The role of tenascin-X in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse: an immunohistochemical study.

INTRODUCTION AND HYPOTHESIS: Abnormalities of connective tissue structure or its repair mechanism may predispose women to pelvic organ prolapse (POP). We hypothesized that the expression of tenascin-X in the uterosacral ligament of postmenopausal women with symptomatic POP is increased compared with postmenopausal women without POP. Furthermore, we identified clinical risk factors associated with POP in our study population. METHODS: We conducted a retrospective case-control study in which 33 postmenopausal women with symptomatic POP ≥ pelvic organ prolapse quantification system (POP-Q) stage II were matched with 33 postmenopausal women without POP. Studied tissue specimens were taken from hysterectomy specimens, and tenascin-X expression was investigated by immunohistochemistry. The immunohistochemical profile of the uterosacral connective tissue of cases and controls was compared. RESULTS: Tenascin-X was expressed in 94% of POP cases and in 91% of controls. Our study failed to show any statistically significant differences in tenascin-X expression between women with and without POP (p = 0.64). However, tenascin-X was significantly more expressed in cases with severe prolapse (POP-Q stage IV) compared with moderate prolapse stages (POP-Q stage II and III) (p = 0.001). Advanced patient age as well as early menopausal age remained independent risk factors associated with POP in multiple logistic regression analysis (p = 0.001). CONCLUSION: No difference could be demonstrated between tenascin-X expression in patients with or without POP. Tenascin-X does not seem to play a major role in the pathogenesis of POP in postmenopausal women.

Expression of far upstream element-binding protein 1 correlates with c-Myc expression in sacral chordomas and is associated with tumor progression and poor prognosis.

The far upstream element (FUSE)-binding protein 1 (FUBP1), a well-known transcriptional regulator of the proto-oncogene c-Myc, has been demonstrated by previous work to be aberrantly expressed in a variety of tumors and plays a critical role in tumor progression; however, its expression and function in relatively rare and aggressive chordomas remains unclear. In this retrospective study, we reviewed clinicopathologic characteristics of 40 patients diagnosed with sacral chordoma, and analyzed 40 tumor and 20 distant normal tissues obtained from patients during the primary surgical tumor excision. Using immunohistochemistry, we observed an up-regulation in the expression of FUBP1 and c-Myc in sacral chordomas compared with the normal tissues (P = 0.001 for both). Additionally, positive correlations of FUBP1 expression with c-Myc (γ = 0.651, P < 0.001) and the cell proliferation index Ki-67 expression (γ = 0.447, P = 0.004) were indicated using Spearman's rank correlation coefficient. Increased expression of FUBP1 was significantly associated with tumor invasion into the surrounding muscles (P = 0.002). Kaplan-Meier curves demonstrated the association between FUBP1 levels and the patients' local recurrence-free survival (LRFS) (P < 0.001) but not with the overall survival (OS) (P = 0.070). The independent prognostic significance of FUBP1 levels for the LRFS was indicated by multivariate analysis (HR = 4.272; 95% CI, 1.133-16.112; P = 0.032). Our findings demonstrate an association between FUBP1 levels and chordoma progression and prognosis, suggesting that FUBP1 can be used as a biomarker and a potential therapeutic target.

C-reactive protein as a prognostic factor in patients with chordoma of lumbar spine and sacrum--a single center pilot study.

STUDY DESIGN: This is a retrospective, diagnostic study, level IV. BACKGROUND: It appears to be necessary to identify prognostic markers for individual risk estimation for progression and survival in patients with chordoma, a rare disease. Are pre-operative serum levels of C-reactive protein (CRP) associated with disease progression and survival? METHODS: Survival rates of 24 patients (18 males, 6 females) (mean age 67 years (SD ± 16; range 20-85 years); minimum follow-up 2 years, mean follow-up 5 years (SD ± 5; range 2-19 years)) with chordoma of the lower spine and sacrum were assessed with a focus on pre-operative CRP levels. RESULTS: The survival rate of patients with pre-operative CRP level of >1.0 mg/dl was lower than that of patients with a CRP level <1.0 mg/dl (p = 0.01). The estimated 10-year survival of patients with pre-operative CRP values <1.0 and >1.0 mg/dl was 76 and 25%, respectively. CRP remained as an independent survival factor (p = 0.025; CI 95% 1.0-2.6) in multivariable analysis. CONCLUSIONS: Pre-operative CRP levels appear to be a biomarker for disease-specific survival in patients with chordoma of the lumbar spine and sacrum. A validation of our finding with larger cohorts and integration of putative risk factor would further elucidate CRP a surrogate for tumor progression.

Presence of relaxin-2, oxytocin and their receptors in uterosacral ligaments of pre-menopausal patients with and without pelvic organ prolapse.

OBJECTIVE: Pelvic organ prolapse (POP) is a major health concern for women. Its pathophysiology is yet not fully understood. We reported an impaired functional state of the smooth muscle compartment in uterosacral ligaments from patients with POP, which was cholinergic, stimulated by oxytocin and modulated by relaxin-2. The current study investigated the presence of oxytocin and relaxin-2 and their receptors in the uterosacral ligament from POP/non-POP patients. DESIGN: Translational investigation on clinical samples. SETTING: University hospital departments. POPULATION AND SAMPLES: Fourty-three samples of uterosacral ligament from pre-menopausal patients with (n = 20) and without POP (n = 23). METHODS: Presence of relaxin-2, its receptors RXFP1 and RXFP2, and of oxytocin and its receptor were analysed by immunohistochemistry and classified using a staining score. Additionally, Western blot analysis was performed. MAIN OUTCOME MEASURES: Presence patterns with respect to POP and non-POP uterosacral ligament samples for pathophysiological understanding of POP. RESULTS: Relaxin-2, oxytocin and their receptors were expressed in endothelial cells, the smooth muscle compartment and vasa vasorum in the arteries and veins of the uterosacral ligament, in the smooth muscle compartment present in the ground reticulum and in nerves running through the uterosacral ligament. The presence level of relaxin-2 was higher in the uterosacral ligament of the POP cohort (p < 0.001). CONCLUSIONS: We demonstrated that relaxin-2 had an increased presence in uterosacral ligaments from patients with POP, suggesting a role of the relaxin system in the pathogenesis of POP and identifying the relaxin system as a potential therapeutic target for the pharmacological treatment of POP.

In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome.

The T-box transcription factor BRACHYURY (T) is a key regulator of mesoderm formation during early development. Complete loss of T has been shown to lead to embryonic lethality around E10.0. Here we characterize an inducible miRNA-based in vivo knockdown mouse model of T, termed KD3-T, which exhibits a hypomorphic phenotype. KD3-T embryos display axial skeletal defects caused by apoptosis of paraxial mesoderm, which is accompanied by urorectal malformations resembling the murine uro-recto-caudal syndrome and human caudal regression syndrome phenotypes. We show that there is a reduction of T in the notochord of KD3-T embryos which results in impaired notochord differentiation and its subsequent loss, whereas levels of T in the tailbud are sufficient for axis extension and patterning. Furthermore, the notochord in KD3-T embryos adopts a neural character and loses its ability to act as a signaling center. Since KD3-T animals survive until birth, they are useful for examining later roles for T in the development of urorectal tissues.

Overexpression of CD40 in sacral chordomas and its correlation with low tumor recurrence.

AIM: To determine the degree of CD40 overexpression in sacral chordomas and its correlation with tumor recurrence. METHODS: CD40 or CD31 overexpression was determined by immunohistochemical staining; the microvessel density (MVD) was calculated according to the CD31 expression. The correlation of CD40 over-expression with tumor recurrence was analyzed. RESULTS: 56% of the specimens from 36 cases of sacral chordomas overexpressed CD40, which is a significantly higher percentage than for the 2 specimens in 10 in normal notochordal tissue (p < 0.05). 36.84% of the specimens of the 19 recurrent cases were CD40 overexpressing, in contrast to less than 76.47% in the no-recurrence group (p < 0.05). Multivariate analysis demonstrated that CD40 overexpression and the resection margins were independent factors contributing to tumor recurrence. The MVD value was 25.71 ± 8.86 mm(-2) in the sacral chordomas and more than 6.63 ± 2.45 mm(-2) in the normal embryonic notochord tissue (p < 0.01). The MVD value in the recurrence group (30.08 ± 7.11 mm(-2)) was significantly higher than that of the no-recurrence group (20.82 ± 8.18 mm(-2); p < 0.05). But the MVD value was significantly lower in the CD40-overexpressing group than in the CD40-less expressing group (p < 0.05). CONCLUSIONS: CD40 was overexpressed in sacral chordomas, and the overexpression was not dependent on the intratumoral MVD. CD40 overexpression was correlated with low recurrence of the tumor, implying that CD40 plays an important role in the antitumor response against sacral chordomas and in the inhibition of tumor recurrence.

Comparative analysis of histopathological parameters, genome-wide copy number alterations, and variants in genes involved in cell cycle regulation in chordomas of the skull base and sacrum.

Chordomas are rare tumors of the axial skeleton that are refractory to conventional therapy. Few studies have compared the morphological and molecular characteristics of chordomas according to the skull base and sacral locations. Histopathological data and changes revealed by array comparative genomic hybridization (CGH) and next-generation sequencing (NGS) of cell cycle regulation genes were analyzed for 28 skull base (SBCs) and 15 sacral (SC) chordomas. All cases were conventional chordomas. SBCs were significantly more frequent in patients aged <40 years and SCs predominated in patients aged >60 years. Mitotic indices ≥2 mitoses/10 high-power fields were correlated with high degrees of nuclear atypia and Ki67 labeling indices ≥6%. We identified 321 genomic positions, and copy number variation losses were more frequent than gain. Moreover, we report a panel of 85 genetic variants of cell cycle genes and the presence of molecular clusters for chordoma as well in CGH as in NGS. These new data strengthen the view that the chordoma should not be considered as a single molecular entity.

Decreased expression of elastin, fibulin-5 and lysyl oxidase-like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse.

AIM: Pelvic organ prolapse is associated with defects in connective tissues, including elastic fibers. The purpose of this study was to investigate the expression of fibulin-5 and lysyl oxidase-like 1 (LOXL1), which play an essential role in the synthesis and assembly of elastic fibers, in the uterosacral ligaments of women with advanced pelvic organ prolapse (POP) compared with controls. METHOD: Specimens were obtained prospectively during transvaginal or abdominal hysterectomy from 30 women with advanced pelvic organ prolapse and 30 controls matched to the POP group for age and parity among postmenopausal women with benign gynecologic diseases. The expressions of elastin, fibulin-5 and LOXL1 in uterosacral ligaments were measured by immunohistochemistry. RESULTS: We detected a decreased, sometimes absent, expression of fibulin-5 and LOXL1 in the uterosacral ligaments of women with POP, despite a positive expression of elastin. There was a decrease in positive percentage of LOXL1 in the POP group (23.3%) compared with the controls (60%) (P = 0.004). With immunolabeling intensity classified as negative, weak, moderate or strong, there was a decrease in the expression of fibulin-5 in the POP group (P = 0.049). We also detected a significantly decreased expression of LOXL1 in the POP group (P = 0.001). CONCLUSIONS: There was decreased expression of fibulin-5 and LOXL1 in the uterosacral ligaments of patients with pelvic organ prolapse, while the elastin expression was equivalent, which may suggest the possibility of defects in elastic fiber remodeling in the postpartum period and contribute to POP.

Neuroprotective Effects of Rhodiola Sacra on Transient Global Cerebral Ischemia Through Activating AMPK/Nrf2 Pathway in Rats.

Aims: Rhodiola sacra is a widely used pharmaceutical component with multiple functions, including anti-oxidation and anti-inflammation. However, the exact mechanisms involved in neuroprotection against transient global cerebral ischemia (tGCI) remain to be elucidated. Herein, we aim at closing the gap in understanding on whether rhodiola sacra reduces neuronal death in hippocampal CA1 and at demonstrating how rhodiola sacra offers neuroprotection after tGCI. Results: The results show that rhodiola sacra (2.4 g/kg/d by feeding) pretreatment or/and postreatment significantly alleviated neuronal injury, inhibited glial activation, and improved cognitive function in male rats subjected to tGCI. The neuroprotection of prophylaxis with rhodiola sacra is equivalent to that of therapeutics. The binding mode of adenosine monophosphate-activated protein kinase (AMPK) α2-subunit with rhodiola sacra was predicted by molecular docking. Further, rhodiola sacra upregulates phosphorylated AMPK and promotes nuclear translocation of nuclear factor erythroid 2 related factor 2 (Nrf2). In addition, rhodiola sacra increases heme oxygenase-1 (HO-1) expression and activity and reduces malondialdehyde (MDA) content in CA1 after tGCI. However, the neuroprotection of rhodiola sacra is abolished by Nrf2 knockdown with small interfering RNA (siRNA) after tGCI. Similarly, the inhibition of AMPK with Compound C or siRNA against AMPK α2 aggravates neuronal death after tGCI through decreasing nuclear Nrf2 and the expression and activity of HO-1, and by increasing the release of MDA. Innovation and Conclusion: For the first time, this study demonstrates that as a prophylactic or therapeutic agent rhodiola sacra prevents oxidant stress, protects neurons, and improves cognitive function through activating the AMPK/Nrf2 pathway in tGCI rats. Antioxid. Redox Signal. 36, 567-591.

Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma.

Sacral chordoma is a vessel-rich and infiltrative tumor, but the fundamental knowledge of its biological behavior remains unknown. This study was designed to investigate the expression levels and contributions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in the angiogenesis and recurrence of sacral chordoma and their correlations. An immunohistochemical method was used to investigate the expression of VEGF, MMP-9, and microvascular density (MVD) in 36 patients with sacral chordoma. Their differences in expressions were statistically analyzed and their correlations with angiogenesis and recurrence were evaluated. The mean MVD of sacral chordomas was significantly higher than that of the adjacent normal tissues (P = 0.033). Immunoreactivity for VEGF and MMP-9 was significantly higher in sacral chordoma tissues than in adjacent normal tissues (P = 0.008, P = 0.005). The mean MVD of VEGF and MMP-9 were statistically higher in positive group than in negative group (P = 0.015, P = 0.004), respectively . Moreover, a significant correlation was found between the VEGF and MMP-9 (P = 0.002). The log-rank test revealed that continuous disease-free survival time (CDFS) was significantly shorter in the MMP-9-positive group than in the MMP-9-negative group (P = 0.019), but the difference in the VEGF-positive group and the VEGF-negative group was not statistically significant (P = 0.938). Our data suggest that VEGF and MMP-9 might act with a synergistic effect and can positively regulate the angiogenesis in sacral chordoma. Positive expression of MMP-9 might indicate the local recurrence of sacral chordoma. The result suggests that some specific drugs which inhibit VEGF, MMP-9, or their receptors may have a good therapeutic effect for sacral chordoma.

Sex differences in c-Fos and EGR-1/Zif268 activity maps of rat sacral spinal cord following cystometry-induced micturition.

Storage and voiding of urine from the lower urinary tract (LUT) must be timed precisely to occur in appropriate behavioral contexts. A major part of the CNS circuit that coordinates this activity is found in the lumbosacral spinal cord. Immediate early gene (IEG) activity mapping has been widely used to investigate the lumbosacral LUT-related circuit, but most reports focus on the effects of noxious stimulation in anesthetized female rats. Here we use c-Fos and EGR-1 (Zif268) activity mapping of lumbosacral spinal cord to investigate cystometry-induced micturition in awake female and male rats. In females, after cystometry c-Fos neurons in spinal cord segments L5-S2 were concentrated in the sacral parasympathetic nucleus (SPN), dorsal horn laminae II-IV, and dorsal commissural nucleus (SDCom). Comparisons of cystometry and control groups in male and female revealed sex differences. Activity mapping suggested dorsal horn laminae II-IV was activated in females but showed net inhibition in males. However, inhibition in male rats was not detected by EGR-1 activity mapping, which showed low coexpression with c-Fos. A class of catecholamine neurons in SPN and SDCom neurons were also more strongly activated by micturition in females. In both sexes, most c-Fos neurons were identified as excitatory by their absence of Pax2 expression. In conclusion, IEG mapping in awake male and female rats has extended our understanding of the functional molecular anatomy of the LUT-related circuit in spinal cord. Using this approach, we have identified sex differences that were not detected by previous studies in anesthetized rats.

18F-fluoride PET/CT for detection of sacroiliitis in ankylosing spondylitis.

PURPOSE: The aim of this study was to evaluate the performance of (18)F-fluoride-PET/CT (PET/CT) for the diagnosis of sacroiliac joint (SIJ) arthritis in patients with active ankylosing spondylitis (AS). METHODS: Included in the study were 15 patients with AS according to the modified New York criteria (AS group) and with active disease and 13 patients with mechanical low back pain (MLBP; control group) who were investigated with whole-body (18)F-fluoride PET/CT. The ratio of the uptake in the SIJ and that in the sacrum (SIJ/S) was calculated for every joint. RESULTS: The mean SIJ/S ratio of 30 quantified joints in the AS group was 1.66 (range 1.10-3.07) with PET/CT, and the mean SIJ/S ratio of 26 quantified joints in the MLBP group was 1.12 (range 0.71-1.52). The area under the receiver operating characteristic curve for SIJ arthritis was 0.84. With plain radiography as a the gold standard and taking an SIJ/S ratio of >1.3 as the threshold, the sensitivity, specificity and accuracy on a per patient basis were 80%, 77% and 79%, respectively. On a per SIJ basis, the greatest sensitivity (94%) was found in grade 3 sacroiliitis (n = 16). CONCLUSION: Our results suggest that quantitative (18)F-fluoride PET/CT may play a role in the diagnosis of sacroiliitis in active AS and is an alternative to conventional bone scintigraphy in times of molybdenum shortage.

Differential expression of fibulins in the uterosacral ligaments of women with uterine prolapse.

PURPOSE: To compare fibulin-3 (FIB-3) and fibulin-5 (FIB-5) expressions in uterosacral ligaments (USL) of women with and without uterine prolapse. STUDY DESIGN: USL were sampled in a standardized fashion from women with (n = 8) or without (n = 8) uterine prolapse. Quantitative Real-Time PCR was performed to measure mRNA and immunohistochemistry to assess protein expression. RESULTS: FIB-3 mRNA expression and FIB-3 staining intensity was similar in the USL of women with and without uterine prolapse {[(FIB-3 mean +/- SD mRNA relative units) 0.45 +/- 0.41 vs. 0.46 +/- 0.82, NS] and [Intensity score, median (range), 1(0-1) vs. 1(0-1), NS]}. Both FIB-5 mRNA expression and FIB-5 staining intensity was significantly decreased in USL from women with uterine prolapse compared to women without prolapse {[(FIB-5 mean +/- SD mRNA relative units) 0.07 +/- 0.02 vs. 0.26 +/- 0.20, P = 0.02] and [Intensity score, median (range), 0(0-2) vs. 3(2-3), P = 0.002]}. CONCLUSION: FIB-5 expression is decreased in USL of women with uterine prolapse.

Low expression of collagen type-1 in sacrouterine ligament as risk factor of stage III-IV uterine prolapse.

BACKGROUND: Despite being non-life threatening, uterine prolapse is a reproductive health problem that interferes psychosocial life, economical and sexual function. Uterine prolapse can be caused by direct trauma resulting in damaged and weakened levator ani muscle which in turn causing sacrouterine ligament to stretch in order to maintain uterus normal position. The main component of sacrouterine ligament is collagen. Types of collagen that was involved in the occurrence of uterine prolapse are which plays a role of risk of occurrence uterine prolapse is collagen type-1 and type-3. Collagen type-1 has a good resistance and flexible to strain. If there is a disruption in the expression of collagen in sacrouterine ligament, it will result in cause uterine prolapse. OBJECTIVE: The aim of this study is to prove low expression of collagen type-1 in sacrouterine ligament is a risk factor for the occurrence of stage III-IV uterine prolapse. STUDY DESIGN: This study was an observational study using case-control approach. A total of 22 cases of stage III-IV uterine prolapse and 22 cases of non-uterine prolapse as control group were selected by consecutive sampling. This study was carried out in Sanglah General Hospital and Pathobiology Laboratory of Veterinary Faculty of Udayana. Samples were taken from sacrouterine ligament of individual with stage III-IV uterine prolapse compared to non-prolapse uterine who had undergone total hysterectomy. RESULTS: Chi-square analysis with 95 % confidence interval indicated that low expression of collagen type-1 was 6 times more likely to be the risk factor of stage III-IV uterine prolapse (OR = 5.95; 95 %CI = 1.59-22.33; p = 0.006). CONCLUSION: Low collagen type-1 in sacrouterine ligament is a risk factor of stage III-IV uterine prolapse.

The clinicopathologic observation, c-KIT gene mutation and clonal status of gastrointestinal stromal tumor in the sacrum.

BACKGROUND: It is very rare that gastrointestinal stromal tumor (GIST) occurs in the sacrum. Only one case of GIST occuring in the sacral region, with intracranial metastasis, has been reported in the literature. Moreover, only few cases have been published in literature about its clonal origin. CASE PRESENTATION: In this report, we present a rare case of GIST occuring in the sacrum and describe its clinicopathologic features, c-KIT gene mutation and clonal status. Microscopically, the lesion was composed of spindle cells arranged in cords, knitted and whirlpool patterns. Trabecula of bone were found in the lesion. The cytoplasm of tumor cells were abundant, and the nuclei were fusiform. Mitotic figures were rare. Immunohistochemically, the tumor cells showed positive reactivity for CD117 and CD34. On mutation analysis, a c-KIT gene mutation was found in exon 11. The result of clonal analysis demonstrated that the GIST was monoclonal. CONCLUSION: In summary, we showed that tumor material, phenotypically identical with GISTs was found in the sacrum. It is difficult to differentiate GISTs from other spindle cell tumors, hence the need for immunohistochemistry, the examination of c-KIT gene amplification and sequencing.

Genome­wide DNA methylation analysis of uterosacral ligaments in women with pelvic organ prolapse.

Pelvic organ prolapse (POP) is an increasingly serious health problem that impairs quality of life and is caused by multiple additive genetic and environmental factors. As the uterosacral ligaments (ULs) provide primary support for the pelvic organs, it was hypothesized that disruption of these ligaments (as a result of aberrant methylation) may lead to a loss of support and eventually contribute to POP. In the present study, whether there are any aberrant methylations in the ULs of patients with POP compared to those of controls was investigated. Genomic DNA was isolated from the ULs of five women with POP and four women without POP, as controls, undergoing hysterectomy for benign conditions. An Illumina Infinium Methylation EPICBeadChips Infinium Human Methylation 850 K bead array was used to investigate the total methylation in the ULs. There were 3,723 differentially methylated CpG sites (Δß<0.14; P<0.05), including 3,576 hypermethylation and 147 hypomethylation sites in the ULs of patients with POP compared with the normal controls. There were more hypermethylated CpG sites, but a high ratio of hypomethylation between CpG islands and the N­shelf; in the gene structure, there was more hypermethylation than hypomethylation in TSS1500 and the 5' untranslated region. Gene ontology analysis demonstrated that these differentially methylated genes were associated with 'cell morphogenesis', 'extracellular matrix', 'cell junction', 'protein binding' and 'guanosine triphosphatase activity'. Several significant pathways were identified, including 'focal adhesion' and 'extracellular matrix­receptor interaction pathway'. This study provides evidence that there are differences in genome­wide DNA methylation between ULs in menopausal women with and without POP, and that epigenetic mechanisms may partly contribute to POP pathogenesis.

Ureteral Stone Mimicking Abnormal Sacral Uptake on 99mTc MDP Bone Scintigraphy: The Usefulness of SPECT/CT.

Bone tracer uptake related to ureteral stones has been reported several times before. We present a right ureteral stone mimicking abnormal focal sacral uptake on planar scan in a patient with rectal cancer. This case highlights the necessity of performing SPECT/CT to ascertain the origin of abnormal focal sacral uptake on planar scan, especially in patients with a history of kidney stones.

ADAM10 Is a Potential Novel Prognostic Biomarker for Sacral Chordoma.

The ADAM (A Disintegrin and Metalloprotease) is a zinc-dependent family of transmembrane proteins upregulated in cancers. As the most frequent member, ADAM10's potential prognostic role in chordoma is unknown. OBJECTIVE: We investigated the expression of ADAM10 protein and its prognostic value in sacral chordoma. DESIGN: Clinical information of patients with sacral chordoma diagnosis during a 7-year period and their archived pathology were retrieved. Immunohistochemistry study of the expression of ADAM10 protein in sacral chordoma and control samples was conducted. The ADAM10 expression was correlated with the patients' clinicopathological information and analyzed by statistical methods. RESULTS: The average age of 64 patients was 57.6 years (range, 35-83 years). Follow-up ranged from 12 to 141 months (mean, 72 months). The histological type included 47 classic, 6 chondroid, and 11 dedifferentiated chordomas. The expression level of ADAM10 was significantly correlated with the histological type (χ 2=11.345, P=0.003), metastasis (χ 2=10.149, P=0.001), overall survival (log-rank test: χ 2=8.177, P=0.004) and disease free survival (log-rank test: χ 2=6.805, P=0.009). The average survival time of patients with weak expression of ADAM10 was longer than that of strong expression. CONCLUSION: The expression of ADAM10 protein is related to the histologic type and the prognosis of sacral chordoma.

Clearance of cerebrospinal fluid from the sacral spine through lymphatic vessels.

The pathways of circulation and clearance of cerebrospinal fluid (CSF) in the spine have yet to be elucidated. We have recently shown with dynamic in vivo imaging that routes of outflow of CSF in mice occur along cranial nerves to extracranial lymphatic vessels. Here, we use near-infrared and magnetic resonance imaging to demonstrate the flow of CSF tracers within the spinal column and reveal the major spinal pathways for outflow to lymphatic vessels in mice. We found that after intraventricular injection, a spread of CSF tracers occurs within both the central canal and the spinal subarachnoid space toward the caudal end of the spine. Outflow of CSF tracers from the spinal subarachnoid space occurred predominantly from intravertebral regions of the sacral spine to lymphatic vessels, leading to sacral and iliac LNs. Clearance of CSF from the spine to lymphatic vessels may have significance for many conditions, including multiple sclerosis and spinal cord injury.