Predictive modeling for pituitary adenomas: single center experience in 501 consecutive patients.

BACKGROUND: Personalized postoperative management of patients with pituitary adenomas requires an early risk stratification system. METHODS: We reviewed 501 cases operated between 10/27/2011 and 5/5/2016 by a single neurosurgeon. We determined biochemical remission and tumor resection at 3 months, and biochemical recurrence, tumor recurrence, radiation and reoperation during follow-up. We considered age, gender, tumor diameter, cavernous sinus invasion (CSI) by MRI, diagnostic category (clinical, biochemical and immunohistochemical), and proliferation markers in a Cox proportional hazards model. We built predictive models with the significant parameters and used Kaplan-Meier survival curves for time-dependent analyses. RESULTS: The 501 cases comprised 141 functional and 360 nonfunctional adenomas. Tumor diameter, CSI, and ki-67 index predicted long-term events. Model 1 (CSI, diameter ≥ 2.9 cm and ki-67 > 3%) identified 18 (3.6%) adenomas and predicted persistent hypersecretory syndrome and residual tumor with 98.7% specificity (OR 8.6; CI 3.0-24.7). Model 2 (ki-67 > 3% and CSI) identified 48 (9.6%) adenomas and had 93.1% specificity (OR 3.3; CI 1.8-6.0). Model 3 (ki-67 > 3%, mitoses and p53, former "atypical" adenoma) identified 26 (5.2%) adenomas and had 96.0% specificity (OR 2.3; CI 1.0-5.0). Model 1 best predicted the long-term event-free survival and was strengthened when Knosp 3-4 CSI grades were used. Model 2 better identified the smaller adenomas at risk. Among the WHO 2017 special PA subtypes, patients with silent corticotroph adenoma had a lower event-free survival than ACTH-negative nonfunctional adenomas. CONCLUSION: Use of CSI, ki-67 and tumor diameter in prediction models facilitates tailored surveillance and management of patients with pituitary adenomas.

Pituitary adenomas: screening for G alpha q mutations.

Mutant, guanosine triphosphatase-deficient, alpha-subunits of the G protein, Gs, gsp ocogene have been discovered in 40% of GH-secreting pituitary adenomas. Therefore, we hypothesized that a novel G protein class, G alpha q, involved in pituitary signal transduction, might be involved in pituitary tumorigenesis. Recombinant mutations of G alpha q result in constitutive activation of phospholipase C and have transforming activity. Therefore, we screened tumor samples from 37 pituitary adenomas for the presence of activating mutations of the G alpha q gene. Importantly, our sample contains 8 FSH and LH adenomas. In the pituitary gland, FSH and LH are linked to the GnRH-G alpha q signaling cascade, making these tumors a logical choice for screening for G alpha q mutations. Complementary DNA (cDNA) was synthesized by RT-PCR with G alpha q specific primers to exclude pseudogene transcripts. Fragments of G alpha q cDNA-encompassing residues (Arg183, Gln209) were screened by single-strand conformation polymorphism and then sequenced in both directions. No mutations were detected. We conclude that mutations in these regions of the G alpha q cDNA occur infrequently, if at all, in human pituitary adenomas. Alternative mechanisms underlying pituitary tumorigenesis should be explored.

Novel patterns of gene expression in pituitary adenomas identified by complementary deoxyribonucleic acid microarrays and quantitative reverse transcription-polymerase chain reaction.

Pituitary adenomas account for approximately 10% of intracranial tumors, but little is known of the oncogenesis of these tumors. The identification of tumor-specific genes may further elucidate the pathways of tumor formation. We used complementary DNA microarrays to examine gene expression profiles in nonfunctioning, PRL, GH, and ACTH secreting adenomas, compared with normal pituitary. Microarray analysis showed that 128 of 7075 genes examined were differentially expressed. We then analyzed three genes with unique expression patterns and oncogenic importance by RT-real time quantitative PCR in 37 pituitaries. Folate receptor gene was significantly overexpressed in nonfunctioning adenomas but was significantly underexpressed in PRL and GH adenomas, compared with controls and to other tumors. The ornithine decarboxylase gene was significantly overexpressed in GH adenomas, compared with other tumor subtypes but was significantly underexpressed in ACTH adenomas. C-mer proto-oncogene tyrosine kinase gene was significantly overexpressed in ACTH adenomas but was significantly underexpressed in PRL adenomas. We have shown that at least three genes involved in carcinogenesis in other tissues are also aberrantly regulated in the major types of pituitary tumors. The evaluation of candidate genes that emerge from these experiments provides a rational approach to investigate those genes significant in tumorigenesis.

Ciliary neurotrophic factor stimulates neurite outgrowth from spinal cord neurons.

Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of motoneurons, but its effects on axonal outgrowth have not been examined in detail. Since nerve growth factor (NGF) promotes the outgrowth of neurites within the same populations of neurons that depend on NGF for survival, we investigated whether CNTF would stimulate neurite outgrowth from motoneurons in addition to enhancing their survival. We found that CNTF is a powerful promoter of neurite outgrowth from cultured chick embryo ventral spinal cord neurons. An effect of CNTF on neurite outgrowth was detectable within 7 hours, and at a concentration of 10 ng/ml, CNTF enhanced neurite length by about 3- to 4-fold within 48 hours. The neurite growth-promoting effect of CNTF does not appear to be a consequence of its survival-promoting effect. To determine whether the effect of CNTF on spinal cord neurons was specific for motoneurons, we analyzed cell survival and neurite outgrowth for motoneurons labeled with diI, as well as for neurons taken from the dorsal half of the spinal cord, which lacks motoneurons. We found that the effect of CNTF was about the same for motoneurons as it was for neurons from the dorsal spinal cord. The responsiveness of a variety of spinal cord neurons to CNTF may broaden the appeal of CNTF as a candidate for the treatment of spinal cord injury or disease.

Moderate head injury: an overview.

This review summarizes currently available epidemiologic, clinical, pathologic, and outcome data in patients with moderate head injury (MHI, GCS 9-12). This important subset comprises about 20% of head injuries in the United States. Affected patients usually are young, and most injuries are due to vehicular accidents. Current evidence (mortality rate and outcome) from various studies suggests an apparent dichotomy within the MHI category (9-10 vs 11-12). The former is more in keeping with the favorable subgroup of severe head injuries, and the latter is more appropriate to the mild head injury group. Should there be a reclassification based on this dichotomy? This is obviously important for clinical management and prognostication in these patients. The experimental evidence for a pathologic and biochemical substrate of MHI is reviewed. It is becoming increasing evident that biochemical mediators of secondary neuronal injury in MHI are at least as important as those attributed to severe head injury, but MHI may be more amenable to therapy. It may be prudent, therefore, to direct further effort to this subgroup of patients. Although additional study is required, the pattern of recovery in MHI as determined by extant neurobehavioral studies is analyzed.

Regional changes in the expression of neurotrophic factors and their receptors following acute traumatic brain injury in the adult rat brain.

We have analyzed the effect of severe traumatic brain injury (TBI) on the levels of mRNA expression of neurotrophic factors (NTFs): brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and their respective receptors: trkB, trkA and CNTFRalpha. The expression was examined in the region of the lesion as well as a region remote from the lesion at 12, 24, and 36 h following the injury. Our data suggest that after the brain injury, the expression of NGF and BDNF mRNAs were early, transiently and significantly upregulated while that of CNTF was a slow and less amplified response in both areas of the brain. We also found that trkA mRNA expression was only upregulated significantly in the remote area; trkB mRNA showed no significant change in either area except an upregulation at 12 h in the remote area. CNTFRalpha was downregulated significantly by 24-36 h in the lesion area and by 24 h in the remote area. These changes suggest that TBI regulates the expression of NTFs and their receptors. These alterations in expression may be involved in modulating the neuronal response after brain injury.

Cocaine-induced aneurysmal rupture: an emergent negative factor in the natural history of intracranial aneurysms?

Recent statistics from the National Institute on Drug Abuse indicate that cocaine abuse continues to be a significant public health problem. Between 1988 and 1990 at Grady Memorial Hospital in metropolitan Atlanta, Georgia, we identified 12 patients in whom subarachnoid hemorrhage was temporally related to cocaine abuse. All 12 patients had underlying cerebral aneurysms that had ruptured. Currently, the incidence of ruptured intracranial aneurysms in patients with cocaine-induced subarachnoid hemorrhage is 84.9% (mean age, 31.1 years; overall mortality, 60.5%). Hypertension is the likely precursive factor in cocaine-induced aneurysmal rupture. Cocaine abuse appears to be a significant negative factor in the natural history of cerebral aneurysms, especially in young adults. We review the epidemiology of cocaine-induced subarachnoid hemorrhage and its effects on the cerebral circulation, and suggest guidelines for patient management.

Cervical spine immobilization before admission to the hospital.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: All trauma patients with a cervical spinal column injury or with a mechanism of injury having the potential to cause cervical spine injury should be immobilized at the scene and during transport by using one of several available methods. A combination of a rigid cervical collar and supportive blocks on a backboard with straps is effective in limiting motion of the cervical spine and is recommended. The long-standing practice of attempted cervical spine immobilization using sandbags and tape alone is not recommended.

Transportation of patients with acute traumatic cervical spine injuries.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Expeditious and careful transport of patients with acute cervical spine or spinal cord injuries is recommended, from the site of injury by the most appropriate mode of transportation available to the nearest capable definitive care medical facility.

Clinical assessment after acute cervical spinal cord injury.

UNLABELLED: NEUROLOGICAL EXAMINATION: STANDARDS: There is insufficient evidence to support neurological examination standards. GUIDELINES: There is insufficient evidence to support neurological examination guidelines. OPTIONS: The American Spinal Injury Association international standards for neurological and functional classification of spinal cord injury are recommended as the preferred neurological examination tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries. FUNCTIONAL OUTCOME ASSESSMENT: STANDARDS: There is insufficient evidence to support functional outcome assessment standards. GUIDELINES: The Functional Independence Measure is recommended as the functional outcome assessment tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries. OPTIONS: The modified Barthel index is recommended as a functional outcome assessment tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries.

Radiographic assessment of the cervical spine in asymptomatic trauma patients.

STANDARDS: Radiographic assessment of the cervical spine is not recommended in trauma patients who are awake, alert, and not intoxicated, who are without neck pain or tenderness, and who do not have significant associated injuries that detract from their general evaluation.

Radiographic assessment of the cervical spine in symptomatic trauma patients.

STANDARDS: A three-view cervical spine series (anteroposterior, lateral, and odontoid views) is recommended for radiographic evaluation of the cervical spine in patients who are symptomatic after traumatic injury. This should be supplemented with computed tomography (CT) to further define areas that are suspicious or not well visualized on the plain cervical x-rays. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: It is recommended that cervical spine immobilization in awake patients with neck pain or tenderness and normal cervical spine x-rays (including supplemental CT as necessary) be discontinued after either a) normal and adequate dynamic flexion/extension radiographs, or b) a normal magnetic resonance imaging study is obtained within 48 hours of injury. Cervical spine immobilization in obtunded patients with normal cervical spine x-rays (including supplemental CT as necessary) may be discontinued a) after dynamic flexion/extension studies performed under fluoroscopic guidance, or b) after a normal magnetic resonance imaging study is obtained within 48 hours of injury, or c) at the discretion of the treating physician.

Initial closed reduction of cervical spine fracture-dislocation injuries.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. Early closed reduction of cervical spine fracture-dislocation injuries with craniocervical traction is recommended to restore anatomic alignment of the cervical spine in awake patients. Closed reduction in patients with an additional rostral injury is not recommended. Patients with cervical spine fracture-dislocation injuries who cannot be examined during attempted closed reduction, or before open posterior reduction, should undergo magnetic resonance imaging (MRI) before attempted reduction. The presence of a significant disc herniation in this setting is a relative indication for a ventral decompression before reduction. MRI study of patients who fail attempts at closed reduction is recommended. Prereduction MRI performed in patients with cervical fracture dislocation injury will demonstrate disrupted or herniated intervertebral discs in one-third to one-half of patients with facet subluxation. These findings do not seem to significantly influence outcome after closed reduction in awake patients; therefore, the usefulness of prereduction MRI in this circumstance is uncertain.

Pharmacological therapy after acute cervical spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment with methylprednisolone for either 24 or 48 hours is recommended as an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit. GM-1 GANGLIOSIDE: STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment of patients with acute spinal cord injuries with GM-1 ganglioside is recommended as an option without demonstrated clinical benefit.

Blood pressure management after acute spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Hypotension (systolic blood pressure <90 mmHg) should be avoided if possible or corrected as soon as possible after acute spinal cord injury. Maintenance of mean arterial blood pressure at 85 to 90 mmHg for the first 7 days after acute spinal cord injury to improve spinal cord perfusion is recommended.

Deep venous thrombosis and thromboembolism in patients with cervical spinal cord injuries.

STANDARDS: Prophylactic treatment of thromboembolism in patients with severe motor deficits due to spinal cord injury is recommended. The use of low-molecular-weight heparins, rotating beds, adjusted dose heparin, or a combination of modalities is recommended as a prophylactic treatment strategy. Low-dose heparin in combination with pneumatic compression stockings or electrical stimulation is recommended as a prophylactic treatment strategy. GUIDELINES: Low-dose heparin therapy alone is not recommended as a prophylactic treatment strategy. Oral anticoagulation alone is not recommended as a prophylactic treatment strategy. OPTIONS: Duplex Doppler ultrasound, impedance plethysmography, and venography are recommended for use as diagnostic tests for deep venous thrombosis in the spinal cord-injured patient population. A 3-month duration of prophylactic treatment for deep venous thrombosis and pulmonary embolism is recommended. Vena cava filters are recommended for patients who do not respond to anticoagulation or who are not candidates for anticoagulation therapy and/or mechanical devices.

Nutritional support after spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Nutritional support of patients with spinal cord injuries is recommended. Energy expenditure is best determined by indirect calorimetry in these patients because equation estimates of energy expenditure and subsequent caloric need tend to be inaccurate.

Management of pediatric cervical spine and spinal cord injuries.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: In children who have experienced trauma and are alert, conversant, have no neurological deficit, no midline cervical tenderness, and no painful distracting injury, and are not intoxicated, cervical spine x-rays are not necessary to exclude cervical spine injury and are not recommended. In children who have experienced trauma and who are either not alert, nonconversant, or have neurological deficit, midline cervical tenderness, or painful distracting injury, or are intoxicated, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. OPTIONS: In children younger than age 9 years who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. In children age 9 years or older who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior, lateral, and open-mouth cervical spine x-rays be obtained. Computed tomographic scanning with attention to the suspected level of neurological injury to exclude occult fractures or to evaluate regions not seen adequately on plain x-rays is recommended. Flexion/extension cervical x-rays or fluoroscopy may be considered to exclude gross ligamentous instability when there remains a suspicion of cervical spine instability after static x-rays are obtained. Magnetic resonance imaging of the cervical spine may be considered to exclude cord or nerve root compression, evaluate ligamentous integrity, or provide information regarding neurological prognosis. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Thoracic elevation or an occipital recess to prevent flexion of the head and neck when restrained supine on an otherwise flat backboard may allow for better neutral alignment and immobilization of the cervical spine in children younger than 8 years because of the relatively large head in these younger children and is recommended. Closed reduction and halo immobilization for injuries of the C2 synchondrosis between the body and odontoid is recommended in children younger than 7 years. Consideration of primary operative therapy is recommended for isolated ligamentous injuries of the cervical spine with associated deformity.

Diagnosis and management of traumatic atlanto-occipital dislocation injuries.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: There is insufficient evidence to support diagnostic guidelines. OPTIONS: A lateral cervical x-ray is recommended for the diagnosis of atlanto-occipital dislocation. If a radiological method for measurement is used, the basion-axial interval-basion-dental interval method is recommended. The presence of upper cervical prevertebral soft tissue swelling on an otherwise nondiagnostic plain x-ray should prompt additional imaging. If there is clinical suspicion of atlanto-occipital dislocation, and plain x-rays are nondiagnostic, computed tomography or magnetic resonance imaging is recommended, particularly for the diagnosis of non-Type II dislocations. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment with internal fixation and arthrodesis using one of a variety of methods is recommended. Traction may be used in the management of patients with atlanto-occipital dislocation, but it is associated with a 10% risk of neurological deterioration.

Isolated fractures of the atlas in adults.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment options in the management of isolated fractures of the atlas are based on the specific atlas fracture type. It is recommended that isolated fractures of the atlas with an intact transverse atlantal ligament be treated with cervical immobilization alone. It is recommended that isolated fractures of the atlas with disruption of the transverse atlantal ligament be treated with either cervical immobilization alone or surgical fixation and fusion.