Brain Metastases Are Regulated by Immuno-inflammatory Signaling Pathways Governed by STAT3, MAPK and Tumor Suppressor p53 Status: Possible Therapeutic Targets.

BACKGROUND/AIM: Brain metastasis (BM) is a complex multi-step process involving various immune checkpoint proteins. Mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) are implicated in tumorigenesis and are critical upstream regulators of Programmed Death Ligand 1 (PD-L1), an immunotherapy target. Tumor suppressor p53, dysregulated in cancers, regulates STAT3 and ERK1/2 signaling. This study examined the roles of STAT3, MAPK and p53 status in BM initiation and maintenance. MATERIALS AND METHODS: Twenty-six BM, with various primary malignancies, were used (IRB-approved) to determine mutant p53 (p53mt), pSTAT3Tyr705, pERK1/2Thr202/Tyr204, and PD-L1 expression using immunohistochemistry. cDNA microarray was used for gene expression analysis. Brain-metastatic breast cancer cells (MDA-MB-231) were treated with STAT3 (NSC74859) or MAPK/ERK1/2 (U0126) inhibitors in regular or astrocytic media. ERK1/2 pathway was assessed using western blotting, and cell proliferation and migration were determined using MTT and scratch-wound assays, respectively. RESULTS: pSTAT3Tyr705 and pERK1/2Thr202/Tyr204 were expressed at tumor margins, whereas p53mt and PD-L1 were uniformly expressed, with significant overlap between expression of these proteins. Gene expression analysis identified alterations in 18 p53- and 32 STAT3- or MAPK-associated genes contributing to dysregulated immune responses and cell cycle regulation. U0126 and NSC74859 reduced pERK1/2Thr202/Tyr204 expression. Cell proliferation decreased following each treatment (p≤0.01). Migration stagnated following U0126 treatment in astrocytic media (p≤0.01). CONCLUSION: Activation of STAT3 and ERK1/2 promotes BM and provides compelling evidence for use of STAT3, ERK1/2 and p53 status as potential immunotherapeutic targets in BM.

Does axial cervical pain improve with surgical fusion? A meta-analysis.

OBJECTIVE: Axial neck pain is a prevalent condition that causes significant morbidity and productivity loss. This study aimed to review the current literature and define the impact of surgical intervention on the management of cervical axial neck pain. METHODS: A search was conducted of three databases (Ovid MEDLINE, Embase, and Cochrane) for randomized controlled trials and cohort studies written in the English language with a minimum 6-month follow-up. The analysis was limited to patients with axial neck pain/cervical radiculopathy and preoperative/postoperative Neck Disability Index (NDI) and visual analog scale (VAS) scores. Literature reviews, meta-analyses, systematic reviews, surveys, and case studies were excluded. Two patient groups were analyzed: the arm pain predominant (pAP) cohort and the neck pain predominant (pNP) cohort. The pAP cohort had preoperative VAS neck scores that were lower than the arm scores, whereas the pNP cohort was defined as having preoperative VAS neck scores higher than the arm scores. A 30% reduction in patient-reported outcome measure (PROM) scores from the baseline represented the minimal clinically important difference (MCID). RESULTS: Five studies met the inclusion criteria, involving a total of 5221 patients. Patients with pAP showed a slightly higher percent reduction in PROM scores from baseline than those with pNP. The NDI reduction in patients with pNP was 41.35% (mean change in NDI score 16.3/mean baseline NDI score 39.42) (p < 0.0001), whereas those with pAP had a reduction of 45.12% (15.86/35.15) (p < 0.0001). Surgical improvement was slightly but similarly greater in pNP patients compared with pAP patients (16.3 vs 15.86 points, respectively; p = 0.3193). Regarding VAS scores, patients with pNP had a greater reduction in neck pain, with a change from baseline of 53.4% (3.60/6.74, p < 0.0001), whereas those with pAP had a change from baseline of 50.3% (2.46/4.89, p < 0.0001). The difference in VAS scores for neck pain improvement was significant (3.6 vs 2.46, p < 0.0134). Similarly, patients with pNP had a 43.6% (1.96/4.5) improvement in VAS scores for arm pain (p < 0.0001), whereas those with pAP had 66.12% (4.43/6.7) improvement (p < 0.0001). The VAS scores for arm pain were significantly greater in patients with pAP (4.43 vs 1.96 points, respectively; p < 0.0051). CONCLUSIONS: Overall, despite significant variations in the existing literature, there is mounting evidence that surgical intervention can lead to clinically meaningful improvements in patients with primary axial neck pain. The studies suggest that patients with pNP tend to have better improvement in neck pain than in arm pain. In both groups, the average improvements exceeded the MCID values and reached substantial clinical benefit in all studies. Further research is necessary to identify which patients and underlying pathologies will benefit most from surgical intervention for axial neck pain because it is a multifaceted condition with many causes.

Lumbar Synovial Cysts-Should You Fuse or Not?

BACKGROUND: Spinal synovial cysts are lesions that most commonly occur in the lumbar region. The need for an instrumented spinal fusion in addition to lumbar decompression with removal of the synovial cyst is unknown. OBJECTIVE: To test the hypothesis that select patients who underwent decompression with instrumented fusion for lumbar synovial cysts would be less likely to have subsequent surgery (SS) in a 2-year period than patients treated with laminectomy alone. METHODS: This retrospective cohort study was performed using IBM MarketScan Commercial Claims and Encounters Database. Patients who had a lumbar synovial cyst diagnosis and laminectomy surgery with or without fusion surgery were included in this study. Patients were tracked for SS 2 years after surgery. Laminectomy patients were propensity score-matched to laminectomy with fusion (LF) patients using a 2:1 ratio. The log-rank test and Cox regression were used to compare the cumulative incidence of SS between groups. RESULTS: There were 7664 and 1631 patients treated with laminectomy and LF before matching. After matching, there were 2212 laminectomy and 1631 LF patients and patient characteristics were balanced. The 2-year incidence of recurrent SS was 3.1% ([CI]: 2.2%, 4.0%) and 1.7% (95% CI: 0.9%, 2.5%) laminectomy and LF, respectively. Compared with laminectomy, LF had a statistically significant lower risk of recurrent SS (hazard ratio: 0.56 [95% CI: 0.32-0.97]; P -value: .04). CONCLUSION: All patients who had concomitant lumbar fusion showed decreased chance of having a cyst- or noncyst-related recurrence SS when compared with all patients undergoing laminectomy alone, regardless of diagnosis at the time of SS.

Preoperative meningioma embolization reduces perioperative blood loss: a multi-center retrospective matched case-control study.

BACKGROUND AND PURPOSE: The utility of preoperative embolization remains controversial within the literature. Here, we evaluate whether preoperative meningioma embolization is effective in reducing intraoperative blood loss, safe to perform, and cost-effective when compared with surgical resection without preoperative embolization. METHODS: Twenty-nine patients with meningiomas were matched by tumor size and location to 29 control patients with meningiomas at another institution where preoperative embolization was not practiced. The variables evaluated were pre- and post-operative hemoglobin and hematocrit levels as a measure of operative blood loss and postoperative morbidity. The additional cost of undergoing angiography and embolization was calculated from hospital charges obtained from the billing department. RESULTS: The mean decrease in perioperative hemoglobin and hematocrit was 0.9 and 2.7, respectively, in the embolization group and 2.8 and 10.0, respectively, in the control group for a significant decrease in operative blood loss as measured by change in hematocrit and hemoglobin levels after surgery. There was no significant difference in operative blood loss when subdividing patients based on tumor location. There were no angiogram-related complications. Twenty-two of 29 patients (76%) underwent embolization of a feeding artery, whereas 7 patients underwent only a diagnostic angiogram. The mean additional charge per patient in the embolization group was $88,767. CONCLUSIONS: Preoperative embolization was safe and effective in reducing the overall perioperative blood loss in patients undergoing meningioma resection, as measured by the change in postoperative hemoglobin and hematocrit levels. However, the cost of embolization was significant.

Spinal Epidural Abscess Patients Have Higher Modified Frailty Indexes Than Back Pain Patients on Emergency Room Presentation: A Single-Center Retrospective Case-Control Study.

OBJECTIVE: Spinal epidural abscess (SEA) patients have increased medical comorbidities and risk factors for infection compared with those without SEA. However, the association between frailty and SEA patients has not been documented. METHODS: A total of 46 SEA patients were randomly paired and matched by age and sex with a control group of patients with back pain who had presented to our emergency department from 2012 to 2017. Statistical analysis identified the risk factors associated with SEA and frailty using the modified frailty index (mFI), and the patients were stratified into robust, prefrail, and frail groups. We examined the value of the mFI as a prognostic predictor and evaluated the classic risk factors (CRFs). RESULTS: The SEA patients had higher mFIs and CRFs (P = 0.023 and P < 0.001, respectively) and a longer length of stay (22.89 days vs. 1.72 days; P < 0.001). Of the mFI variables, only diabetes had a significant association with SEA (odds ratio [OR], 3.60; P = 0.012). Among the stratified mFI subgroups, a frail ranking (mFI >2) was the strongest risk factor for SEA (OR, 5.18; P = 0.003). A robust ranking (mFI, 0-1) was a weak negative predictor for SEA (OR, 0.41; P = 0.058). The robust patients were also more likely to be discharged to home (OR, 7.58; P = 0.002). Of the CRF variables, only intravenous drug use had a statistically significant association with SEA (OR, 10.72; P = 0.015). CONCLUSIONS: Patients with SEA were more frail compared with the control back pain patients. Frailty was determined to be an independent risk factor for SEA, outside of the CRFs. The use of the mFI could be potentially useful in predicting the diagnosis, prognosticating, and guiding SEA treatment.

Retrosigmoid Craniectomy for Resection of Epidermoid causing Trigeminal Neuralgia.

The differential diagnosis for trigeminal neuralgia like-symptoms includes cerebellopontine angle lesions causing regional mass effect upon the trigeminal nerve ( Fig. 1 ). Here we present an operative video manuscript of a patient experiencing trigeminal neuralgia, secondary to an epidermoid cyst, in which a retrosigmoid craniectomy was performed to resect the epidermoid and decompress the trigeminal nerve ( Fig. 2 ). This video highlights the operative nuances to achieving a successful surgery, including appropriate patient positioning, dural exposure to the transverse-sigmoid sinus junction, arachnoid dissection, and decompression of cranial nerves. A gross total resection was achieved; the patient reported immediate relief of facial pain postoperatively and has been pain free at the ten month follow-up. The link to the video can be found at: https://youtu.be/Ja2eE0uGk4E .

Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship.

Activation of Mechanistic target of rapamycin (mTOR) signaling plays a crucial role in tumorigenesis of numerous malignancies including glioblastoma (GB). The Canonical PI3K/Akt/mTOR signaling cascade is commonly upregulated due to loss of the tumor suppressorm PTEN, a phosphatase that acts antagonistically to the kinase (PI3K) in conversion of PIP2 to PIP3. mTOR forms two multiprotein complexes, mTORC1 and mTORC2 which are composed of discrete protein binding partners to regulate cell growth, motility, and metabolism. These complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients while mTORC2 is regulated via PI3K and growth factor signaling. The main function of mTORC1 is to regulate protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. On the other hand, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK and it also plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. mTORC1 and mTORC2 regulate each other, as shown by the fact that Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin1 to modulate mTORC2 activity. Allosteric inhibitors of mTOR, rapamycin and rapalogs, remained ineffective in clinical trials of Glioblastoma (GB) patients, in part due to their incomplete inhibition of mTORC1 as well as unexpected activation of mTOR via the loss of negative feedback loops. In recent years, novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6KSer235/236, while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAKTSer473. Furthermore by these novel combined mTORC1/mTORC2 inhibitors reduced the proliferation and self-renewal of GB cancer stem cells. However, a search of more effective way to target mTOR has generated a third generation inhibitor of mTOR, "Rapalink", that bivalently combines rapamycin with an ATP-binding inhibitor, which effectively abolishes the mTORC1 activity. All in all, the effectiveness of inhibitors of mTOR complexes can be judged by their ability to suppress both mTORC1/mTORC2 and their ability to impede both cell proliferation and migration along with aberrant metabolic pathways.

Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition.

BACKGROUND: Traumatic spinal cord injury (SCI) triggers a chain of events that is accompanied by an inflammatory reaction leading to necrotic cell death at the core of the injury site, which is restricted by astrogliosis and apoptotic cell death in the surrounding areas. Activation of nuclear factor-κB (NF-κB) signaling pathway has been shown to be associated with inflammatory response induced by SCI. Here, we elucidate the pattern of activation of NF-κB in the pathology of SCI in rats and investigate the effect of transplantation of spinal neural precursors (SPC-01) on its activity and related astrogliosis. METHODS: Using a rat compression model of SCI, we transplanted SPC-01 cells or injected saline into the lesion 7 days after SCI induction. Paraffin-embedded sections were used to assess p65 NF-κB nuclear translocation at days 1, 3, 7, 10, 14, and 28 and to determine levels of glial scaring, white and gray matter preservation, and cavity size at day 28 after SCI. Additionally, levels of p65 phosphorylated at Serine536 were determined 10, 14, and 28 days after SCI as well as levels of locally secreted TNF-α. RESULTS: We determined a bimodal activation pattern of canonical p65 NF-κB signaling pathway in the pathology of SCI with peaks at 3 and 28 days after injury induction. Transplantation of SCI-01 cells resulted in significant downregulation of TNF-α production at 10 and 14 days after SCI and in strong inhibition of p65 NF-κB activity at 28 days after SCI, mainly in the gray matter. Moreover, reduced formation of glial scar was found in SPC-01-transplanted rats along with enhanced gray matter preservation and reduced cavity size. CONCLUSIONS: The results of this study demonstrate strong immunomodulatory properties of SPC-01 cells based on inhibition of a major signaling pathway. Canonical NF-κB pathway activation underlines much of the immune response after SCI including cytokine, chemokine, and apoptosis-related factor production as well as immune cell activation and infiltration. Reduced inflammation may have led to observed tissue sparing. Additionally, such immune response modulation could have impacted astrocyte activation resulting in a reduced glial scar.

The role of 5-aminolevulinic acid in spinal tumor surgery: a review.

PURPOSE: Primary intradural spinal neoplasms account for a small proportion of central nervous system tumors. The primary treatment for these tumors consists of maximal safe resection and preservation of neurologic function. Gross total resection, which is associated with the lowest rate of tumor recurrence and longer progression-free survival for most histologies, can be difficult to achieve. Currently, the use of 5-aminolevulinc acid (5-ALA) which takes advantage of Protoporphyrin IX (PpIX) fluorescence, is a well-established technique for improving resection of malignant cerebral gliomas. This technique is being increasingly applied to other cerebral neoplasms, and multiple studies have attempted to evaluate the utility of 5-ALA-aided resection of spinal neoplasms. METHODS: The authors reviewed the existing literature on the use of 5-ALA and PpIX fluorescence as an aid to resection of primary and secondary spinal neoplasms by searching the PUBMED and EMBASE database for records up to March 2018. Data was abstracted from all studies describing spinal neurosurgical uses in the English language. RESULTS: In the reviewed studies, the most useful fluorescence was observed in meningiomas, ependymomas, drop metastases from cerebral gliomas, and hemangiopericytomas of the spine, which is consistent with applications in cerebral neoplasms. CONCLUSIONS: The available literature is significantly limited by a lack of standardized methods for measurement and quantification of 5-ALA fluorescence. The results of the reviewed studies should guide future development of rational trial protocols for the use of 5-ALA guided resection in spinal neoplasms.

Spinal Cord Compression Secondary to Metastatic Sinonasal Undifferentiated Carcinoma.

Sinonasal undifferentiated carcinoma (SNUC) is a rare malignancy of the upper airways and anterior skull base that carries a poor prognosis. The tumor is known to be invasive into the surrounding structures of the skull base and brain. To date, there is only one existing case report documenting drop metastasis to the intradural extramedullary spinal cord. To the best of our knowledge, we present the second case of metastatic SNUC to the spine. This report describes a 59-year-old male with a history of head and neck SNUC who presented with thoracic back pain and bilateral lower extremity paresis. Neuroimaging demonstrated an extradural thoracic mass with severe spinal cord compression. The patient underwent thoracic laminectomy and fusion for decompression of the spinal cord and internal stabilization. The pathology returned as SNUC. The patient was subsequently lost to follow-up from our institution. Metastatic SNUC is rare. We discuss the relevant clinical imaging and review the literature. Such a malignancy portends a very poor prognosis.