Stereotactic radiosurgery/radiotherapy for pituitary adenomas: a review of recent literature

The recent clinical results are reviewed of stereotactic radiosurgery/radiotherapy for the treatment of pituitary adenomas. The outcomes of pituitary adenomas treated by stereotactic radiosurgery/radiotherapy with gamma knife, CyberKnife, or linear accelerator (LINAC) radiosurgery were evaluated from articles published after 2004. Each study was evaluated for the number of patients, radiosurgical parameter (marginal dose), length of follow up, tumor growth control, rate of hormonal normalization in secretary adenomas, and adverse events. After gamma knife radiosurgery, the tumor reduction rates varied from 42.3% to 89% in non-secreting adenomas. However, the tumor control rates in non-secreting adenomas were more than 90% in most studies. In growth hormone-secreting adenomas, the rates of insulin-like growth factor-1 normalization ranged from 36.9% to 82%. In adrenocorticotropin-secreting adenomas, the rates for 24-hour urine free cortisol normalization ranged from 27.9% to 54%. In prolactin-secreting adenomas, the prolactin normalization ranged from 17.4% to 50%. New hormonal deficits ranged from 0% to 34%. New visual deficits were relatively low. The number of patients treated with CyberKnife and LINAC radiosurgery/radiotherapy was small and follow-up periods were relatively short compared to those with gamma knife treatment, but the clinical outcomes after these therapies were similar to those after gamma knife therapy. Image-guided stereotactic radiosurgery/radiotherapy with the gamma knife, CyberKnife, or LINAC system is effective and safe against pituitary adenomas. Careful long-term follow up of the patients is necessary because of long-term anti-tumor effects and delayed adverse events.     

Comparative results of conservative treatments for isolated anterior talofibular ligament (ATFL) injury and injury to both the ATFL and calcaneofibular ligament of the ankle as assessed by subtalar arthrography

Background There have been no reports describing the results of conservative treatment of acute lateral ligament injury of the ankle in detail in terms of the severity of the injury, and the results of conservative treatment for injury with severe instability are still controversial. The purpose of this study was to assess the results of nonoperative treatment of acute lateral ligament injury according to its severity. Methods Fifty-five consecutive acute lateral ankle ligament injuries in 54 patients who were treated nonoperatively were followed up as a prospective study. Twenty-seven were male patients and 27 were female patients; the average age was 23.9 years (12–55 years). The patients were divided into two groups according to the extent of the ligament injury: patients with an isolated injury of the anterior talofibular ligament and those with combined injuries of the anterior talofibular ligament and the calcaneofibular ligament. In addition to the routine examinations for inversion ankle sprain, subtalar arthrography was mainly used to assess the condition of the calcaneofibular ligament. The arthrography was performed an average of 3.5 days after the injury (0–5 days). Results Fifty-five ankles of patients who were treated nonoperatively according to the same protocol were included in this study, and were followed up for an average of 5.0 years (37–86 months). At the time of the final follow-up, 22 of 25 (88%) ankles with an isolated injury to the anterior talofibular ligament were asymptomatic; in contrast, only 9 of 30 (30%) ankles with combined injuries of the anterior talofibular and calcaneofibular ligament were asymptomatic. The average American Orthopaedic Foot and Ankle Society score of the isolated injuries was 97.8 points, in contrast to 92.4 points for the combined injuries. Conclusions The results of nonoperative treatment with 1 week immobilization followed by a functional brace were excellent in patients with an isolated injury of the anterior talofibular ligament, but were unsatisfactory in those with combined injuries of the anterior talofibular and calcaneofibular ligaments.     

Genetic evidence points to an osteocalcin‐independent influence of osteoblasts on energy metabolism

The skeleton has been shown recently to regulate glucose metabolism through an osteoblast‐specific hormone, osteocalcin, which favors β‐cell proliferation, insulin secretion, insulin sensitivity, and energy expenditure. An implication of this finding is that a decrease in osteoblast numbers would compromise glucose metabolism in an osteocalcin‐dependent manner. To test this hypothesis, osteoblasts were inducibly ablated by cross‐breeding transgenic mice expressing a tamoxifen‐regulated Cre under the control of the osteocalcin promoter with mice in which an inactive form of the diphtheria toxin A chain was introduced into a ubiquitously expressed locus. Ablation of osteoblasts in adult mice profoundly affected glucose metabolism. In a manner similar to what is seen in the case of osteocalcin deficiency, a partial ablation of this cell population resulted in hypoinsulinemia, hyperglycemia, glucose intolerance, and decreased insulin sensitivity. However, and unlike what is seen in osteocalcin‐deficient mice, osteoblast ablation also decreased gonadal fat and increased energy expenditure and the expression of resistin, an adipokine proposed to mediate insulin resistance. While administration of osteocalcin reversed (fully) the glucose intolerance and reinstated normal blood glucose and insulin levels, it only partially restored insulin sensitivity and did not affect the improved gonadal fat weight and energy expenditure in osteoblast‐depleted mice. These observations not only strengthen the notion that osteoblasts are necessary for glucose homeostasis and energy expenditure but also suggest that in addition to osteocalcin, other osteoblast‐derived hormones may contribute to the emerging function of the skeleton as a regulator of energy metabolism. © 2011 American Society for Bone and Mineral Research     

PKCα suppresses osteoblastic differentiation

Protein kinase C (PKC) plays an essential role in cellular signal transduction for mediating a variety of biological functions. There are 11 PKC isoforms and these isoforms are believed to play distinct roles in cells. Although the role of individual isoforms of PKC has been investigated in many fields, little is known about the role of PKC in osteoblastic differentiation. Here, we investigated which isoforms of PKC are involved in osteoblastic differentiation of the mouse preosteoblastic cell line MC3T3-E1. Treatment with G?6976, an inhibitor of PKCα and PKCβI, increased alkaline phosphatase (ALP) activity as well as gene expression of ALP and Osteocalcin (OCN), and enhanced calcification of the extracellular matrix. Concurrently, osteoblastic cell proliferation decreased at a concentration of 1.0 μM. In contrast, a PKCβ inhibitor, which inhibits PKCβI and PKCβII, did not significantly affect osteoblastic differentiation or cell proliferation. Knockdown of PKCα using MC3T3-E1 cells transfected with siRNA also induced an increase in ALP activity and in gene expression of ALP and OCN. In contrast, overexpression of wild-type PKCα decreased ALP activity and attenuated osteoblastic differentiation markers including ALP and OCN, but promoted cell proliferation. Taken together, our results indicate that PKCα suppresses osteoblastic differentiation, but promotes osteoblastic cell proliferation. These results imply that PKCα may have a pivotal role in cell signaling that modulates the differentiation and proliferation of osteoblasts.     

Dose-related cellular effects of platelet-derived growth factor-BB differ in various types of rabbit tendons in vitro

Cellular responsiveness to growth factors that can affect tendon healing may be site-specific. We have compared the dose-response effects of platelet-derived growth factor-BB (PDGF-BB) on proteoglycan, collagen, noncollagen protein and DNA synthesis between intrasynovial intermediate and proximal segments of deep flexor tendons, and extrasynovial peroneal tendons of rabbits during short-term cultures. PDGF-BB stimulated matrix and DNA synthesis of the three types of tendon segments in a dose-dependent manner in the range from 0.1 to 100 ng/mL. PDGF-BB stimulated collagen synthesis and noncollagen protein synthesis (calculated from LogED50) in proximal intrasynovial tendon segments more than in extrasynovial peroneal tendon segments, and DNA synthesis less in proximal than in intermediate intrasynovial tendons. However, the estimated maximal stimulations (Emax) by PDGF-BB were similar in the three types of tendon segments. These findings show that PDGF-BB stimulates DNA and matrix synthesis differently in various types and regions of tendons during short term explant culture and suggests that there may be differences in cellular responsiveness during tendon healing.     

The relationship between apoptosis of endplate chondrocytes and aging and degeneration of the intervertebral disc.

STUDY DESIGN: Apoptosis in cervical intervertebral disc cells and cartilaginous endplate cells was examined by the nick end labeling (TUNEL) technique during the process of natural aging and in a mouse experimental spondylosis model. OBJECTIVES: To determine the role of apoptosis in aging and degeneration of intervertebral discs by monitoring chronologic changes in the quantity and localization of apoptotic cells. SUMMARY OF BACKGROUND DATA: Apoptosis occurs within human intervertebral discs, but little is known about the pathologic significance of this process. On the other hand, the cartilaginous endplate is known to decrease in thickness and to disappear with aging and degeneration. The cause of this age-related change remains unclear. METHODS: A mouse spondylosis model was prepared via surgical resection of the posterior spinal element in 12 mice to examine the experimentally induced spondylosis process. Eighteen naturally aged mice were also used to examine the influence of aging. Paraffin-embedded midsagittal sections of the cervical spine were obtained 2, 3, 6, and 12 months after surgery in the spondylosis model and in the age-matched naturally aged mice, as well as in 4-week-old and 18-month-old naturally aged mice. Sections were stained with hematoxylin and eosin, safranin-O, and the TUNEL procedure. The number of apoptotic cells and vital cells were counted in the cartilaginous endplate of the intervertebral disc excluding the growth cartilage, and the degree of disappearance of the cartilaginous endplate was evaluated. RESULTS: Apoptosis, particularly noticeable in the cartilaginous endplate, increased with age and resulted in a marked decrease in cell density. Subsequently, the structure of the cartilaginous endplate began to disappear. Apoptosis was more evident and the structure of the cartilaginous endplate began to disappear more rapidly in the surgically treated group than in the naturally aged group. CONCLUSIONS: TUNEL-positive cells in the cartilaginous endplate increased with age, with destruction of the cartilaginous endplate after apoptosis (TUNEL-positive cell death). The application of the spondylosis model increased the incidence of apoptosis preceding the development of spondylosis. This suggests that apoptosis plays a role in the age-related changes seen in the cartilaginous endplate of the intervertebral disc and in the experimentally induced spondylosis process.     

Persistent local pain after posterior spine surgery for thoracic lesions

Many surgeons have investigated local pain associated with posterior spine surgery for cervical or lumbar lesions. However, little information is available concerning local pain after posterior thoracic spine surgery. This prospective study was, thus, performed to investigate the frequency and clinical features of local pain after posterior spine surgery for thoracic lesions. In 29 consecutive patients undergoing posterior spine surgery for various thoracic spinal disorders, local pain was investigated before and after surgery. In all 19 patients with preoperative back pain presumably due to thoracic lesions, pain was well alleviated after surgery. In contrast, 6 patients (21%) newly developed persistent shoulder angle pain after surgery, which resembled axial pain after cervical laminoplasty. In 5 of these 6 patients surgical exposure was extended to the cervicothoracic junction, whereas persistent shoulder angle pain was independent of disease etiologies and surgical procedure, and all of the 5 patients had no other etiologies of local pain such as surgical site infections, hardware failures, pseudoarthrosis, other metastasis, and vertebral fractures. These results suggest that dissection of muscle attachments to the cervicothoracic junction would play some part in the development of persistent local pain after posterior spine surgery for thoracic lesions, although surgical exposure of the zygapophysial joints at the cervicothoracic junction might be a possible source of postoperative shoulder pain. Therefore, to minimize such surgical complications, muscle insertions into the cervicothoracic junction should be preserved as far as possible.     

Ureteral avulsion: a rare complication of ureteroscopy

A case of ureteral avulsion as a complication of ureteroscopy is presented. A 55-year-old woman was admitted to the hospital with the complaint of hematuria. The intravenous pyelography revealed a calculus measuring 16 x 12 mm located in the left upper ureter. Transurethral ureterolithotripsy was performed with 8 F rigid ureteroscopy. A safety guide wire was inserted and left ureteral olifice was dilated to 9 F. The ureteroscopy was smoothly introduced just under the stone. The stone was fragmentated with a pneumatic lithotripter. A part of the stone was pushed back to the renal pelvis, so the ureteroscope was passed to that stone and fragmentation was done as much as possible. The ureteroscopy was gently pulled out to the bladder, but the distal ureter was torn at the ureteral orifice and could be seen at the urethral orifice. Pelvis, upper ureter and middle ureter were intact, so open intervention for repair was not performed. A 6Fr double pigtail stent was placed over the safety guidewire. Cystscopy indicated a part of the distal ureter was protruded from the ureteral orifice. Eight weeks later, the protruded part of ureter was necrotic and calcified for ischemia. Transurethral resection of necrotic ureter was performed. Histologically, resected ureter changed necrotic tissue for ischema. Postoperatively intravenous pyelography did not reveal left hydronephrosis and cystoscopy indicated that the left ureteral orifice was almost normally repaired.     

Prognostic value of changes in spinal cord signal intensity on magnetic resonance imaging in patients with cervical compressive myelopathy

Background contextSignal intensity on preoperative cervical magnetic resonance imaging (MRI) of the spinal cord has been shown to be a potential predictor of outcome of surgery for cervical compressive myelopathy. However, the prognostic value of such signal remains controversial. One reason for the controversy is the lack of proper quantitative methods to assess MRI signal intensity.PurposeTo quantify signal intensity and to correlate intramedullary signal changes on MRI T1- and T2-weighted images (WIs) with clinical outcome and prognosis.Study designRetrospective case study.Patient samplePatients (n=148; cervical spondylotic myelopathy, n=102 and ossified posterior longitudinal ligament, n=46) who underwent surgery for cervical compressive myelopathy and had high signal intensity change on sagittal T2-WI MRI before surgery between 2006 and 2010.Outcome measureNeurologic assessment was conducted with the Japanese Orthopedic Association (JOA) scoring system for cervical myelopathy. The rate of neurologic improvement was calculated with the use of preoperative and postoperative JOA scores.MethodsQuantitative analysis of MRI signal on both T1- and T2-WIs via use of the signal intensity ratio (SIR; signal intensity of lesion relative to that at C7-T1 disc level) was performed. Correlations between SIR on T1- and T2-WIs and preoperative JOA score, JOA improvement rate, disease duration, and MRI morphologic classification (cystic or diffuse type) were analyzed. Multivariate regression analysis for JOA improvement rate was also analyzed. In a substudy, 25 patients underwent follow-up MRI starting from 6 months after surgery to analyze the relationship between changes in SIR on follow-up MRI and clinical outcome.ResultsSIR on T1-WIs, but not SIR on T2-WIs, correlated with postoperative neurologic improvement. The disease duration correlated negatively with SIR on T1-WIs and JOA improvement rate but not with SIR on T2-WIs. SIR on T2-WIs of “cystic type” was significantly greater than of “diffuse type,” but SIR on T1-WI and JOA improvement rate were not different in the two types. Stepwise multivariate regression analysis indicated that SIR on T1-WIs and long disease duration were significant predictors of postoperative neurologic outcome. SIR on follow-up T1-WI and changes in SIR on T1-WI after surgery correlated positively with postoperative improvement rate. SIR on follow-up T2-WI and changes on T2-WI correlated negatively with postoperative neurologic improvement.ConclusionsOur results suggest that low intensity signal on preoperative T1-WIs but not T2-WIs correlated with poor postoperative neurologic outcome. Furthermore, decreased signal intensity on postoperative T1-WIs and increased signal intensity on postoperative T2-WIs are predictors of poor neurologic outcome.     

Kinematics of the thoracic spine in trunk lateral bending: in vivo three-dimensional analysis

Background contextIn vivo three-dimensional kinematics of the thoracic spine in trunk lateral bending with an intact rib cage and soft tissues has not been well documented. There is no quantitative data in the literature for lateral bending in consecutive thoracic spinal segments, and there has not been consensus on the patterns of coupled motion with lateral bending.PurposeTo demonstrate segmental ranges of motion (ROMs) in lateral bending and coupled motions of the thoracic spine.Study designIn vivo three-dimensional biomechanics study of the thoracic spine.Patient sampleFifteen healthy male volunteers.Outcome measuresComputed analysis by using voxel-based registration.MethodsParticipants underwent computed tomography of the thoracic spine in three supine positions: neutral, right maximum lateral bending, and left maximum lateral bending. The relative motions of vertebrae were calculated by automatically superimposing an image of vertebrae in a neutral position over images in bending positions, using voxel-based registration. Mean values of lateral bending were compared among the upper (T1–T2 to T3–T4), the middle-upper (T4–T5 to T6–T7), the middle-lower (T7–T8 to T9–T10), and the lower (T10–T11 to T12–L1) parts of the spine.ResultsAt lateral bending, the mean ROM (±standard deviation) of T1 with respect to L1 was 15.6°±6.3° for lateral bending and 6.2°±4.8° for coupled axial rotation in the same direction as lateral bending. The mean lateral bending of each spinal segment with respect to the inferior adjacent vertebra was 1.4°±1.3° at T1–T2, 1.3°±1.2° at T2–T3, 1.4°±1.3° at T3–T4, 0.9°±0.9° at T4–T5, 0.8°±1.0° at T5–T6, 1.1°±1.1° at T6–T7, 1.7°±1.2° at T7–T8, 1.3°±1.2° at T8–T9, 1.6°±0.7° at T9–T10, 1.8°±0.8° at T10–T11, 2.3°±1.0° at T11–T12, and 2.2°±0.8° at T12–L1. The smallest and the largest amounts of lateral bending were observed in the middle-upper and the lower parts, respectively. There was no significant difference in lateral bending between the upper and the middle-lower parts. Coupled axial rotation of each segment was generally observed in the same direction as lateral bending. However, high variability was found at the T2–T3 to T5–T6 segments. Coupled flexion was observed at the upper and middle parts, and coupled extension was observed at the lower part.ConclusionsThis study revealed in vivo three-dimensional motions of consecutive thoracic spinal segments in trunk lateral bending. The thoracolumbar segments significantly contributed to lateral bending. Coupled axial rotation generally occurred in the same direction with lateral bending. However, more variability was observed in the direction of coupled axial rotation at T2–T3 to T5–T6 segments in the supine position. These results are useful for understanding normal kinematics of the thoracic spine.