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.

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.

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.

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 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.

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.

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.

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.

Targeting the Cohesive Cluster Phenotype in Chordoma via ß1 Integrin Increases Ionizing Radiation Efficacy.

Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis. DDR to IR in U-CH1 cells was compared to normal prostate epithelial (PrEC) and tumor cells (DU145). Flow cytometry showed a dose- and time-dependent increase in γH2AX and pKAP1 expression in all cell lines. However, nearly 50% of U-CH1 cells exhibited nonresponsive phenotype to IR (measured by γH2AX and pKAP1) independent of cell cycle status. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (versus 80% of nonclustered cells) 2 hours following 2-Gy IR. Conversely, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. ß1 integrin-blocking antibody (AIIB2) decreased cell survival 50% itself and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype.

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.

Cushing's syndrome in infancy due to ectopic ACTH secretion by a sacro-coccygeal teratoma.

BACKGROUND: Adenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in infancy is extremely rare. We describe the case of a sacro-coccygeal ectopic ACTH-secreting immature teratoma in an infant who also presented the triad of defects characteristic of Currarino syndrome. CASE PRESENTATION: A girl was born with a large immature teratoma in the sacro-coccygeal region associated with anal atresia. At the age of 7 days, the concentration of α-fetoprotein (AFP) was above the age-specific normal range. Two non-radical surgical excisions of the tumour were performed. At the age of 7 months, she developed polyphagia, acne, hirsutism, hypertension and hypokalemia with elevated ACTH and absence of serum cortisol circadian rhythm. Immunostaining of tumour tissue showed ACTH-immunoreactive cells. Due to unsuccessful therapy with ketoconazole and resistance to antihypertensive medications [blood pressure (BP) 210/160 mmHg], metyrapone was administered, which controlled her ACTH and cortisol levels in the normal range. Following further removal of tumour bulk after three operations during the first year of life, there was a decrease of BP to normal values. CONCLUSIONS: A rare case of ectopic ACTH syndrome causing Cushing's syndrome in infancy in the context of Currarino syndrome is reported. Radical surgery has resulted in excision of the tumour and current control of Cushing's syndrome.

Microarray gene expression analysis of uterosacral ligaments in uterine prolapse.

OBJECTIVES: Pelvic organ prolapse (POP) is a major health problem that impairs the quality of life with a wide clinical spectrum. Since the uterosacral ligaments provide primary support for the uterus and the upper vagina, we hypothesize that the disruption of these ligaments may lead to a loss of support and eventually contribute to POP. DESIGN AND METHODS: In this study, we therefore investigated whether there are any differences in the transcription profile of uterosacral ligaments in patients with POP when compared to those of the control samples. Seventeen women with POP and 8 non-POP controls undergoing hysterectomy for benign conditions were included in the study. Affymetrix® Gene Chip microarrays (Human Hu 133 plus 2.0) were used for whole genome gene expression profiling analysis. RESULTS: There was 1 significantly down-regulated gene, NKX2-3 in patients with POP compared to the controls (p=4.28464e-013). KIF11 gene was found to be significantly down-regulated in patients with ≥3 deliveries compared to patients with <3 deliveries (p=0.0156237). UGT1A1 (p=2.43388e-005), SCARB1 (p=1.19001e-006) and NKX2-3 (p=2.17966e-013) genes were found to be significantly down-regulated in the premenopausal patients compared to the premenopausal controls. UGT1A1 gene was also found to be significantly down-regulated in the post menopausal patients compared to the postmenopausal controls (p=0.0005). CONCLUSION: This study provides evidence for a significant down-regulation of the genes that take role in cell cycle, proliferation and embryonic development along with cell adhesion process on the development of POP for the first time.

Median Sacral Artery, Sympathetic Nerves, and the Coccygeal Body: A Study Using Serial Sections of Human Embryos and Fetuses.

To examine how the median sacral artery (MSA) is involved with the coccygeal body or glomus coccygeum, we studied serial frontal or sagittal sections of 14 embryos (approximately 5-6 weeks of gestation) and 12 fetuses (10-18 weeks). At five weeks, the caudal end of the dorsal aorta (i.e., MSA) accompanied putative sympathetic ganglion cells in front of the upper coccygeal and lower sacral vertebrae. At six weeks, a candidate for the initial coccygeal body was identified as a longitudinal arterial plexus involving nerve fibers and sympathetic ganglion cells between arteries. At 10-18 weeks, the MSA exhibited a highly tortuous course at the lower sacral and coccygeal levels, and was attached to and surrounded by veins, nerve fibers, and sympathetic ganglion cells near and between the bilateral origins of the levator ani muscle. Immunohistochemistry demonstrated expression of tyrosine hydroxylase and chromogranin A in the nerves. However, throughout the stages examined, we found no evidence suggestive of an arteriovenous anastomosis, such as well-developed smooth muscle. An acute anterior flexure of the vertebrae at the lower sacrum, as well as regression of the secondary neural tube, seemed to induce arterial plexus formation from an initial straight MSA. Nerves and ganglion cells were likely to be secondarily involved with the plexus because of the close topographical relationship. However, these nerves might play a major role in the extreme change into adult morphology. An arteriovenous anastomosis along the MSA might be an overinterpretation, at least in the prenatal human. Anat Rec, 299:819-827, 2016. © 2016 Wiley Periodicals, Inc.

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.

Proteomic Analysis of the Uterosacral Ligament in Postmenopausal Women with and without Pelvic Organ Prolapse.

BACKGROUND: Pelvic organ prolapse (POP) is a major health problem in adult women that involves many factors. No proteomic analysis has been conducted exclusively in POP patients. This study aimed to identify the differential expression of proteins that may be involved in POP by proteomic analysis. METHODS: Samples of the uterosacral ligament (USL) were collected from five POP patients and five non-POP patients matched according to age, parity, and menopausal status and analyzed using two-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to verify the mRNA expression of proteins that showed differential expression in the proteomic analyses. RESULTS: Proteins differentially expressed between POP and non-POP patients were detected. Eight proteins that were down-regulated in the POP group were identified by MALDI-TOF-MS. These proteins included electron transfer flavoprotein, apolipoprotein A-I, actin, transgelin, cofilin-1, cyclophilin A, myosin, and galectin-1, and their expression was verified by qRT-PCR. CONCLUSION: Using comparative proteomics, we identified eight differentially expressed proteins (including four cytoskeleton proteins and three proteins related to apoptosis) in the USL that may be involved in apoptosis associated with the tissue effects in POP pathophysiology.

Primary intraosseous ganglioneuromatous paraganglioma of the sacrum with immunopositivity for cytokeratin.

BACKGROUND: Paragangliomas are derived from neurosecretory cells believed to be of neural crest origin. A spinal location of paraganglioma is rare and usually presents as an intradural mass. PATIENT AND METHODS: A primary intraosseous paraganglioma of sacrum is extremely unusual, and only 6 cases were reported. In this study, we report a rare case of a 44-year-old man with the complaint of low back pain and lower extremity weakness. Imaging workup, including computerized tomography (CT), and magnetic resonance imaging (MRI) presented an intraosseous sacral lesion with invasion of sacrum in the S1-S3 vertebrae, and extension to L4-L5 spinal canal. The patient underwent subtotal tumor resection, followed by radiation therapy. RESULTS: The morphological and immunohistochemical studies revealed a composite tumor of paraganglioma and ganglioneuroma components, with immunopositivity for cytokeratin. CONCLUSIONS: To the best of our knowledge, this is the first report in the literature demonstrating an intraosseous sacral paraganglioma with these 2 pathological features.

High expression of SPHK1 in sacral chordoma and association with patients' poor prognosis.

Sacral chordoma is an aggressive bone tumor with a high local recurrence rate. Surgery remains the standard treatment because of its resistance to chemotherapy and radiotherapy. However, recurrence occurs frequently even after complete surgical resection. Great effort has been invested in discovering novel biomarkers and therapeutic targets. To date, the molecular mechanism is still unclear. In this study, we evaluated the expression of sphingosine kinase 1 (SPHK1) in 42 sacral chordoma samples and 16 distant normal tissue specimens by immunohistochemical staining. In addition, we analyzed its association with the clinical factors and patients' prognosis. Of all the chordoma samples, 69 % (29/42) showed high expression of SPHK1, whereas, only 19 % (3/16) of distant normal tissues expressed a high level of SPHK1 (p = 0.001). Chi-square analysis revealed that high expression of SPHK1 was significantly correlated with tumor recurrence (p = 0.019) and invasion into surrounding muscle (p = 0.005), while the data did not indicate any association with patients' gender, age, tumor location and size (p > 0.05). Kaplan-Meier survival curve and log-rank test showed that patients with high expression of SPHK1 possessed shorter continuous disease-free survival time. Conclusively, SPHK1 may become a potential biomarker for sacral chordoma in predicting its recurrence and patients' prognosis.

90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution.

BACKGROUND: Biodistribution data to date using In-ibritumomab tiuxetan have been initially obtained in patients with less than 25% lymphomatous bone marrow involvement and adequate hematopoietic synthetic function. In this article we present the results of an analysis of the biodistribution data obtained from a cohort of patients with extensive bone marrow involvement, baseline cytopenias, and chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: Thirty-nine patients with a diagnosis of B-cell lymphoma or CLL expressing the CD20 antigen, who had failed at least one prior regimen, and had evidence of persistent disease were included in this analysis; however, only 38 of them completed the treatment. Semiquantitative analysis of the biodistribution was performed using regions of interest over the liver, lungs, kidneys, spleen, and sacrum. The observed interpatient variability including higher liver uptake in four patients is discussed. RESULTS: No severe solid organ toxicity was observed at the maximum administered activity of 1184 MBq (32 mCi) Y-ibritumomab tiuxetan. After accounting for differences in marrow involvement, patients with CLL exhibit comparable biodistributions to those with B-NHL. We found that the estimated sacral marrow uptake on 48 h images in patients with bone marrow involvement may be an indicator of bone marrow involvement. There was no correlation between tumor visualization and response to treatment. CONCLUSION: These data suggest that the imaging step is not critical when the administered activity is below 1184 MBq (32 mCi). However, our analysis confirms that the semiquantitative imaging data can be used to identify patients at risk for liver toxicity when higher doses of Y-ibritumomab tiuxetan are used. Patients with CLL can have excellent targeting of disease by In-ibritumomab tiuxetan, indicating potential efficacy in this patient population.