic denervated muscles while a parent innervation is reestablished. Hindlimb kinematic parameters differed between younger (those at 90 days) and older (those at 180 days) rats.

The use of appropriate analgesia in laboratory mice may be suboptimal because of concerns about adverse events (AE). Target Animal Safety trials were conducted to determine the safety of an extended-release suspension of buprenorphine. Drug or control suspensions were injected subcutaneously in surgically-treated BALB/c mice anesthetized with ketamine-xylazine to mimic post-operative conditions in which the compound might commonly be administered. Single and repeat five-fold (5×) excesses of the 3.25 mg/kg intended dose were used to provoke potential AE. Trials included prospective measurements of weight changes, blood chemistry, hematology, and histopathology. Clinical and histopathology findings were similar in drug-treated and control mice in a four-day trial using a single 16.25 mg/kg, 5× overdose of the drug. In a 12-day trial, which used a total buprenorphine dose of 48.75 mg/kg, clinical and histopathology values were also similar in control and drug-treated female mice. In the male arm of the repeat-overdose trial, two of eight mice died on the morning of day 12, three days following the third 16.25 mg/kg overdose administration. Histopathology did not reveal a cause of death. In a 14-month trial using a single 3.25 mg/kg dose of the drug, no significant findings identified potential AE. These findings indicate a high tolerance to an extended-release buprenorphine suspension administered post-operatively in mice with appropriate husbandry., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Object: The goal of this study was to optimize local delivery of magnetic nanoparticles in a rat model of metastatic breast cancer in the spine for tumor hyperthermia while minimizing systemic exposure., Methods: A syngeneic mammary adenocarcinoma was implanted into the L-6 vertebral body of 69 female Fischer rats. Suspensions of 100-nm starch-coated iron oxide magnetic nanoparticles (micromod Partikeltechnologie GmbH) were injected into tumors 9 or 13 days after implantation. For nanoparticle distribution studies, tissues were harvested from a cohort of 36 rats, and inductively coupled plasma mass spectrometry and histopathological studies with Prussian blue staining were used to analyze the samples. Intratumor heating was tested in 4 anesthetized animals with a 20-minute exposure to an alternating magnetic field (AMF) at a frequency of 150 kHz and an amplitude of 48 kA/m or 63.3 kA/m. Intratumor and rectal temperatures were measured, and functional assessments of AMF-exposed animals and histopathological studies of heated tumor samples were examined. Rectal temperatures alone were tested in a cohort of 29 rats during AMF exposure with or without nanoparticle administration. Animal studies were completed in accordance with the protocols of the University Animal Care and Use Committee., Results: Nanoparticles remained within the tumor mass within 3 hours of injection and migrated into the bone at 6, 12, and 24 hours. Subarachnoid accumulation of nanoparticles was noted at 48 hours. No evidence of lymphoreticular nanoparticle exposure was found on histological investigation or via inductively coupled plasma mass spectrometry. The mean intratumor temperatures were 43.2°C and 40.6°C on exposure to 63.3 kA/m and 48 kA/m, respectively, with histological evidence of necrosis. All animals were ambulatory at 24 hours after treatment with no evidence of neurological dysfunction., Conclusions: Locally delivered magnetic nanoparticles activated by an AMF can generate hyperthermia in spinal tumors without accumulating in the lymphoreticular system and without damaging the spinal cord, thereby limiting neurological dysfunction and minimizing systemic exposure. Magnetic nanoparticle hyperthermia may be a viable option for palliative therapy of spinal tumors.

Background Context: Cancer is a major global public health problem responsible for one in every four deaths in the United States. Prostate cancer alone accounts for 29% of all cancers in men and is the sixth leading cause of death in men. It is estimated that up to 30% of patients with cancer will develop metastatic disease, the spine being one of the most frequently affected sites in patients with prostate cancer., Purpose: To study this condition in a preclinical setting, we have created a novel animal model of human metastatic prostate cancer to the spine and have characterized it histologically, functionally, and via bioluminescence imaging., Study Design: Translational science investigation of animal model of human prostate cancer in the spine., Methods: Luciferase-positive human prostate tumor cells PC3 (PC3-Luc) were injected in the flank of athymic male rats. PC3-Luc tumor samples were then implanted into the L5 vertebral body of male athymic rats (5 weeks old). Thirty-two rats were randomized into three surgical groups: experimental, control, and sham. Tumor growth was assessed qualitatively and noninvasively via bioluminescence emission, upon luciferin injection. To determine the functional impact of tumor growth in the spine, rats were evaluated for gait abnormalities during gait locomotion using video-assisted gait analysis. Rats were euthanized 22 days after tumor implantation, and spines were subjected to histopathological analyses., Results: Twenty days after tumor implantation, the tumor-implanted rats showed distinct signs of gait disturbances: dragging tail, right- or left-hind limb uncoordination, and absence of toe clearance during forward limb movement. At 20 days, all rats experienced tumor growth, evidenced by bioluminescent signal. Locomotion parameters negatively affected in tumor-implanted rats included stride length, velocity, and duration. At necropsy, all spines showed evidence of tumor growth, and the histological analysis found spinal cord compression and peritumoral osteoblastic reaction characteristic of bony prostate tumors. None of the rats in the sham or control groups demonstrated any evidence of bioluminescence signal or signs of gait disturbances., Conclusions: In this project, we have developed a novel animal model of metastatic spine cancer using human prostate cancer cells. Tumor growth, evaluated via bioluminescence and corroborated by histopathological analyses, affected hind limb locomotion in ways that mimic motor deficits present in humans afflicted with metastatic spine disease. Our model represents a reliable method to evaluate the experimental therapeutic approaches of human tumors of the spine in animals. Gait locomotion and bioluminescence analyses can be used as surrogate noninvasive methods to evaluate tumor growth in this model., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Object: Metastatic spine disease is prevalent in cancer victims; 10%-30% of the 1.2 million new patients diagnosed with cancer in the US exhibit spinal metastases. Unfortunately, treatments are limited for these patients, as disseminated disease is often refractory to chemotherapy and is difficult to treat with surgical intervention alone. New animal models that accurately recapitulate the human disease process are needed to study the behavior of metastases in real time., Methods: In this study the authors report on a cell line that reliably generates bony metastases following intracardiac injection and can be tracked in real time using optical bioluminescence imaging. This line, RBC3, was derived from a metastatic breast adenocarcinoma lesion arising in the osseous spine of a rat following intracardiac injection of MDA-231 human breast cancer cells., Results: Upon culture and reinjection of RBC3, a statistically significantly increased systemic burden of metastatic tumor was noted. The resultant spine lesions were osteolytic, as demonstrated by small animal CT scanning., Conclusions: This cell line generates spinal metastases that can be tracked in real time and may serve as a useful tool in the study of metastatic disease in the spine.

Buprenorphine is a long-acting opiate with a high therapeutic index. The authors review the pharmacology, toxicity, analgesic effects and delivery of buprenorphine for use in laboratory mice and rats. Buprenorphine-based analgesic therapy has a substantial record of safety, and there is growing evidence of its effectiveness for treating post-operative pain. Nonetheless, more research is needed to determine optimal delivery systems and analgesic regimens for pain therapy in laboratory animals.

Object: Recombinant human bone morphogenetic proteins (rhBMPs) are FDA-approved for specific spinal fusion procedures, but their use is contraindicated in spine tumor resection beds because of an unclear interaction between tumor tissue and such growth factors. Interestingly, a number of studies have suggested that BMPs may slow the growth of adenocarcinomas in vitro, and these lesions represent the majority of bony spine tumors. In this study, the authors hypothesized that rhBMP-2 placed in an intraosseous spine tumor in the rat could suppress tumor and delay the onset of paresis in such animals., Methods: Twenty-six female nude athymic rats were randomized into an experimental group (Group 1) or a positive control group (Group 2). Group 1 (tumor + 15 μg rhBMP-2 sponge, 13 rats) underwent transperitoneal exposure and implantation of breast adenocarcinoma (CRL-1666) into the L-6 spine segment, followed by the implantation of a bovine collagen sponge impregnated with 15 μg of rhBMP-2. Group 2 (tumor + 0.9% NaCl sponge, 13 rats) underwent transperitoneal exposure and tumor implantation in the lumbar spine but no local treatment with rhBMP-2. An additional 8 animals were randomized into 2 negative control groups (Groups 3 and 4). Group 3 (15 μg rhBMP-2 sponge, 4 rats) and Group 4 (0.9% NaCl sponge, 4 rats) underwent transperitoneal exposure of the lumbar spine along with the implantation of rhBMP-2- and saline-impregnated bovine collagen sponges, respectively. Neither of the negative control groups was implanted with tumor. The Basso-Beattie-Bresnahan (BBB) scale was used to monitor daily motor function regression and the time to paresis (BBB score ≤ 7)., Results: In comparison with the positive control animals (Group 2), the experimental animals (Group 1) had statistically significant longer mean (25.8 ± 12.2 vs 13 ± 1.4 days, p ≤ 0.001) and median (20 vs 13 days) times to paresis. In addition, the median survival time was significantly longer in the experimental animals (20 vs 13.5 days, p ≤ 0.0001). Histopathological analysis demonstrated bone growth and tumor inhibition in the experimental animals, whereas bone destruction and cord compression were observed in the positive control animals. Neither of the negative control groups (Groups 3 and 4) demonstrated any evidence of neurological deterioration, morbidity, or cord compromise on either gross or histological analysis., Conclusions: This study shows that the local administration of rhBMP-2 (15 μg, 10 μl of 1.5-mg/ml solution) in a rat spine tumor model of breast cancer not only fails to stimulate local tumor growth, but also decreases local tumor growth and delays the onset of paresis in rats. This preclinical experiment is the first to show that the local placement of rhBMP-2 in a spine tumor bed may slow tumor progression and delay associated neurological decline.