Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.

High-Volume Centers Provide Superior Value of Care in the Surgical Treatment of Malignant Brain Tumor.

BACKGROUND: Improved outcomes in surgical patients have been associated with increasing volume of cases. This has led to the development of centers that facilitate care for a specific patient population. This study aimed to evaluate associations of outcomes with hospital characteristics in patients undergoing resection of malignant brain tumors. METHODS: The 2016-2020 National Inpatient Sample was queried for patients undergoing resection of malignant brain tumors. Teaching hospitals with caseloads >2 standard deviations above the mean (140 cases) were categorized as high-volume centers (HVCs). Value of care was evaluated by adding one point for each of the following: short length of stay, low total charges, favorable discharge disposition, and lack of major comorbidity or complication. RESULTS: In 3009 hospitals, 118,390 patients underwent resection of malignant brain tumors. HVC criteria were met by 91 (3%) hospitals. HVCs were more likely to treat patients of younger age or higher socioeconomic status (P < 0.01 for all). The Mid-Atlantic and South Atlantic regions had the highest percentage of cases and number of HVCs. Value of care was higher at HVCs (P < 0.01). Care at HVCs was associated with decreased complications (P < 0.01 for all) and improved patient outcomes (P < 0.01 for all). CONCLUSIONS: Patients undergoing craniotomy for malignant brain neoplasms have superior outcomes in HVCs. Trends of centralization may reflect the benefits of multidisciplinary treatment, geographic preferences, publicity, and cultural impact. Improvement of access to care is an important consideration as this trend continues.

Distinctive Characteristics of Thoracolumbar Junction Region Stenosis.

STUDY DESIGN: Retrospective case series and systemic literature meta-analysis. BACKGROUND: Thoracolumbar junction region stenosis produces spinal cord compression just above the conus and may manifest with symptoms that are not typical of either thoracic myelopathy or neurogenic claudication from lumbar stenosis. OBJECTIVE: As few studies describe its specific pattern of presenting symptoms and neurological deficits, this investigation was designed to improve understanding of this pathology. METHODS: A retrospective review assessed surgically treated cases of T10-L1 degenerative stenosis. Clinical outcomes were evaluated with the thoracic Japanese Orthopedic Association score. In addition, a systematic review and meta-analysis was performed in accordance with guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Of 1069 patients undergoing laminectomy at 1477 levels, 31 patients (16M/15F) were treated at T10-L1 a mean age 64.4 (SD=11.8). Patients complained of lower extremity numbness in 29/31 (94%), urinary dysfunction 11/31 (35%), and back pain 11/31 (35%). All complained about gait difficulty and objective motor deficits were detected in 24 of 31 (77%). Weakness was most often seen in foot dorsiflexion 22/31 (71%). Deep tendon reflexes were increased in 10 (32%), decreased in 11 (35%), and normal 10 (32%); the Babinski sign was present 8/31 (26%). Mean thoracic Japanese Orthopedic Association scores improved from 6.4 (SD=1.8) to 8.4 (SD=1.8) ( P <0.00001). Gait subjectively improved in 27/31 (87%) numbness improved in 26/30 (87%); but urinary function improved in only 4/11 (45%). CONCLUSIONS: Thoracolumbar junction stenosis produces distinctive neurological findings characterized by lower extremity numbness, weakness particularly in foot dorsiflexion, urinary dysfunction, and inconsistent reflex changes, a neurological pattern stemming from epiconus level compression and the myelomeres for the L5 roots. Surgery results in significant clinical improvement, with numbness and gait improving more than urinary dysfunction. Many patients with thoracolumbar junction stenosis are initially misdiagnosed as being symptomatic from lumbar stenosis, thus delaying definitive surgery.

The story of dexamethasone and how it became one of the most widely used drugs in neurosurgery.

Dexamethasone, a long-acting potent glucocorticoid, is one of the most widely used medications in neurosurgery. In this paper, the authors recount the history of dexamethasone's rise in neurosurgery and discuss its use in brain tumors in the context of emerging neuro-oncological immunotherapies. In 1958, Glen E. Arth synthesized a 16-alpha-methylated analog of cortisone (dexamethasone) for treatment of rheumatoid arthritis. Joseph Galicich, a neurosurgery resident at the time, applied the rheumatological drug to neurosurgery. He gave doses to patients who had undergone craniotomy for tumor removal and saw their paresis improve, midline shift resolve, and mortality rates decrease. He advocated for clinical trials and the drug became a mainstay in neurosurgery. As neuro-oncological treatments evolve to include immunotherapy, the immunosuppressive effects of dexamethasone are becoming an unwanted effect. The question then becomes: how does one treat the patient's symptoms if the only drug that has been used throughout history may become a detriment to their oncological treatment? Since its discovery, dexamethasone has maintained an impressive staying power in the field, acting as a standard drug for cerebral edema for more than 60 years. However, with the advent of immunotherapy, research is warranted to evaluate ways of treating symptomatic edema in the context of modern neuro-oncological therapies.

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.

Independent predictors of systemic inflammatory response syndrome for intramedullary nailing of femoral shaft fractures: Analysis of national inpatient sample database.

Background: The systemic inflammatory response syndrome (SIRS) is a clinical reaction that can occur due to a variety of stimuli. Reamed intramedullary femoral nailing is a common orthopedic surgery that has been shown to induce SIRS. To date, no nationwide analyses have been performed to evaluate the incidence, risk factors, and economic burdens of SIRS following intramedullary femoral nailing for femoral shaft fractures. The objective of this study is to investigate the independent predictors, incidence, post-operative, and economic burden of SIRS among patients treated with intramedullary nailing for femoral shaft fractures. Methods: We utilized the 2016-2019 National Inpatient Sample (NIS) to identify patients who underwent intramedullary femoral nailing and were diagnosed with non-infectious SIRS (NI-SIRS) based on ICD-10-CM coding. Identified patients who underwent intramedullary femoral nailing were dichotomized into SIRS and Non-SIRS groups to assess independent predictors of SIRS development, and to compare post-operative complications and costs. Results: A total of 65,240 patients with femur shaft fractures underwent IMFN, of which 665 (1.0 %) developed NI-SIRS. Patients with NI-SIRS had a higher incidence of laparotomy (OR = 13.97, p < 0.001), initial treatment with external fixation (OR = 1.845, p < 0.001), and late application of external fixation (OR = 4.884, p = 0.005). Routine discharge (OR = 0.491, p < 0.001) was less likely in patients with NI-SIRS. Length of stay (12.38 days vs 7.16 days, p < 0.001) and total charges ($278, 590 vs $145,118, p < 0.001) were both increased in patients with NI-SIRS. Conclusion: NI-SIRS is associated with increasing injury severity and post-operative complications. Those that developed NI-SIRS experienced higher healthcare resource utilization. Risk factors associated with development of NI-SIRS warrant further investigation.

Dural Closure Techniques and Cerebrospinal Fluid Leak Incidence After Resection of Primary Intradural Spinal Tumors: A Systematic Review.

STUDY DESIGN: This is a systematic review of primary intradural spinal tumors (PIDSTs) and the frequency of postoperative cerebrospinal fluid (CSF) leaks. OBJECTIVE: This study aimed to compare CSF leak rates among techniques for dural watertight closure (WTC) after the resection of PIDSTs. SUMMARY OF BACKGROUND DATA: Resection of PIDSTs may result in persistent CSF leak. This complication is associated with infection, wound dehiscence, increased length of stay, and morbidity. Dural closure techniques have been developed to decrease the CSF leak rate. METHODS: A PubMed search was performed in 2022 with these inclusion criteria: written in English, describe PIDST patients, specify the method of dural closure, report rates of CSF leak, and be published between 2015 and 2020. Articles were excluded if they had <5 patients. We used standardized toolkits to assess the risk of bias. We assessed patient baseline characteristics, tumor pathology, CSF leak rate, and dural closure techniques; analysis of variance and a 1-way Fisher exact test were used. RESULTS: A total of 4 studies (201 patients) satisfied the inclusion criteria. One study utilized artificial dura (AD) and fibrin glue to perform WTC and CSF diversion, with lumbar drainage as needed. The rate of CSF leak was different among the 4 studies (P=0.017). The study using AD with dural closure adjunct (DCA) for WTC was associated with higher CSF leak rates than those using native dura (ND) with DCA. There was no difference in CSF leak rate between ND-WTC and AD-DCA, or with any of the ND-DCA studies. CONCLUSIONS: After resection of PIDSTs, the use of autologous fat grafts with ND resulted in lower rates of CSF leak, while use of fibrin glue and AD resulted in the highest rates. These characteristics suggest that a component of hydrophobic scaffolding may be required for WTC. A limitation included articles with low levels of evidence. Continued investigation to understand mechanisms for WTC is warranted. LEVEL OF EVIDENCE: Level 3.

Comparison of Characteristics, Inpatient Outcomes, and Trends in Percutaneous Versus Open Placement of Spinal Cord Stimulators.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective treatment modality for chronic pain conditions for which other treatment modalities have failed to provide relief. Ample prospective studies exist supporting its indications for use and overall efficacy. However, less is known about how SCS is used at the population level. Our objective is to understand the demographics, clinical characteristics, and utilization patterns of open and percutaneous SCS procedures. MATERIALS AND METHODS: The Nationwide Inpatient Sample data base of 2016-2019 was queried for cases of percutaneous or open placement (through laminotomy/laminectomy) of SCS (excluding SCS trials) using International Classification of Disease (ICD), 10th revision, procedure coding system. Baseline demographic characteristics, complications, ICD-Clinical Modification, Diagnosis Related Group, length of stay (LOS), and yearly implementation data were collected. Complications and outcomes were evaluated in total and between the open and percutaneous SCS groups. RESULTS: A total of 2455 inpatients had an SCS placed, of whom 1970 (80.2%) received SCS through open placement. Placement of open SCS was associated with Caucasian race (odds ratio [OR] = 1.671, p < 0.001), private insurance (OR = 1.332, p = 0.02), and age more than 65 years (OR = 1.25, p = 0.034). The most common diagnosis was failed back surgery syndrome (23.8%). Patients with percutaneous SCS were more likely to have a hospital stay of < 1 day (OR = 2.318; 95% CI, 1.586-3.387; p < 0.001). Implant complications during the inpatient stay were positively associated with open SCS placement and reported in 9.4% of these cases (OR = 3.247, p < 0.001). CONCLUSIONS: Patients who underwent open SCS placement were more likely to be older, Caucasian, and privately insured. Open SCS placement showed greater LOS and implant-related complications during their hospital stay. These findings highlight both potential socioeconomic disparities in health care access for chronic pain relief and the importance of increasing age and medical comorbidities as important factors that can influence SCS implants in the inpatient setting.

Adult Trauma Patients With Thoracolumbar Injury Classification and Severity Score of 4: A Systematic Review.

STUDY DESIGN: Systematic review. OBJECTIVE: Evaluate characteristics of patients with thoracolumbar injury classification and severity (TLICS) score of 4 (To4) severity traumatic thoracolumbar injury. SUMMARY OF BACKGROUND DATA: The TLICS score is used to predict the need for operative versus nonoperative management in adult patients with traumatic thoracolumbar injury. Ambiguity exists in its application and score categorization. METHODS: A systematic review of the literature was performed. The databases of MEDLINE, Embase, Web of Science, and Cochrane Review were queried. Studies included adults with traumatic thoracolumbar injury with assigned TLICS score and description of management strategy. RESULTS: A total of 16 studies met inclusion criteria representing 1911 adult patients with traumatic thoracolumbar injury. There were 503 (26.32%) patients with To4, of which 298 (59.24%) were operative. Studies focusing on the thoracolumbar junction and AO Type A fracture morphology had To4 patient incidences of 11.15% and 52.94%, respectively. Multiple studies describe better quality of life, pain scores, and radiographic outcomes in To4 who underwent operative treatment patients. CONCLUSION: To4 injuries are more commonly AO Type A and located in the thoracolumbar junction in adult patients with traumatic thoracolumbar injury. Despite ambiguous recommendations regarding treatment provided by TLICS, outcomes favor operative intervention in this subset of traumatic thoracolumbar injury patients.

Frailty Is Superior to Age for Predicting Readmission, Prolonged Length of Stay, and Wound Infection in Elective Otology Procedures.

OBJECTIVE: To determine the predictive ability of the 5-point modified frailty index relative to age in elective otology patients. STUDY DESIGN: Retrospective database analysis. SETTING: Multicenter, national database of surgical patients. PATIENTS: We selected all elective surgical patients who received tympanoplasty, tympanomastoidectomy, mastoidectomy, revision mastoidectomy, and cochlear implant procedures from 2016 to 2019 from the National Surgical Quality Improvement database. INTERVENTIONS: Therapeutic. MAIN OUTCOME MEASURES: Readmission rates, discharge disposition, reoperation rates, and extended length of hospital stay. RESULTS: Utilizing receiver operating characteristics with area under the curve (AUC) analysis, nonrobust status was determined to be a superior predictor relative to age of readmission (AUC = 0.628 [p < 0.001] versus AUC = 0.567 [p = 0.047], respectively) and open wound infection relative to age (AUC = 0.636 [p = 0.024] versus AUC = 0.619 [p = 0.048], respectively). Nonrobust otology patients were more likely to have dyspnea at rest and an American Society of Anesthesiology score higher than 2 before surgery (odds ratios, 13.304 [95% confidence interval, 2.947-60.056; p < 0.001] and 7.841 [95% confidence interval, 7.064-8.704; p < 0.001], respectively). CONCLUSION: Nonrobust status was found to be a useful predictor of readmission and prolonged length of stay in patients undergoing elective otology procedures, which generally have low complication rate. Given the aging population and corresponding increase in otology disease, it is important to use age-independent risk stratification measures. Frailty may provide a useful risk stratification tool to select surgical candidates within the aging population.

Management and outcomes of adult traumatic cervical spondyloptosis: A case report and systematic review.

STUDY DESIGN: Systematic Review. OBJECTIVE: To elucidate treatment modalities and outcomes of patients with traumatic cervical spondyloptosis (TCS). SUMMARY: Traumatic cervical spondyloptosis (TCS) is rare and typically leads to devastating neurological injury. Management strategies vary from case to case. METHODS: A systematic review of the literature identified cases of adult TCS, and data was analyzed to characterize the patient population and to assess factors that influenced clinical outcome. In addition, an illustrative case is presented in which closed reduction of a severe C7-T1 spondyloptosis injury was guided with the use of cone beam computerized tomography (O-Arm) to overcome difficulties with visualizing the cervicothoracic junction region. RESULTS: In addition to our case, we identified 52 cases of adult TCS from 34 articles. Patient age ranged from 18 to 73 (average 45.6) with male a predominance (n = 37, 71.2%). Neurological function on presentation was most commonly ASIA E (34.6%), followed by ASIA D (21.2%) and ASIA A (19.2%). The most frequently affected levels were C7-T1 (44.2%) followed by C6-7 (33.0%). Closed reduction was attempted in 42 (80.8%) patients. A total of 49 (94.2%) patients underwent surgical treatment, with 31 (63.3%) undergoing single-approach procedures. The presence of neurological injury, cervical level of injury, and age were not significant predictors of successful closed reduction. Similarly, successful closed reduction, age, cervical level of injury, and neurological injury were not predictors of a single-approach treatment. CONCLUSION: TCS is rare and most frequently appears at or near the cervicothoracic junction and in males. The presentation is typically that of severe neurological injury, but partial neurological recovery occurs in many patients. No predictors of successful closed reduction or single approach surgery are identified. We postulate that the use of intraoperative multiplanar imaging technology like the O-Arm may enhance the ability to achieve a successful closed reduction given the predilection for the injury to occur at the cervicothoracic junction. Prospective study of the durability of constructs by single or combined approaches is warranted.

Cervical fusion for adult patients with atlantoaxial rotatory subluxation.

Background: Atlantoaxial rotatory subluxation (AARS) is a rare injury of the C1/C2 junction. It is often associated with trauma in adults. Treatment may depend on the duration of symptoms and clinical presentation, but there is no consensus regarding the ideal management of these injuries. Our objective is to ascertain the prevalence of neurological deficit, complications, and outcomes of patients diagnosed with AARS undergoing cervical fusion (CF) versus those treated without CF. Methods: The 2016-2019 National Inpatient Sample (NIS) was queried using International Classification of Diseases, 10th revision (ICD-10) for adult patients with C1/C2 subluxation. Patients undergoing CF were defined through ICD-10 procedure codes. Baseline health and acute illness severity was calculated using the 11-point modified frailty index (mFI-11). Presenting characteristics, treatment complications, and outcomes were evaluated of CF vs. non-CF patients. Results: Of 990 adult patients with AARS, 720 were treated without CF and 270 were treated with CF. CF patients were more often myelopathic. Patients that had undergone CF treatment were negatively associated with having had extensive trauma. Patients undergoing CF experienced significantly longer length of stay (LOS), increased healthcare resource utilization, and decreased inpatient mortality. Sepsis had a negative association with patients that underwent CF treatment while pneumonia had a positive association. Conclusions: Adult patients undergoing CF for AARS demonstrated an increase in healthcare resource utilization but also a significant decrease in mortality. Extent of acute injury appears to have a strong influence on decision making for CF. Further study of decision making for treatment of this rare injury in adults is warranted.

Characteristics of Patients Selected for Surgical Treatment of Spinal Meningioma.

BACKGROUND: Spinal meningiomas are benign extra-axial tumors that can present with neurological deficits. Treatment partly depends on the degree of disability as there is no agreed-upon patient selection algorithm at present. We aimed to elucidate general patient selection patterns in patients undergoing surgery for spinal meningioma. METHODS: Data for patients with spinal tumors admitted between 2016 and 2019 were extracted from the U.S. Nationwide Inpatient Sample. We identified patients with a primary diagnosis of spinal meningioma (using International Classification of Disease, 10th revision codes) and divided them into surgical and nonsurgical treatment groups. Patient characteristics were evaluated for intergroup differences. RESULTS: Of 6395 patients with spinal meningioma, 5845 (91.4%) underwent surgery. Advanced age, nonwhite race, obesity, diabetes mellitus, chronic renal failure, and anticoagulant/antiplatelet use were less prevalent in the surgical group (all P < 0.001). The only positive predictor of surgical treatment was elective admission status (odds ratio, 3.166; P < 0.001); negative predictors were low income, Medicaid insurance, anxiety, obesity, and plegia. Patients with bowel-bladder dysfunction, plegia, or radiculopathy were less likely to undergo surgical treatment. The surgery group was less likely to experience certain complications (deep vein thrombosis, P < 0.001; pulmonary embolism, P = 0.002). Increased total hospital charges were associated with nonwhite race, diabetes, depression, obesity, myelopathy, plegia, and surgery. CONCLUSIONS: Patients treated surgically had a decreased incidence of complications, comorbidities, and Medicaid payer status. A pattern of increased utilization of health care resources and spending was also observed in the surgery group. The results indicate a potentially underserved population of patients with spinal meningioma.

Responsive Neurostimulation Targeting the Anterior, Centromedian and Pulvinar Thalamic Nuclei and the Detection of Electrographic Seizures in Pediatric and Young Adult Patients.

Background: Responsive neurostimulation (RNS System) has been utilized as a treatment for intractable epilepsy. The RNS System delivers stimulation in response to detected abnormal activity, via leads covering the seizure foci, in response to detections of predefined epileptiform activity with the goal of decreasing seizure frequency and severity. While thalamic leads are often implanted in combination with cortical strip leads, implantation and stimulation with bilateral thalamic leads alone is less common, and the ability to detect electrographic seizures using RNS System thalamic leads is uncertain. Objective: The present study retrospectively evaluated fourteen patients with RNS System depth leads implanted in the thalamus, with or without concomitant implantation of cortical strip leads, to determine the ability to detect electrographic seizures in the thalamus. Detailed patient presentations and lead trajectories were reviewed alongside electroencephalographic (ECoG) analyses. Results: Anterior nucleus thalamic (ANT) leads, whether bilateral or unilateral and combined with a cortical strip lead, successfully detected and terminated epileptiform activity, as demonstrated by Cases 2 and 3. Similarly, bilateral centromedian thalamic (CMT) leads or a combination of one centromedian thalamic alongside a cortical strip lead also demonstrated the ability to detect electrographic seizures as seen in Cases 6 and 9. Bilateral pulvinar leads likewise produced reliable seizure detection in Patient 14. Detections of electrographic seizures in thalamic nuclei did not appear to be affected by whether the patient was pediatric or adult at the time of RNS System implantation. Sole thalamic leads paralleled the combination of thalamic and cortical strip leads in terms of preventing the propagation of electrographic seizures. Conclusion: Thalamic nuclei present a promising target for detection and stimulation via the RNS System for seizures with multifocal or generalized onsets. These areas provide a modifiable, reversible therapeutic option for patients who are not candidates for surgical resection or ablation.

Frailty is a risk factor for intracranial abscess and is associated with longer length of stay: a retrospective single institution case-control study.

BACKGROUND: Intracranial abscess (IA) causes significant morbidity and mortality. The impact of baseline frailty status on post-operative outcomes of IA patients remains largely unknown. The present study evaluated if frailty status can be used to prognosticate outcomes in IA patients. METHODS: We retrospectively reviewed all IA patients undergoing craniotomy at our institution from 2011 to 2018 (n =18). These IA patients were age and gender matched with patients undergoing craniotomy for intracranial tumor (IT), an internal control for comparison. Demographic and clinical data were collected to measure frailty, using the modified frailty index-11 (mFI-11), pre-operative American Society of Anesthesiologists Physical Status Classification System (ASA), and study their association with post-operative complications, as measured by the Clavien-Dindo Grade (CDG). RESULTS: No significant difference in mFI-11 or ASA score was observed between the IA and IT groups (p = 0.058 and p = 0.131, respectively). IA patients had significantly higher CDG as compared with the control IT patients (p < 0.001). There was a trend towards increasing LOS in the IA group as compared to the IT group (p = 0.053). Increasing mFI and ASA were significant predictors of LOS by multiple linear regression in the IA group (p = 0.006 and p = 0.001, respectively), but not in the control IT group. Neither mFI-11 nor ASA were found to be predictors for CDG in either group. Within this case-control group of patients, we found an increase for odds of having IA with increasing mFI (OR 1.838, CI 95% 1.016-3.362, p = 0.044). CONCLUSIONS: Frail IA patients tend to have more severe postoperative complications. The mFI-11 seems to predict increased resource utilization in the form of LOS. This study provides the initial retrospective data of another neurosurgical pathology where frailty leads to significantly worse outcomes. We also found that mFI may serve as a potential risk factor for severe disease.

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets - Beyond B Lymphocytes.

The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.

Correction of Sagittal Balance With Resection of Kissing Spines.

Kissing spines syndrome, also known as Baastrup's disease, is a common yet underdiagnosed disorder involving close approximation of adjacent spinous processes. These painful pseudoarticulations may be secondary to the compensatory mechanisms that result from sagittal imbalance. Conventional operative correction of sagittal balance includes a wide range of procedures from facetectomies to vertebral column resection. Resection of kissing spines for the operative management of sagittal imbalance is a treatment modality not extensively discussed in the literature but may offer improved patient outcomes with shorter operative times, lower risk, and reduced length of stay. A 67-year old male with a history of degenerative disk disease and scoliosis presented with neurogenic claudication and severe back pain that worsened with walking and improved with sitting. X-ray imaging of the lumbar spine revealed straightening of the normal lumbar lordotic curvature with mild rotoscoliosis. There was also evidence of retrolisthesis of L2 on L3 that worsened with flexion. The patient had Baastrup's disease at the L3-4 and L4, 5 levels that contributed to his reduced range of motion on extension imaging. Operative treatments including long-segment fusion with interbody cages to correct sagittal balance were considered with a discussion of possible debilitating and high-risk post-surgical outcomes. Instead, the patient underwent a simple decompression surgery involving laminectomies and resection of kissing spines to correct his sagittal imbalance. Postoperative follow-up imaging demonstrated significant improvement in sagittal balance, and the patient expressed relief of back and leg pain. Although underdiagnosed, consideration of kissing spines syndrome in the surgical correction of sagittal imbalance may offer an improvement over conventional operations. Our case presents a unique surgical perspective on the treatment of spinal stenosis with kissing spines with particular regard to correcting the sagittal imbalance, avoiding debilitating procedures, and providing better immediate postoperative outcomes.