Spinal metastases are becoming increasingly common because patients with metastatic disease are living longer. The close proximity of the spinal cord to the vertebral column limits many conventional ...therapeutic options that can otherwise be used to treat cancer. In response to this problem, an innovative multidisciplinary approach has been developed for the management of spinal metastases, leveraging the capabilities of image-guided stereotactic radiosurgery, separation surgery, vertebroplasty, and minimally invasive local ablative approaches. In this Review, we discuss the variables that should be considered during the management of these patients and review the role of each discipline and their respective management options to provide optimal care. This work is synthesised into a practical algorithm to aid clinicians in the management of patients with spinal metastasis.
Glioblastoma (GBM) is distinguished by a high degree of intratumoral heterogeneity, which extends to the pattern of expression and amplification of receptor tyrosine kinases (RTKs). Although most ...GBMs harbor RTK amplifications, clinical trials of small-molecule inhibitors targeting individual RTKs have been disappointing to date. Activation of multiple RTKs within individual GBMs provides a theoretical mechanism of resistance; however, the spectrum of functional RTK dependence among tumor cell subpopulations in actual tumors is unknown. We investigated the pattern of heterogeneity of RTK amplification and functional RTK dependence in GBM tumor cell subpopulations. Analysis of The Cancer Genome Atlas GBM dataset identified 34 of 463 cases showing independent focal amplification of two or more RTKs, most commonly platelet-derived growth factor receptor α (PDGFRA) and epidermal growth factor receptor (EGFR). Dual-color fluorescence in situ hybridization was performed on eight samples with EGFR and PDGFRA amplification, revealing distinct tumor cell subpopulations amplified for only one RTK; in all cases these predominated over cells amplified for both. Cell lines derived from coamplified tumors exhibited genotype selection under RTK-targeted ligand stimulation or pharmacologic inhibition in vitro. Simultaneous inhibition of both EGFR and PDGFR was necessary for abrogation of PI3 kinase pathway activity in the mixed population. DNA sequencing of isolated subpopulations establishes a common clonal origin consistent with late or ongoing divergence of RTK genotype. This phenomenon is especially common among tumors with PDGFRA amplification: overall, 43% of PDGFRA-amplified GBM were found to have amplification of EGFR or the hepatocyte growth factor receptor gene (MET) as well.
OBJECTIVE Spinal cord injury (SCI) results in significant morbidity and mortality. Improving neurological recovery by reducing secondary injury is a major principle in the management of SCI. To ...minimize secondary injury, blood pressure (BP) augmentation has been advocated. The objective of this study was to review the evidence behind BP management after SCI. METHODS This systematic review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Using the PubMed database, the authors identified studies that investigated BP management after acute SCI. Information on BP goals, duration of BP management, vasopressor selection, and neurological outcomes were analyzed. RESULTS Eleven studies that met inclusion criteria were identified. Nine studies were retrospective, and 2 were single-cohort prospective investigations. Of the 9 retrospective studies, 7 reported a goal mean arterial pressure (MAP) of higher than 85 mm Hg. For the 2 prospective studies, the MAP goals were higher than 85 mm Hg and higher than 90 mm Hg. The duration of BP management varied from more than 24 hours to 7 days in 6 of the retrospective studies that reported the duration of treatment. In both prospective studies, the duration of treatment was 7 days. In the 2 prospective studies, neurological outcomes were stable to improved with BP management. The retrospective studies, however, were contradictory with regard to the correlation of BP management and outcomes. Dopamine, norepinephrine, and phenylephrine were the agents that were frequently used to augment BP. However, more complications have been associated with dopamine use than with the other vasopressors. CONCLUSIONS There are no high-quality data regarding optimal BP goals and duration in the management of acute SCI. Based on the highest level of evidence available from the 2 prospective studies, MAP goals of 85-90 mm Hg for a duration of 5-7 days should be considered. Norepinephrine for cervical and upper thoracic injuries and phenylephrine or norepinephrine for mid- to lower thoracic injuries should be considered.
Roughly 400,000 people in the U.S. are living with bone metastases, the vast majority occurring in the spine. Metastases to the spine result in fractures, pain, paralysis, and significant health care ...costs. This predilection for cancer to metastasize to the bone is seen across most cancer histologies, with the greatest incidence seen in prostate, breast, and lung cancer. The molecular process involved in this predilection for axial versus appendicular skeleton is not fully understood, although it is likely that a combination of tumor and local micro-environmental factors plays a role. Immune cells are an important constituent of the bone marrow microenvironment and many of these cells have been shown to play a significant role in tumor growth and progression in soft tissue and bone disease. With this in mind, we sought to examine the differences in immune landscape between axial and appendicular bones in the normal noncancerous setting in order to obtain an understanding of these landscapes. To accomplish this, we utilized mass cytometry by time-of-flight (CyTOF) to examine differences in the immune cell landscapes between the long bone and vertebral body bone marrow from patient clinical samples and C57BL/6J mice. We demonstrate significant differences between immune populations in both murine and human marrow with a predominance of myeloid progenitor cells in the spine. Additionally, cytokine analysis revealed differences in concentrations favoring a more myeloid enriched population of cells in the vertebral body bone marrow. These differences could have clinical implications with respect to the distribution and permissive growth of bone metastases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hypoxia-based cell culture experiments are routine and essential components of in vitro cancer research. Most laboratories use low-cost portable modular chambers to achieve hypoxic conditions for ...cell cultures, where the sealed chambers are purged with a gas mixture of preset O2 concentration. Studies are conducted under the assumption that hypoxia remains unaltered throughout the 48 to 72 hour duration of such experiments. Since these chambers lack any sensor or detection system to monitor gas-phase O2, the cell-based data tend to be non-uniform due to the ad hoc nature of the experimental setup.
With the availability of low-cost open-source microcontroller-based electronic project kits, it is now possible for researchers to program these with easy-to-use software, link them to sensors, and place them in basic scientific apparatus to monitor and record experimental parameters. We report here the design and construction of a small-footprint kit for continuous measurement and recording of O2 concentration in modular hypoxia chambers. The low-cost assembly (US$135) consists of an Arduino-based microcontroller, data-logging freeware, and a factory pre-calibrated miniature O2 sensor. A small, intuitive software program was written by the authors to control the data input and output. The basic nature of the kit will enable any student in biology with minimal experience in hobby-electronics to assemble the system and edit the program parameters to suit individual experimental conditions.
We show the kit's utility and stability of data output via a series of hypoxia experiments. The studies also demonstrated the critical need to monitor and adjust gas-phase O2 concentration during hypoxia-based experiments to prevent experimental errors or failure due to partial loss of hypoxia. Thus, incorporating the sensor-microcontroller module to a portable hypoxia chamber provides a researcher a capability that was previously available only to labs with access to sophisticated (and expensive) cell culture incubators.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This prospective observational cohort study of high-school football athletes was performed to determine if high-acceleration head impacts (HHIs) that do not result in clinically diagnosed concussion ...still lead to increases in serum levels of biomarkers indicating traumatic brain injury (TBI) in asymptomatic athletes and to determine the longitudinal profile of these biomarkers over the course of the football season.
Sixteen varsity high-school football athletes underwent baseline neurocognitive testing and blood sampling for the biomarkers tau, ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light protein (NF-L), glial fibrillary acidic protein (GFAP), and spectrin breakdown products (SBDPs). All athletes wore helmet-based accelerometers to measure and record head impact data during all practices and games. At various time points during the season, 6 of these athletes met the criteria for HHI (linear acceleration > 95g and rotational acceleration > 3760 rad/sec2); in these athletes a second blood sample was drawn at the end of the athletic event during which the HHI occurred. Five athletes who did not meet the criteria for HHI underwent repeat blood sampling following the final game of the season. In a separate analysis, all athletes who did not receive a diagnosis of concussion during the season (n = 12) underwent repeat neurocognitive testing and blood sampling after the end of the season.
Total tau levels increased 492.6% ± 109.8% from baseline to postsession values in athletes who received an HHI, compared with 164% ± 35% in athletes who did not receive an HHI (p = 0.03). Similarly, UCH-L1 levels increased 738.2% ± 163.3% in athletes following an HHI, compared with 237.7% ± 71.9% in athletes in whom there was no HHI (p = 0.03). At the end of the season, researchers found that tau levels had increased 0.6 ± 0.2 pg/ml (p = 0.003) and UCH-L1 levels had increased 144.3 ± 56 pg/ml (p = 0.002). No significant elevations in serum NF-L, GFAP, or SBDPs were seen between baseline and end-of-athletic event or end-of-season sampling (for all, p > 0.05).
In this pilot study on asymptomatic football athletes, an HHI was associated with increased markers of neuronal (UCH-L1) and axonal (tau) injury when compared with values in control athletes. These same markers were also increased in nonconcussed athletes following the football season.
Purpose
Spinal metastases are common in cancer. This preferential migration/growth in the spine is not fully understood. Dura has been shown to affect the surrounding microenvironment and promote ...cancer growth. Here, we investigate the role of dural cytokines in promoting the metastatic potential of prostate cancer (PCa) and the involvement of the CXCR2 signaling pathway.
Methods
The role of dural conditioned media (DCM) in proliferation, migration and invasion of five PCa cell lines with various hormone sensitivities was assessed in the presence or absence of the CXCR2 inhibitor, SB225002. CXCR2 surface protein was examined by FACS. Cytokine levels were measured using a mouse cytokine array.
Results
We observed high levels of cytokines produced by dura and within the vertebral body bone marrow, namely CXCL1 and CXCL2, that act on the CXCR2 receptor. All prostate cell lines treated with DCM demonstrated significant increase in growth, migration and invasion regardless of androgen sensitivity, except PC3, which did not significantly increase in invasiveness. When treated with SB225002, the growth response to DCM by cells expressing the highest levels of CXCR2 as measured by FACS (LNCaP and 22Rv1) was blunted. The increase in migration was significantly decreased in all lines in the presence of SB225002. Interestingly, the invasion increase seen with DCM was unchanged when these cells were treated with the CXCR2 inhibitor, except PC3 did demonstrate a significant decrease in invasion.
Conclusion
DCM enhances the metastatic potential of PCa with increased proliferation, migration and invasion. This phenomenon is partly mediated through the CXCR2 pathway.
Hybrid Therapy for Spinal Metastases Rothrock, Robert; Pennington, Zach; Ehresman, Jeff ...
Neurosurgery clinics of North America
31, Številka:
2
Journal Article
Recenzirano
The combination of separation surgery and stereotactic body radiotherapy optimizes the treatment of metastatic spine tumors. The integration of SBRT into treatment paradigms produces superb local ...control rates and consequently has diminished the role of surgery from principle treatment to one of adjuvant therapy. Under this paradigm, hybrid therapy for the treatment of metastatic spine tumors employs separation surgery to decompress the spinal cord and stabilize the spine while creating a safe target for ablative SBRT. Hybrid therapy is well tolerated, allows an early return to systemic therapy, and provides durable, local tumor control compared with more aggressive traditional approaches.
Previous studies have shown that clinically asymptomatic high-acceleration head impacts (HHIs) may be associated with neuronal and axonal injury, as measured by advanced imaging and biomarkers. ...Unfortunately, these methods of measurement are time-consuming, invasive, and costly. A quick noninvasive measurement tool is needed to aid studies of head injury and its biological impact. Quantitative pupillometry is a potential objective, rapid, noninvasive measurement tool that may be used to assess the neurological effects of HHIs. In this study, the authors investigated the effect of HHIs on pupillary metrics, as measured using a pupillometer, in the absence of a diagnosed concussion.
A prospective observational cohort study involving 18 high school football athletes was performed. These athletes were monitored for both the frequency and magnitude of head impacts that they sustained throughout a playing season by using the Head Impact Telemetry System. An HHI was defined as an impact exceeding 95g linear acceleration and 3760 rad/sec2 rotational acceleration. Pupillary assessments were performed at baseline, midseason, after occurrence of an HHI, and at the end of the season by using the NeurOptics NPi-200 pupillometer. The Sport Concussion Assessment Tool, 5th Edition (SCAT5), was also used at each time point. Comparisons of data obtained at the various time points were calculated using a repeated-measures analysis of variance and a t-test.
Seven athletes sustained HHIs without a related diagnosed concussion. Following these HHIs, the athletes demonstrated decreases in pupil dilation velocity (mean difference 0.139 mm/sec; p = 0.048), percent change in pupil diameter (mean difference 3.643%; p = 0.002), and maximum constriction velocity (mean difference 0.744 mm/sec; p = 0.010), compared to measurements obtained at the athletes' own midseason evaluations. No significant changes occurred between the SCAT5 subtest scores calculated at midseason and those after a high impact, although the effect sizes (Cohen's d) on individual components ranged from 0.41 to 0.65.
Measurable changes in pupil response were demonstrated following an HHI. These results suggest that clinically asymptomatic HHIs may affect brain reflex pathways, reflecting a biological injury previously seen when more invasive methods were applied.
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