The Diagnostic and Therapeutic Role of Leptin and Its Receptor ObR in Glioblastoma Multiforme.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.

Leptin and Associated Mediators of Immunometabolic Signaling: Novel Molecular Outcome Measures for Neurostimulation to Treat Chronic Pain.

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.

Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study.

OBJECTIVE: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. METHODS: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. RESULTS: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1ß was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p < 0.05]. Concentrations of high-mobility group box-1 (HMGB-1), IL-6, tumor-necrosis factor-α (TNF-α), leptin, adiponectin, ghrelin remained unchanged [p > 0.05]. No severe device-/stimulation-related adverse events occurred. CONCLUSION: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/month. Pro-inflammatory IL-1ß plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro- [IL-6, HMGB-1, TNF-α, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics].

Selective L4 Dorsal Root Ganglion Stimulation Evokes Pain Relief and Changes of Inflammatory Markers: Part I Profiling of Saliva and Serum Molecular Patterns.

OBJECTIVES: Complex regional pain syndrome (CRPS) and associated comorbidities have been linked to a pro-inflammatory state driven by different mediators. Targeted dorsal root ganglion stimulation (DRGSTIM ) suppressed pain levels and improved functional capacity in intractable CRPS. However, clinical trials assessing the impact of DRG stimulation on the neuroimmune axis are lacking. METHODS: This study enrolled 24 subjects (12 refractory CRPS patients plus suitably matched healthy controls) and performed immunoassays of inflammatory mediators in saliva and serum along with score-based assessments of pain, mood, and sleep quality at baseline and after three months of selective L4-DRGSTIM . RESULTS: After three-month L4-DRGSTIM CRPS associated pain significantly decreased. In addition, disturbed sleep and mood improved post-DRGSTIM , although statistically not significant. Significantly increased serum values of pro-inflammatory markers were detected pre- and post L4-DRGSTIM for high-mobility group box 1, tumor-necrosis factor α, interleukin (IL) 6, and leptin. IL-1ß was significantly elevated pre-L4 DRGSTIM , but not posttreatment. Elevated anti-inflammatory IL-10 significantly decreased after three months in serum, while saliva oxytocin concentrations increased in CRPS subjects after L4-DRGSTIM (p = 0.65). No severe implantation and stimulation associated adverse events were recorded. CONCLUSIONS: Selective L4-DRGSTIM improved neuropathic pain and functional impairment in CRPS as previously reported. CRPS patients displayed a pro-inflammatory molecular pattern in serum. Serum anti-inflammatory IL-10 significantly declined, while saliva oxytocin nonsignificantly increased after L4-DRGSTIM . An evidence-based relational interpretation of our study is limited due to the uncontrolled study design. However, molecular profiling of biofluids (saliva, serum) represents a novel and experimental field in applied neuromodulation, which warrant further investigations to unveil mechanisms of neuroimmune modulation.

Burst Spinal Cord Stimulation Increases Peripheral Antineuroinflammatory Interleukin 10 Levels in Failed Back Surgery Syndrome Patients With Predominant Back Pain.

OBJECTIVES: Burst spinal cord stimulation (SCS) has been reported to reduce back pain and improve functional capacity in Failed Back Surgery Syndrome (FBSS). However, its mechanism of action is not completely understood. Systemic circulating cytokines have been associated with the development of chronic back pain. METHODS: This prospective, feasibility study enrolled 12 refractory FBSS patients with predominant back pain (70% of overall pain) suitable for Burst SCS. Back and leg pain intensity (back pain [VASB ]/leg pain [VASL ]), functional capacity (sleep quality [PSQI]), depressive symptoms (BDI), body weight, stimulation parameters, and plasma levels of pro-inflammatory (Il-1b; TNF; HMGB1)/anti-inflammatory (Il-10) cytokines were collected at baseline and after three months of Burst SCS and compared to healthy controls. RESULTS: Pain intensity (pre VASB : 8.25 ± 0.75 vs. post 1.42 ± 1.24) and functional capacity (PSQI: pre 7.92 ± 3.92 vs. post 3.42 ± 1.24; BDI: pre 20.83 ± 3.56 vs. post 10.92 ± 0.75) significantly improved compared to baseline. Pro-inflammatory HMGB1 remained unchanged (preburst: 3.35 ± 3.25 vs. postburst: 3.78 ± 3.83 ng/mL; p = 0.27; W = -30) versus the HC group (2.53 ± 2.6 ng/mL; p = 0.47; U = 59), while anti-inflammatory IL-10 levels were significantly elevated after burst SCS as compared to baseline (preburst 12.54 ± 22.95 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48) and HC group (HC: 7.03 ± 11.6 vs. postburst 43.16 ± 74.71 pg/mL; p = 0.03; W = -48; p = 0.04). Baseline preburst IL-10 values and preburst VASB significantly correlated (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while correlation was not significant between postburst IL-10 values and postburst VASB (Spearman correlation r = -0.49; p = 0.18; 95 CI -0.83 to -0.15). Postburst IL-10 values correlated significantly with postburst PSQI scores (Spearman correlation r = -0.66; p = 0.05; 95 CI -0.86 to -0.24), while no correlation was found between preburst and postburst changes related to the BDI. CONCLUSIONS: Burst SCS increased systemic circulating anti-inflammatory IL-10, improved FBSS back pain and back pain associated co-morbidities like disrupted sleep architecture and depressive symptoms in FBSS patients. Thus, suggesting a possible relationship between burst SCS and burst-evoked modulation of peripheral anti-inflammatory cytokine IL-10 in chronic back pain.