Risk Factors for Sacroiliac Joint Fusion after Instrumented Spinal Fusion.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: To identify risk factors for sacroiliac (SI) joint fusion after instrumented spinal fusion. METHODS: Patients were identified from the PearlDiver BiscayneBay database. Patients who underwent 1 level (CPT: 22840), 3-6 vertebral segment (22842), and 7+ vertebral segment spinal fusions (22843 and 22844) were identified. Patients were separated based on whether they received an SI joint fusion (27280 and 27279) after their spinal fusion. A univariate analysis and multivariate logistic regression was performed to evaluate the associations between patient factors and incidence of SI joint fusion. RESULTS: 549,625 patients who underwent posterior spinal fusions were identified, 6068 of whom underwent subsequent SI joint fusion (1.1%). Factors associated with future SI joint fusion included female gender, patients with obesity, fibromyalgia, diabetes, tobacco use, increased construct length, and prior SI joint injection. Prior SI joint injection had the highest odds ratio (OR: 8.70; 95% CI: 8.25-9.16; P < 0.001), followed by 7+ vertebral segment (OR: 2.17; 95% CI: 2.03-2.33; P < 0.001) and 3-6 vertebral segment fusion (OR: 1.49; 95% CI: 1.42-1.57; P < 0.001). CONCLUSIONS: The highest predictor of requiring subsequent SI joint fusion is a prior SI joint injection. We also found that longer fusion constructs are associated with increased risk for future SI joint fusion.

Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain.

Objective: Nav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain. Methods: To study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin-Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP). Results: We show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel's maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8. Conclusion: Computational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain.

Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer.

Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4-12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.

Differences and Similarities in Spontaneous Activity Between Animal Models of Cancer-Induced Pain and Neuropathic Pain.

Background: Clinical data on cancer-induced pain (CIP) demonstrate widespread changes in sensory function. It is characterized in humans not only by stimulus-invoked pain, but also by spontaneous pain. In our previous studies in an animal model of CIP, we observed changes in intrinsic membrane properties and excitability of dorsal root ganglion (DRG) sensory neurons corresponding to mechanical allodynia and hyperalgesia, of which abnormal activities of Aß-fiber sensory neurons are consistent in a rat model of peripheral neuropathic pain (NEP). Objective: To investigate whether there are related peripheral neural mechanisms between the CIP and NEP models of spontaneous pain, we compared the electrophysiological properties of DRG sensory neurons at 2-3 weeks after CIP and NEP model induction. Methods: CIP models were induced with metastasis tumour-1 rat breast cancer cells implanted into the distal epiphysis of the femur. NEP models were induced with a polyethylene cuff implanted around the sciatic nerve. Spontaneous pain in animals is measured by spontaneous foot lifting (SFL). After measurement of SFL, the animals were prepared for electrophysiological recordings of spontaneous activity (SA) in DRG neurons in vivo. Results: Our data showed that SFL and SA occurred in both models. The proportion of SFL and SA of C-fiber sensory neurons in CIP was more significantly increased than in NEP models. There was no difference in duration of SFL and the rate of SA between the two models. The duration of SFL is related to the rate of SA in C-fiber in both models. Conclusion: Thus, SFL may result from SA activity in C-fiber neurons in CIP and NEP rats. The differences and similarities in spontaneous pain between CIP and NEP rats is related to the proportion and rate of SA in C-fibers, respectively.

Electrochemical sensing: A prognostic tool in the fight against COVID-19.

The COVID-19 pandemic has devastated the world, despite all efforts in infection control and treatment/vaccine development. Hospitals are currently overcrowded, with health statuses of patients often being hard to gauge. Therefore, methods for determining infection severity need to be developed so that high-risk patients can be prioritized, resources can be efficiently distributed, and fatalities can be prevented. Electrochemical prognostic biosensing of various biomarkers may hold promise in solving these problems as they are low-cost and provide timely results. Therefore, we have reviewed the literature and extracted the most promising biomarkers along with their most favourable electrochemical sensors. The biomarkers discussed in this paper are C-reactive protein (CRP), interleukins (ILs), tumour necrosis factor alpha (TNFα), interferons (IFNs), glutamate, breath pH, lymphocytes, platelets, neutrophils and D-dimer. Metabolic syndrome is also discussed as comorbidity for COVID-19 patients, as it increases infection severity and raises chances of becoming infected. Cannabinoids, especially cannabidiol (CBD), are discussed as a potential adjunct therapy for COVID-19 as their medicinal properties may be desirable in minimizing the neurodegenerative or severe inflammatory damage caused by severe COVID-19 infection. Currently, hospitals are struggling to provide adequate care; thus, point-of-care electrochemical sensor development needs to be prioritized to provide an approximate prognosis for hospital patients. During and following the immediate aftermath of the pandemic, electrochemical sensors can also be integrated into wearable and portable devices to help patients monitor recovery while returning to their daily lives. Beyond the COVID-19 pandemic, these sensors will also prove useful for monitoring inflammation-based diseases such as cancer and cardiovascular disease.

Performance Outcomes and Return-to-Sport Rate of National Hockey League Athletes Vary After Common Orthopedic Surgical Procedures.

OBJECTIVE: Evaluate performance-based outcomes and return-to-sport rate in National Hockey League (NHL) athletes. DESIGN: Retrospective cohort study. SETTING: Public records. No direct patient care was provided. PARTICIPANTS: National Hockey League athletes who underwent different orthopedic procedures were identified using public records. Three hundred thirty-seven athletes met inclusion criteria. INDEPENDENT VARIABLES: Common orthopedic surgical procedures in NHL athletes. MAIN OUTCOME MEASURES: Return-to-play and preoperative and postoperative performance measures were collected to calculate a position-specific performance score. Short-term and medium-term outcomes were defined as 1 and 2 to 3 seasons after surgery, respectively. RESULTS: Three hundred seven athletes (92.6%) successfully returned to play. The number of games played during the first season after surgery compared with baseline was significantly decreased for hip arthroscopy (HA), noninstability shoulder arthroscopy (ie, shoulder arthroscopy procedure to address pathology other than shoulder instability), knee arthroscopy, and sports hernia repair (P = 0.002, 0.009, 0.03, and 0.01, respectively). The number of games played for seasons 2 and 3 after surgery was significantly decreased for both HA and noninstability shoulder arthroscopy (P = 0.01 and 0.001, respectively). Short-term postoperative performance scores were significantly decreased for HA, noninstability shoulder arthroscopy, and anterior cruciate ligament reconstruction (P = 0.00004, 0.02, and 0.02, respectively) while medium-term scores were significantly decreased for HA only (P = 0.009). CONCLUSIONS: National Hockey League athletes return to play at a high rate after common orthopedic surgeries. However, certain procedures portend poorer performance scores and game participation than others. In particular, HA and noninstability shoulder arthroscopy have the greatest negative effect on NHL careers after surgery.

Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma.

We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.

Evaluation of the preclinical analgesic efficacy of naturally derived, orally administered oil forms of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their 1:1 combination.

Chronic neuropathic pain (NP) is a growing clinical problem for which effective treatments, aside from non-steroidal anti-inflammatory drugs and opioids, are lacking. Cannabinoids are emerging as potentially promising agents to manage neuroimmune effects associated with nociception. In particular, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their combination are being considered as therapeutic alternatives for treatment of NP. This study aimed to examine whether sex affects long-term outcomes on persistent mechanical hypersensitivity 7 weeks after ceasing cannabinoid administration. Clinically relevant low doses of THC, CBD, and a 1:1 combination of THC:CBD extracts, in medium chain triglyceride (MCT) oil, were orally gavaged for 14 consecutive days to age-matched groups of male and female sexually mature Sprague Dawley rats. Treatments commenced one day after surgically inducing a pro-nociceptive state using a peripheral sciatic nerve cuff. The analgesic efficacy of each phytocannabinoid was assessed relative to MCT oil using hind paw mechanical behavioural testing once a week for 9 weeks. In vivo intracellular electrophysiology was recorded at endpoint to characterize soma threshold changes in primary afferent sensory neurons within dorsal root ganglia (DRG) innervated by the affected sciatic nerve. The thymus, spleen, and DRG were collected post-sacrifice and analyzed for long-term effects on markers associated with T lymphocytes at the RNA level using qPCR. Administration of cannabinoids, particularly the 1:1 combination of THC, elicited a sustained mechanical anti-hypersensitive effect in males with persistent peripheral NP, which corresponded to beneficial changes in myelinated Aß mechanoreceptive fibers. Specific immune cell markers associated with T cell differentiation and pro-inflammatory cytokines, previously implicated in repair processes, were differentially up-regulated by cannabinoids in males treated with cannabinoids, but not in females, warranting further investigation into sexual dimorphisms that may underlie treatment outcomes.

Applying Serum Cytokine Levels to Predict Pain Severity in Cancer Patients.

BACKGROUND AND AIM: Cancers originating in the breast, lung and prostate often metastasize to the bone, frequently resulting in cancer-induced bone pain that can be challenging to manage despite conventional analgesic therapy. This exploratory study's aim was to identify potential biomarkers associated with cancer-induced pain by examining a sample population of breast cancer patients undergoing bisphosphonate therapy. METHODS: A secondary analysis of the primary study was performed to quantify serum cytokine levels for correlation to pain scores. Cytokines with statistically significant correlations were then input into a stepwise regression analysis to generate a predictive equation for a patient's pain severity. In an effort to find additional potential biomarkers, correlation analysis was performed between these factors and a more comprehensive panel of cytokines and chemokines from breast, lung, and prostate cancer patients. RESULTS: Statistical analysis identified nine cytokines (GM-CSF, IFNγ, IL-1ß, IL-2, IL-4, IL-5, IL-12p70, IL-17A, and IL-23) that had significant negative correlations with pain scores and they could best predict pain severity through a predictive equation generated for this specific evaluation. After performing a correlation analysis between these factors and a larger panel of cytokines and chemokines, samples from breast, lung and prostate patients showed distinct correlation profiles, highlighting the clinical challenge of applying pain-associated cytokines related to more defined nociceptive states, such as arthritis, to a cancer pain state. CONCLUSION: Exploratory analyses such as the ones presented here will be a beneficial tool to expand insights into potential cancer-specific nociceptive mechanisms and to develop novel therapeutics.

An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.

BACKGROUND AND PURPOSE: Chronic neuropathic pain (NEP) is associated with growing therapeutic cannabis use. To promote quality of life without psychotropic effects, cannabinoids other than Δ9-tetrahydrocannabidiol, including cannabidiol and its precursor cannabidiolic acid (CBDA), are being evaluated. Due to its instability, CBDA has been understudied, particularly as an anti-nociceptive agent. Adding a methyl ester group (CBDA-ME) significantly enhances its stability, facilitating analyses of its analgesic effects in vivo. This study examines early treatment efficacy of CBDA-ME in a rat model of peripherally induced NEP and evaluates sex as a biological variable. EXPERIMENTAL APPROACH: After 14 consecutive days of intraperitoneal CBDA-ME administration at 0.01, 0.1 and 1 µg·kg-1 , commencing 1 day after surgically implanting a sciatic nerve-constricting cuff to induce NEP, the anti-nociceptive efficacy of this cannabinoid was assessed in male and female Sprague-Dawley rats relative to vehicle-treated counterparts. In females, 2 and 4 µg·kg-1 daily doses of CBDA-ME were also evaluated. Behavioural tests were performed for hind paw mechanical and thermal withdrawal thresholds once a week for 8 weeks. At endpoint, in vivo electrophysiological recordings were obtained to characterize soma threshold changes in primary sensory neurons. KEY RESULTS: In males, CBDA-ME elicited a significant concentration-dependent chronic anti-hyperalgesic effect, also influencing both nociceptive and non-nociceptive mechanoreceptors, which were not observed in females at any of the concentrations tested. CONCLUSION AND IMPLICATIONS: Initiating treatment of a peripheral nerve injury with CBDA-ME at an early stage post-surgery provides anti-nociception in males, warranting further investigation into potential sexual dimorphisms underlying this response.

Glutamate sensing in biofluids: recent advances and research challenges of electrochemical sensors.

Glutamate is a nonessential amino acid and a putative neurotransmitter. When its consumption exceeds its synthesis, it becomes necessary to monitor its levels. Hence, a low-cost, sensitive and real-time monitoring of glutamate to quantify pain and detect neurodegenerative diseases is imperative to improve pharmacotherapy and early diagnosis for health care. While enzymatic electrochemical sensors are promising to address issues in lab-based detection techniques, non-enzymatic sensors are better due to their higher stability and lower cost. In this review, we aim to discuss the recent advances and remaining challenges of sensing glutamate in biofluids. First, we discuss the metabolic routes of glutamate, followed by its transmission processes to the biofluids. Second, we identify the connection of glutamate to pathologies as a potential biomarker. Third, we emphasize electrochemical sensors instantaneously detect glutamate in biofluids in real-time, quantifying pain and monitoring neurodegenerative diseases. The literature shows the concentration of glutamate in biofluids, such as plasma, cerebral spinal fluid, urine, and saliva are in the range of 5-100 µM, 0.5-2 µM, 8.5 (3.3-18.4) µM mM-1 creatinine, and 0.232 ± 0.177 µM respectively. While these concentration levels are sometimes lower than the detection limit of electrochemical sensors, functionalization of the nanomaterials currently being used such as NiO and Co3O4 with carbon nanotubes or beta-cyclodextrin may improve the sensing performance. Another key challenge in the research is to develop relationships between glutamate and biofluids. Finally, we have to advance electrochemical sensors that are compatible to detect glutamate in physiological conditions for long durations of time.

Response to pregabalin and progesterone differs in male and female rat models of neuropathic and cancer pain.

Background: Cancer pain involves nervous system damage and pathological neurogenesis. Neuropathic pain arises from damage to the nervous system and is driven by ectopic signaling. Both progesterone and pregabalin are neuroprotective in animal models, and there is evidence that both drugs bind to and inhibit voltage-gated calcium channels. Aims: This study was designed to characterize the effects of progesterone and pregabalin in preclinical models of cancer and neuropathic pain in both sexes. Methods: We measured peripheral sensory signaling by intracellular in vivo electrophysiology and behavioral indicators of pain in rat models of cancer-induced bone pain and neuropathic pain. Results: Female but not male models of cancer pain showed a behavioral response to treatment and pregabalin reduced excitability in C and A high-threshold but not low-threshold sensory neurons of both sexes. Male models of neuropathic pain treated with pregabalin demonstrated higher signaling thresholds only in A high-threshold neurons, and behavioral data indicated a clear recovery to baseline mechanical withdrawal thresholds in all treatment groups. Female rat treatment groups did not show excitability changes in sensory neurons, but all demonstrated higher mechanical withdrawal thresholds than vehicle-treated females, although not to baseline levels. Athymic female rat models of neuropathic pain showed no behavioral or electrophysiological responses to treatment. Conclusions: Both pregabalin and progesterone showed evidence of efficacy in male models of neuropathic pain. These results add to the evidence demonstrating differential effects of treatments for pain in male and female animals and widely differing responses in models of cancer and neuropathic pain.

Contexte: La douleur cancéreuse implique des lésions du système nerveux et une neurogenèse pathologique. La douleur neuropathique résulte d'une lésion du système nerveux et est provoquée par une signalisation ectopique. La progestérone et la prégabaline sont toutes deux neuroprotectrices dans les modèles animaux et il est prouvé que ces deux médicaments se lient aux canaux calciques à tension contrôlée et les inhibent.Objectifs: Cette étude visait à caractériser les effets de la progestérone et de la prégabaline dans des modèles précliniques de cancer et de douleur neuropathique chez les deux sexes.Méthodes: Nous avons mesuré la signalisation sensorielle périphérique par électrophysiologie intracellulaire in vivo, ainsi que les indicateurs comportementaux de la douleur dans des modèles de rats atteints de douleurs osseuses et de douleurs neuropathiques induites par le cancer.Résultats: Contrairement aux modèles masculins, les modèles féminins atteints de douleur cancéreuse ont montré une réponse comportementale au traitement, tandis que la prégabaline a réduit l'excitabilité des neurones sensoriels C et A à seuil élevé mais non à seuil bas chez les deux sexes. Les modèles masculins atteints de douleur neuropathique traités à la prégabaline ont montré des seuils de signalisation plus élevés uniquement dans les neurones A à seuil élevé, tandis que les données comportementales ont indiqué un net retour aux seuils de retrait mécanique de départ dans tous les groupes de traitement. Les groupes de rats femelles traités n'ont pas montré de changements d'excitabilité dans les neurones sensoriels, mais tous ont montré des seuils de retrait mécanique plus élevés que les femelles traitées avec le vecteur, sans toutefois atteindre les niveaux de départ. Les modèles atteints de douleur neuropathique parmi les rats femelles athymiques n'ont montré aucune réponse comportementale ou électrophysiologique au traitement.Conclusions: La prégabaline et la progestérone ont toutes deux démontré leur efficacité dans les modèles masculins atteints de douleur neuropathique. Ces résultats s'ajoutent aux données probantes démontrant les effets différentiels des traitements de la douleur chez les animaux mâles et femelles, et les réponses très différentes dans les modèles atteints de cancer et de douleur neuropathique.

Spinal microglia contribute to cancer-induced pain through system xC --mediated glutamate release.

INTRODUCTION: Microglial cells, the resident macrophages of the central nervous system, are a key contributor to the generation and maintenance of cancer-induced pain (CIP). In healthy organisms, activated microglia promote recovery through the release of trophic and anti-inflammatory factors to clear toxins and pathogens and support neuronal survival. Chronically activated microglia, however, release toxic substances, including excess glutamate, causing cytotoxicity. Accordingly, rising attention is given to microglia for their role in abnormal physiology and in mediating neurotoxicity. OBJECTIVES: To examine the nociceptive relationship between peripherally-released glutamate and microglial xCT. METHODS: A validated murine model of 4T1 carcinoma cell-induced nociception was used to assess the effect of peripheral tumour on spinal microglial activation and xCT expression. Coculture systems were then used to investigate the direct effect of glutamate released by wildtype and xCT knockdown MDA-MB-231 carcinoma cells on microglial activation, functional system xC - activity, and protein levels of interferon regulatory factor 8 (IRF8), a transcription factor implicated in microglia-mediated nociception. RESULTS: Blockade of system xC - with sulfasalazine (SSZ) in vivo attenuated nociception in a 4T1 murine model of CIP and attenuates tumour-induced microglial activation in the dorsal horn of the spinal cord. Furthermore, knockdown of xCT in MDA-MB-231 cells mitigated tumour cell-induced microglial activation and functional system xC - activity in vitro. CONCLUSIONS: These data collectively demonstrate that the system xCT antiporter is functionally implicated in CIP and may be particularly relevant to pain progression through microglia. Upregulated xCT in chronically activated spinal microglia may be one pathway to central glutamate cytotoxicity. Microglial xCT may therefore be a valuable target for mitigating CIP.

Effect of glutaminase inhibition on cancer-induced bone pain.

PURPOSE: The complex nature of cancer-induced bone pain (CIBP) has led to investigation into cancer-targeted therapies. This has involved targeting glutamate release from the tumor, secreted as a byproduct of antioxidant responses and metabolic disruption. Cancer cells undergo many metabolic changes that result in increased glutamine metabolism and subsequently the production of glutamate. Glutaminase (GLS) is the enzyme that mediates the conversion of glutamine to glutamate and has been shown to be upregulated in many cancer types including malignancies of the breast. This enzyme, therefore, represents another potential therapeutic target for CIBP, one that lies upstream of glutamate secretion. METHODS: A recently developed inhibitor of GLS, CB-839, was tested in an animal model of CIBP induced by intrafemoral MDA-MB-231 xenografts. CIBP behaviors were assessed using Dynamic Weight Bearing and Dynamic Plantar Aesthesiometer readings of mechanical hyperalgesia and allodynia. RESULTS: CB-839 failed to modulate any of the associated nociceptive behaviors induced by intrafemoral MDA-MB-231 tumor growth. Further investigation in vitro revealed the sensitivity of the drug is dependent on the metabolic flexibility of the cell line being tested which can be modulated by cell culture environment. CONCLUSION: Adaptation to metabolic disturbances may explain the failure of CB-839 to exhibit any significant effects in vivo and the metabolic flexibility of the cell line tested should be considered for future investigations studying the metabolic effects of glutaminase inhibition.

The Variability of Lumbar Facet Joint Synovial Cyst Recurrence Requiring Revision Surgery After Decompression-only and Decompression/Fusion.

STUDY DESIGN: This is a retrospective study. OBJECTIVE: The objective of this study was to evaluate lumbar spine synovial cyst recurrence rates of decompression-alone versus decompression/fusion procedures. BACKGROUND: Improvements in imaging modalities allow for increased diagnosis and surgical treatment of symptomatic spinal juxtafacet synovial cysts. Conservative management may be used as a first-line management strategy, however rarely provides durable, effective relief of symptoms. Surgical treatment of spinal synovial cysts ranges from decompression and cyst excision to decompression with fusion procedures. Decompression procedures alone have a higher risk of recurrence of spinal synovial cysts. METHODS: We retrospectively reviewed 87 patients undergoing surgical treatment of lumbar spinal juxtafacet synovial cysts as a single institution over 20 years. Surgical treatment consisted of either decompression versus decompression/fusion procedures. Preoperative symptoms included back pain, radiculopathy, motor deficits, or sensory deficits. The incidence of recurrence of spinal synovial cysts at the same-site or differing sites was compared between 2 categories of surgical treatment. Revision surgical procedure rates were also evaluated. RESULTS: A total of 55 (63%) patients were treated with an index decompression-only procedure for the lumbar spinal synovial cyst compared with 32 (37%) patients treated with an index decompression and fusion procedure. Fifty-eight (68%) of the lumbar spinal cysts occurred at the L4-L5 level. There were 10 (11.5%) spinal synovial cyst recurrences in the decompression-only group, and 0 recurrences in the decompression/fusion group. Revision decompression procedures were performed in 4 of the 10 (4.6%) recurrences, and 6 of 10 (6.9%) recurrences had subsequent decompression and fusion surgery. The mean time to recurrence was 23.9±17.3 months. The mean length of follow-up was 65.1±48.6 months. Both recurrence and nonrecurrence cohorts had significant symptomatic improvement using Odom criteria. CONCLUSIONS: Decompression and cyst excision was the more common surgical treatment of lumbar spinal synovial cysts compared with decompression/fusion procedure in our study. The rate of synovial cyst recurrence and revision surgery in patients undergoing index decompression was relatively low and comparable to current literature. Symptomatic improvement of patients undergoing decompression versus decompression/fusion was similar in our study. Although the fusion may be required for the extent of pathology or coexisting instability, decompression and excision of spinal synovial cysts provide durable, effective treatment with a known, appropriate risk of recurrence and subsequent revision surgery.

Activation of hippocampal microglia in a murine model of cancer-induced pain.

INTRODUCTION: Pain is a common and debilitating comorbidity of metastatic breast cancer. The hippocampus has been implicated in nociceptive processing, particularly relating to the subjective aspect of pain. Here, a syngeneic mouse model was used to characterize the effects of peripheral tumors on hippocampal microglial activation in relation to cancer-induced pain (CIP). MATERIALS AND METHODS: Mice were systemically treated with the colony-stimulating factor 1 receptor inhibitor Pexidartinib prior to intrafemoral (IF) or subcutaneous 4T1 carcinoma cell inoculation. Spontaneous and evoked nociceptive responses were quantitated throughout tumor development, and contralateral hippocampi were collected via endpoint microdissection for RNA analysis. Additionally, IF tumor-bearing animals were sacrificed on days 5, 10, 15, and 20 post 4T1 cell inoculation, and brain sections were immunofluorescently stained for Iba1, a marker of activated microglia. RESULTS: Ablation of these neuroimmune cells with the CSF1R inhibitor Pexidartinib delayed the onset and severity of cancer-induced nociceptive behaviors in IF tumor-bearing animals, adding to the body of literature that demonstrates microglial contribution to the development and maintenance of CIP. Furthermore, in untreated IF tumor-bearing mice, nociceptive behaviors appeared to progress in parallel with microglial activation in hippocampal regions. Immunofluorescent Iba1+ microglia increased in the dentate gyrus and cornu ammonis 1 hippocampal regions in IF tumor-bearing animals over time, which was confirmed at the mRNA level using relevant microglial markers. CONCLUSION: This is the first experimental evidence to demonstrate the effects of peripheral tumor-induced nociception on hippocampal microglial activation. The increase in hippocampal microglia observed in the present study may reflect the emotional and cognitive deficits reported by patients with CIP.

xCT knockdown in human breast cancer cells delays onset of cancer-induced bone pain.

Cancers in the bone produce a number of severe symptoms including pain that compromises patient functional status, quality of life, and survival. The source of this pain is multifaceted and includes factors secreted from tumor cells. Malignant cells release the neurotransmitter and cell-signaling molecule glutamate via the oxidative stress-related cystine/glutamate antiporter, system xC-, which reciprocally imports cystine for synthesis of glutathione and the cystine/cysteine redox cycle. Pharmacological inhibition of system xC- has shown success in reducing and delaying the onset of cancer pain-related behavior in mouse models. This investigation describes the development of a stable siRNA-induced knockdown of the functional trans-membrane system xC- subunit xCT ( SLC7A11) in the human breast cancer cell line MDA-MB-231. Clones were verified for xCT knockdown at the transcript, protein, and functional levels. RNAseq was performed on a representative clone to comprehensively examine the transcriptional cellular signature in response to xCT knockdown, identifying multiple differentially regulated factors relevant to cancer pain including nerve growth factor, interleukin-1, and colony-stimulating factor-1. Mice were inoculated intrafemorally and recordings of pain-related behaviors including weight bearing, mechanical withdrawal, and limb use were performed. Animals implanted with xCT knockdown cancer cells displayed a delay until the onset of nociceptive behaviors relative to control cells. These results add to the body of evidence suggesting that a reduction in glutamate release from cancers in bone by inhibition of the system xC- transporter may decrease the severe and intractable pain associated with bone metastases.

Inhibiting STAT3 in a murine model of human breast cancer-induced bone pain delays the onset of nociception.

Aggressive breast cancer subtypes utilize system xc-, a membrane antiporter, to import cystine for glutathione synthesis and maintenance of redox homeostasis, in turn releasing glutamate as a metabolic pro-nociceptive by-product. Metastatic breast cancers establish themselves at distal sites including bone, where changes in extracellular glutamate levels contribute to cancer-induced bone pain. We previously established that stearically blocking system xc- activity with sulfasalazine delays the onset of nociceptive behaviours and that xCT, the functional antiporter subunit, is positively regulated by signal transducer and activator of transcription 3 (STAT3). In the current investigation, a murine xenograft cancer-induced bone pain model was applied to examine whether pharmacological inhibition of phosphorylated STAT3 (pSTAT3) induces changes in nociception. A high glutamate-releasing, xCT/pSTAT3 over-expressing human breast cancer cell line was selected for injection into the distal epiphysis of the right femur of female nude mice. A 14-day regimen of intraperitoneal injections with either vehicle or the novel STAT3 inhibitor DR-1-55 commenced three weeks after initial intrafemoral bone injection. Nociceptive behaviours were temporally monitored by automated von Frey, dynamic weight bearing and open-field testing for the duration of the study, beginning at the baseline. Prior to sacrifice and at ethical end point, tumour-induced osteolytic lesions were radiographically assessed. Treatment with DR-1-55 significantly delayed the onset and severity of spontaneous and induced nociceptive behaviours, also decreasing human SLC7A11 ( xCT) mRNA levels in tumour-bearing limbs without altering osteolysis. In addition, two pro-inflammatory cytokines released by this cell line, interleukin 6 and interleukin 1ß, were also down-regulated at the mRNA level in response to DR-1-55 treatment in vivo, with lower human interleukin 6 levels detected in the host circulation. This study demonstrates that targeting pSTAT3 may be a viable therapeutic means to manage cancer-induced bone pain, alone or in combination with stearic system xc- blockers.

Development of a polyclonal antibody-based indirect competitive ELISA for determination of sterigmatocystin in wheat and corn flours.

Sterigmatocystin (STC) is a toxic secondary metabolite produced by more than 50 fungal species, including Aspergillus flavus, A. parasiticus, A. nidulans, and A. versicolor. The Joint FAO/WHO Expert Committee on Food Additives concluded that sterigmatocystin is genotoxic and carcinogenic with the critical effect determined to be carcinogenicity. The present study describes a simple method to prepare hapten and immunogens in order to generate polyclonal antibodies against this metabolite. We developed a sensitive and specific polyclonal antibody-based competitive indirect enzyme-linked immunosorbent assay (ciELISA) for monitoring STC in wheat and corn flours without the need for derivatisation of STC or clean-up of samples by immunoaffinity chromatography for quantification. The half inhibitory concentration (IC50) of the established method was 4.52 ± 0.81 ng mL-1, with the limit of detection (IC10) being 0.19 ± 0.04 ng mL-1 in wheat and corn flour matrices with the coefficient of variation of less than 22%.The assay was very specific to STC and showed no cross-reactivity with its analogue structures. The ELISA allowed for up to 5% methanol without significant influence on the IC50 value. Validation of the assay was performed by spiking STC into a blank flour matrix and the recoveries were in the range of 75.3 % to 104.5 % with a coefficient of variation less than 15%. A small retail survey was conducted by purchasing wheat (n = 8) and corn flours (n = 2) from local grocery stores. All of these retail samples were negative for STC using the developed ELISA method and were confirmed by LC-MS/MS. We demonstrated a rapid, simple, and reliable method for screening STC in wheat and corn flours.