Natural History of a Patient with Sacral Chordoma: Case Report and Literature Review.

BACKGROUND: Chordomas are rare, slow-growing, locally aggressive, malignant tumors of the spine. Chordomas are conventionally treated with surgical resection with or without radiation. There is an absence of literature documenting the natural history of a primary sacral chordoma. CASE DESCRIPTION: A 65-year-old man presented with rectal pain, constipation, urinary and fecal incontinence, S1 radiculopathy, and a palpable rectal mass. A needle biopsy confirmed the pathologic diagnosis of sacral chordoma. The patient declined to have surgery because of the surgical risks involved. He was managed conservatively with supportive care only. The patient was routinely followed in clinic and had a subjective and objective excellent quality of life with adequate pain management. Meanwhile, his neurologic status did not deteriorate. During follow-up, some posterolateral aspects of the chordoma regressed. However, the bulk of the lesion continued to slowly progress. The patient survived for 7.5 years. He eventually succumbed to urosepsis and new-onset peritoneal metastasis. CONCLUSIONS: To our knowledge, the patient is the only documented case in the literature of an untreated biopsy-proven sacral chordoma. The patient's tumor was intended for resection, and therefore comparable with data from treated chordomas. The patient's survival is similar to the median survival in treated chordomas. The patient's survival was despite negative prognosticators, such as advanced age of the patient and high sacral location above S2.

Development of a Novel Orthotopic Primary Human Chordoma Xenograft Model: A Relevant Support for Future Research on Chordoma.

Chordomas are slow-growing rare malignant neoplasms. The aim of this study was to establish a primary model of chordoma in the lumbosacral orthotopic area, to compare the growth rate to the subcutaneous site, and to show that this new graft site optimizes tumor growth and bony invasion. Eleven chordoma samples were transplanted subcutaneously in the flank and/or in contact with the lumbosacral region and grown into nude mice. Engraftment rate was significantly more successful in the lumbosacral environment compared with the flank at P0. Two xenografts from 2 patients showed bone invasion. One tumor was maintained through multiple rounds of serial transplantation, creating a model for study. Histological and immunostaining analysis confirmed that tumor grafts recapitulated the primary tumor from which they were derived, consisting of a myxoid chordoma expressing brachyury, cytokeratin AE1, EMA, and VEGF. Clear destruction of the bone by the tumor cells could be demonstrated. Molecular studies revealed PIK3CA and PTEN mutations involved in PI3K signaling pathway and most of the frequently reported chromosomal alterations. We present a novel orthotopic primary xenograft model of chordoma implanted for the first time in the lumbosacral area showing bone invasion, PIK3CA, and PTEN mutations that will facilitate preclinical studies.

Endoscopic endonasal skull base surgery for pediatric brain tumors.

PURPOSE: The utility of endoscopic endonasal skull base surgery (EES) in various pathologic entities in adults has been published in the literature. However, the role of EES in children has not been clearly elucidated. We evaluated the feasibility of EES in children with brain tumors. METHODS: We retrospectively reviewed clinical features, surgical outcomes, and complications in children who underwent EES for intracranial and skull base tumors at a single institution from July 2010 to October 2018. RESULTS: A total of 82 patients underwent EESs for 77 intracranial and 5 skull base bony tumors. The mean age at diagnosis was 11.4 years (range 4-18 years), and the mean follow-up period was 46.8 months. The most common tumors were craniopharyngioma in the intracranial tumor and chordoma in the skull base. Gross total resection was the goal of surgery in 55 patients and achieved in 90.9%. The vision was improved in 76.1% of patients with visual impairments. Preoperatively, various endocrinological deficiencies were revealed in 73.7% of 76 patients with hypothalamus-pituitary lesions, and the hyposomatotropism was most common. Endocrinological status was improved only in 10. Aseptic or bacterial meningitis (7.3%) was the most common surgical complication, and the cerebrospinal fluid leakage rate was 2.4%. CONCLUSIONS: EES provides favorable neurological outcomes with acceptable risk for children with brain tumors. The high incidence of endocrinological deficits in cases with hypothalamus-pituitary lesions emphasizes the importance of judicious pre- and postoperative evaluation.

A giant lumbar chordoma: A case report.

RATIONALE: Chordomas are malignant neoplasms derived from incomplete regression of notochordal tissue along the craniococcygeal axis.It is rare for Chordoma arising from the lumbar spine and the traditional long-term prognosis is typically poor. PATIENT CONCERNS: The persistent pain in the left side of the waist about 2 years. DIAGNOSES: Chordoma. INTERVENTIONS: The patient was treated with surgical resection of the total tumor, followed by the spinal internal fixation of L1 to L2 with pedicle screws. OUTCOMES: After 5 month follow-up,we find the recurrence in the original lesion.At the 15 month follow-up,the patient was dead after a lot of times revisit by various doctor. LESSONS: So It is suggest that the diagnosis should be carried out accurately at the early stage, the lesions and source of lesions should be cut away as broadly as possible, also the radiation and chemotherapy should be carried out after the operation as necessary.

High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations. In the present study, we investigate the SMARCB1 abnormalities in a group of nine well-characterized PDCs and to establish the sensitivity of the FISH method in detecting these changes in the clinical setting. We further assessed the pathologic features and clinical behavior of this cohort managed at our referral center over a 20-year period. The mean age at diagnosis was 10 years-of-age. All except one case occurred in the cranial region. All demonstrated strong nuclear expression of brachyury and loss of SMARCB1 expression. FISH identified homozygous SMARCB1 deletions in all except one case; additionally two cases revealed a heterozygous EWSR1 locus co-deletion. Clinical follow-up information was available in five patients. Two patients presented with distant metastases at initial diagnosis. Two of the three remaining patients with primary disease failed both locally and distantly after multimodality therapy. We conclude that PDCs are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH.

Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model.

OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty-four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100ß, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma-engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies.

What Are the Conditional Survival and Functional Outcomes After Surgical Treatment of 115 Patients With Sacral Chordoma?

BACKGROUND: Conditional survival is a measure of prognosis for patients who have already survived for a specific period of time; however, data on conditional survival after sacrectomy in patients with sacral chordoma are lacking. In addition, because sacral tumors are rare and heterogeneous, classifying them in a way that allows physicians to predict functional outcomes after sacrectomy remains a challenge. QUESTIONS/PURPOSES: (1) What is the overall survival and disease-free survival in patients treated by sacrectomy for chordoma? (2) What is the conditional survival probability and how do prognostic factors change over time in patients undergoing surgical resection for sacral chordoma? (3) What is the local recurrence rate after surgery, how was it treated, and what factors impact on local recurrence? (4) What is the postoperative motor, sensory, bowel, and bladder function by level of resection as determined by using a newly designed scoring method? METHODS: Between 2003 and 2012, our center treated 122 patients surgically for sacral chordoma. Of those, two died and five were lost before a minimum followup of 1 year was achieved, leaving 115 patients available for analysis in this retrospective study at a mean of 4.9 years (range, 1.3-10.8 years). Basically, single posterior or combined approaches were chosen based on the most cephalad extent of the tumor and resection level was normally at half or one sacral vertebrae above the tumor. The 5-year conditional survival rate was calculated based on Kaplan-Meier survival analysis. The effect of prognostic factors on conditional survival was also explored. A newly designed score method was proposed and adopted in the current study to critically evaluate the functional outcome after resection of the sacrum. Inter- and intraobserver reliability was tested by a preliminary study using kappa statistics and Spearman rank correlation coefficients. Significant interobserver (p < 0.01) and intraobserver agreement (κ > 0.75) were found in nine items between each observer. RESULTS: The estimated 5-year overall survival rate was 81% (95% confidence interval [CI], 72%-90%) at diagnosis. The 5-year disease-free survival rate was 52% (95% CI, 43%-63%). The 5-year conditional overall survival decreased with each additional year in the first 4 years (81% at diagnosis versus 60% at the fourth year, p < 0.0001) and increased slightly in the fifth year. Patients with adequate surgical margins displayed a higher 5-year survival than those with an inadequate margin (86% [95% CI, 76%-95%] versus 67% [95% CI, 48%-85%], p = 0.01) at diagnosis. Conditional survival estimates for patients who received operations elsewhere were lower than that of newly diagnosed patients treated by us at diagnosis (64% [95% CI, 46%-83%] versus 90% [95% CI, 82%-99%], p = 0.012), but with the numbers we had, we could not detect a difference in conditional survival between those treated elsewhere first compared with those initially treated by us at 5 years. The proposed score system for function evaluation was able to distinguish different levels of resection. The overall functional results for the preservation of bilateral S1, S2, and S3 were 40 ± 8%, 60 ± 12%, and 82 ± 11%, respectively. Patients who had preservation of only one S3 nerve root had more severe incontinence (1.99 ± 0.79 versus 2.60 ± 0.63, p = 0.01) and more sensory loss (1.88 ± 0.82 versus 2.31 ± 0.59, p = 0.02) than those patients with preservation of bilateral S3 nerve roots. CONCLUSIONS: The 5-year conditional survival for sacral chordoma decreased with each additional year and began to improve after the fourth year. In addition, the effect of the surgical margin and influence of previous surgery on conditional survival were not linear over time. The level of nerve root resections corresponded with the overall function scores according to the proposed scoring method. This information and scoring system should be valuable in discussing outcomes of sacrectomy in patients with chordoma who are considering this operation and serve as the basis for further study. LEVEL OF EVIDENCE: Level III, therapeutic study.

How Does the Level of Nerve Root Resection in En Bloc Sacrectomy Influence Patient-Reported Outcomes?

BACKGROUND: For patients with sacral tumors, who are well enough for surgery, en bloc resection is the preferred treatment. Survival, postoperative complications, and recurrent rates have been described, but patient-reported outcomes often are not included in these studies. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare patient-reported outcomes after en bloc sacrectomy, based on the level of sacral nerve root resection, in terms of mental health, physical health, bowel function, and sexual function; and (2) to assess differences in terms of mental health, physical health, and pain between patients with and without a colostomy. METHODS: A total of 74 patients, of whom 58 (78%) were diagnosed with chordoma, were surveyed between February 2012 and October 2014. This represented 48% of patients with sacral chordoma who were alive and who had been treated with a transverse sacral resection between June 2000 and August 2013 at three institutions with a minimum followup of 6 months (mean, 59 months; range, 6-255 months). We chose 6 months because we believe that neurologic deficits generally are stable by this point and that patients generally have recovered from the operation by this time. Patients were divided into five groups based on the most caudal nerve root spared: L5 (N = 10), S1 (N = 22), S2 (N = 17), S3 (N = 18), and S4 (N = 7). Only postoperative outcomes were collected using the National institute of Health's Patient Reported Measurement Information System (PROMIS) Global Health survey, PROMIS Pain Interference survey, PROMIS Pain Intensity survey, PROMIS Sexual Function survey, and the Modified Obstruction and Defecation Score survey. RESULTS: Differences between two adjacent levels were found in terms of mental health, physical health, and sexual function. Patients in whom the S2 nerve roots were spared had a lower mental health score (median = 44, interquartile range [IQR] = 41-51) than patients in whom the S3 nerve roots were spared (median = 53, IQR = 48-56, q = 0.049). Patients in whom the S2 nerve roots were spared had a slightly lower physical health score (median = 42, IQR = 40-51) than patients in whom the S3 nerve roots were spared (median = 47, IQR = 45-54, q = 0.043). Patients in whom the S1 roots were spared (median = 1.0, range = 1.0-1.0) had a lower orgasm score than patients in whom the S2 nerve roots were spared (median = 3, range = 2-5, q = 0.027). No differences in terms of mental health, physical health, or pain were found between the colostomy group and the no colostomy group. CONCLUSIONS: The combination of our findings can be used to further educate patients and discuss expectations. In an operative setting, these data can be considered when deciding to place a colostomy. LEVEL OF EVIDENCE: Level III, therapeutic study.

Establishment and characterization of a chordoma cell line from the tissue of a patient with dedifferentiated-type chordoma.

OBJECTIVE Chordoma is a rare bone tumor of the axial skeleton believed to originate from the remnants of the embryonic notochord. The available tumor cells are characteristically physaliferous and express brachyury, a transcription factor critical for mesoderm specification. Although chordomas are histologically not malignant, treatments remain challenging because they are resistant to radiation therapy and because wide resection is impossible in most cases. Therefore, a better understanding of the biology of chordomas using established cell lines may lead to the advancement of effective treatment strategies. The authors undertook a study to obtain this insight. METHODS Chordoma cells were isolated from the tissue of a patient with dedifferentiated-type chordoma (DTC) that had recurred. Cells were cultured with DMEM/F12 containing 10% fetal bovine serum and antibiotics (penicillin and streptomycin). Cell proliferation rate was measured by MTS assay. Cell-cycle distribution and cell surface expression of proteins were analyzed by fluorescence-activated cell sorting (FACS) analysis. Expression of proteins was analyzed by Western blot and immunocytochemistry. Radiation resistance was measured by clonogenic survival assay. Tumor formation was examined by injection of chordoma cells at hindlimb of nude mice. RESULTS The putative (DTC) cells were polygonal and did not have the conventional physaliferous characteristic seen in the U-CH1 cell line. The DTC cells exhibited similar growth rate and cell-cycle distribution, but they exhibited higher clonogenic activity in soft agar than U-CH1 cells. The DTC cells expressed high levels of platelet-derived growth factor receptor-ß and a low level of brachyury and cytokeratins; they showed higher expression of stemness-related and epithelial to mesenchymal transition-related proteins than the U-CH1 cells. Intriguingly, FACS analysis revealed that DTC cells exhibited marginal surface expression of CD24 and CD44 and high surface expression of CXCR4 in comparison to U-CH1 cells. In addition, blockade of CXCR4 with its antagonist AMD3100 effectively suppressed the growth of both cell lines. The DTC cells were more resistant to paclitaxel, cisplatin, etoposide, and ionizing radiation than the U-CH1 cells. Injection of DTC cells into the hindlimb region of nude mice resulted in the efficient formation of tumors, and the histology of xenograft tumors was very similar to that of the original patient tumor. CONCLUSIONS The use of the established DTC cells along with preestablished cell lines of chordoma may help bring about greater understanding of the mechanisms underlying the chordoma that will lead to therapeutic strategies targeting chordomas.

Effective palliative radiofrequency ablation for tumors causing pain, numbness and motor function disorders: case series.

BACKGROUND: We present a case series of a palliative radiofrequency ablation (RFA) for the tumors that lead to the resolution of pain and motor function disorders. RFA is widely used on tumors in various organs and often reported in good outcome. There are some reports that RFA was performed as a palliative treatment but a few reports of RFA that performed for lung tumor as a palliative treatment. This case series includes two cases, palliative RFA for a sacrum and a lung tumor. The results of this case series presented that a palliative RFA is effective in improving the symptoms of patients. CASE PRESENTATION: Case 1. A 64-year-old Japanese woman with a chordoma at her sacrum presented with pain in her left leg and claudication. Though operations, radiation therapy and GS-TAE (gelatin sponge-transarterial embolization, via the L5 lumbar artery) were performed, the size of the tumor leading pain and claudication increased. RFA was performed for the sacral tumor, and these symptoms resolved one year after the procedure. Case 2. A 68-year-old Japanese man with a leiomyosarcoma at the apex of left lung presented with pain and motor function disorders of the left upper limb. Dissemination in the pleura was appeared after the operation for a leiomyosarcoma at the mediastinum. Though radiation therapy and a second operation were performed, the tumor at the apex of the left lung increased and pain and numbness of the left upper limb were appeared after the second operation. RFA was performed for the left lung tumor, and the symptoms resolved 3 months after RFA. CONCLUSION: RFA is effective as a palliative treatment and has a potential to salvage the patients from the symptoms of the tumors when conventional palliative treatments such as surgery, radiation therapy, and chemotherapy are difficult or contraindicated.

MicroRNA-1 (miR-1) inhibits chordoma cell migration and invasion by targeting slug.

Recent studies have revealed that expression of miRNA-1 (miR-1) is frequently down-regulated in several cancer types including chordoma. Identifying and validating novel targets of miR-1 is useful for understanding the roles of miR-1 in chordoma. We aimed to further investigate the functions of miR-1 in chordoma. Specifically, we assessed whether restoration of miR-1 affects cell migration and invasion in chordoma, and focused on the miR-1 potential target Slug gene. Migratory and invasive activities were assessed by wound healing and Matrigel invasion assays, respectively. Cell proliferation was determined by MTT assay. Slug expression was evaluated by Western blot, immunofluorescence, and immunohistochemistry. Restoration of miR-1 expression suppressed the migratory and invasive activities of chordoma cells. Transfection of miR-1 inhibited cell proliferation both time- and dose-dependently in chordoma. MiR-1 transfected cells showed inhibited Slug expression. Slug was over-expressed in chordoma cell lines and advanced chordoma tissues. In conclusion, we have shown that miR-1 directly targets the Slug gene in chordoma. Restoration of miR-1 suppressed not only proliferation, but also migratory and invasive activities, and reduced the Slug expression in chordoma cells. These results collectively indicate that miR-1/Slug pathway is a potential therapeutic target because of its crucial roles in chordoma cell growth and migration.

The influence of skull base chordoma on lower urinary tract symptoms.

OBJECTIVE: To provide the first insights into the potential role of skull base chordoma, which causes brainstem compression in and around Barrington's nucleus and its effect on the micturition center. Chordoma is a rare malignant bone tumor that originates from the remnants of the embryonic notochord, which normally forms and dissolves during early fetal development. Although it is a slowly growing tumor, it displays local invasive growth. METHODS: Urodynamic testing of 22 symptomatic patients was performed. All women and men with skull base chordoma treated in 2 hospitals in Germany between 1986 and 2007 were studied. Follow-up periods ranged from 6 months to 10 years. Lower urinary tract symptoms were documented in patients with acute brainstem compression because of local chordoma growth. RESULTS: Of 74 patients treated, 22 (7 women, 15 men) with a median age of 37 years were evaluated with voiding diaries and computer urodynamic investigation. Urodynamic testing of 22 symptomatic patients revealed detrusor overactivity in 55%, low compliance bladder in 14%, detrusor-sphincter dyssynergia in 45%, and uninhibited sphincter relaxation in 27%. Despite the description of incomplete emptying and urgency, 4 patients had normal urodynamic findings (18%). Brain magnetic resonance images of the lesions of the symptomatic patients were obtained to determine the side of lesions. CONCLUSION: The dorsolateral pons, including pontine reticular nucleus and the reticular formation and the locus coeruleus, seems to be mainly responsible for lower urinary tract symptoms in our patients with skull base chordoma and brainstem compression.

Delayed recurrence of intracranial chordoma.

PURPOSE: Although a chordoma is extremely rare, it commonly presents with ocular symptoms, often impacting one or more cranial nerves. CASE REPORT: The authors describe a unique case of rapidly developing intracranial chordoma that recurred 9 years after the original mass was successfully diagnosed and treated. It is noteworthy that, although the tumor originated within the cranium at the base of the skull, it presented primarily with clinical signs of a unilateral orbital mass because of tumor extension. CONCLUSIONS: The lifetime recurrence rate for chordoma is high after treatment; therefore, a high level of suspicion is warranted in any patient with new symptoms and a history of intracranial chordoma.

Long-term outcome following surgical treatment of sacral chordoma.

BACKGROUND: Sixteen sacral chordoma surgeries performed at a single institution during the 1983-2008 period were retrospectively studied. Our aim is to assess surgical treatment and long-term outcomes. METHODS: Fifteen patients underwent primary wide excision, and one intralesional excision using ethanol for local control and radiation therapy (RT). A combined anteroposterior approach for large tumors above S2, and wide excision was performed with the modified threadwire-saw (MT-saw) after 1997. RESULTS: Fourteen of the 15 patients had wide margins, one a wide margin with contamination. The MT-saw was facilitated sacral excision with wide margins. Eleven patients are alive for 5-28 years. Five patients died before 10 years, two patients experienced sepsis, and one of another disease. Two patients died of local recurrence (LR) and another of multiple metastases after intralesional excision and wide excision with contamination, respectively. LR and complications occurred 4 each of 11 patients with tumors ≥ 10 cm, neither with tumors < 10 cm. The overall 5- and 10-year survival rate with wide surgical margins was 13/16 (81.3%) and 8/13 (61.5%). CONCLUSIONS: A combined anteroposterior approach for large tumors, and the MT-saw facilitates sacral excision with wide margins. Wide excision is recommended for younger patients.

Benign notochordal cell tumors of the spine: natural history of 8 patients with histologically confirmed lesions.

BACKGROUND: Notochord-related lesions of the spinal column include benign notochordal cell tumors (BNCTs), ecchordosis physaliphora, both generally considered benign lesions, and chordomas, which represent malignant tumors. The histological similarity of these lesions to the notochord and each other and their strong predilection to the axial skeleton have led to the hypothesis that these lesions represent a continuum of malignant transformation from notochordal remnants, BNCTs, and finally chordomas. OBJECTIVE: To present a cohort of biopsy-proven BNCTs with a description of radiographic features, histology, and follow-up to help elucidate the optimal management of these lesions. METHODS: A retrospective chart review identified 13 patients with notochordal rest lesions confirmed by histology. Histologic inclusion criteria included notochordal features without evidence of septation, myxoid matrix, nuclear atypia, or mitotic figures. Tumors exhibiting evidence of cortical expansion or destruction were excluded. The natural history and histological and radiographic features were examined. RESULTS: Sixteen spinal lesions from 8 patients met the diagnostic criteria for BNCTs, identified on imaging after the patient presented with back pain. Radiographically, all lesions were hypointense on T1-weighted magnetic resonance imaging sequences and hyperintense on T2-weighted and short T1 inversion recovery. The median radiographic follow-up was 21.6 months (range, 8.5-71.2 months). None of the lesions exhibited radiographic or symptomatic progression. CONCLUSION: Although limited by short follow-up, our series confirms that these lesions may be safely observed without evidence of malignant transformation, which emphasizes the importance of distinction of BNCT from chordoma at diagnosis and the possibility of close follow-up for these lesions instead of aggressive treatment indicated in patients with chordomas.

Electrophysiological monitoring in patients with tumors of the skull base treated by carbon-12 radiation therapy.

PURPOSE: To report the results of short-term electrophysiologic monitoring of patients undergoing (12)C therapy for the treatment of skull chordomas and chondrosarcomas unsuitable for radical surgery. METHODS AND MATERIALS: Conventional electroencephalogram (EEG) and retinal and cortical electrophysiologic responses to contrast stimuli were recorded from 30 patients undergoing carbon ion radiation therapy, within a few hours before the first treatment and after completion of therapy. Methodologies and procedures were compliant with the guidelines of the International Federation for Clinical Neurophysiology and International Society for Clinical Electrophysiology of Vision. RESULTS: At baseline, clinical signs were reported in 56.6% of subjects. Electrophysiologic test results were abnormal in 76.7% (EEG), 78.6% (cortical evoked potentials), and 92.8% (electroretinogram) of cases, without correlation with neurologic signs, tumor location, or therapy plan. Results on EEG, but not electroretinograms and cortical responses, were more often abnormal in patients with reported clinical signs. Abnormal EEG results and retinal/cortical responses improved after therapy in 40% (EEG), 62.5% (cortical potentials), and 70% (electroretinogram) of cases. Results on EEG worsened after therapy in one-third of patients whose recordings were normal at baseline. CONCLUSIONS: The percentages of subjects whose EEG results improved or worsened after therapy and the improvement of retinal/cortical responses in the majority of patients are indicative of a limited or negligible (and possibly transient) acute central nervous system toxicity of carbon ion therapy, with a significant beneficial effect on the visual pathways. Research on large samples would validate electrophysiologic procedures as a possible independent test for central nervous system toxicity and allow investigation of the correlation with clinical signs; repeated testing over time after therapy would demonstrate, and may help predict, possible late toxicity.

'The chicken or the egg?' dilemma strikes back for the controlling mechanism in chordoma(#).

Chordoma is a rare malignant tumour of bone showing notochordal differentiation with characteristic expression of the transcription factor brachyury (T). Next to giving insight into its differentiation spectrum, the expression of T can be used as an adjunct diagnostic tool. The expression of brachyury in chordoma is necessary to maintain cell proliferation in chordoma cell lines, indicating that in chordoma it might be a master regulator of oncogenesis. Identification and mapping of the full gene regulatory network in a recent work in The Journal of Pathology by Nelson and colleagues not only shed light on involved pathways but also indicated pathways for targeted therapy, including brachyury itself.

An integrated functional genomics approach identifies the regulatory network directed by brachyury (T) in chordoma.

Chordoma is a rare malignant tumour of bone, the molecular marker of which is the expression of the transcription factor, brachyury. Having recently demonstrated that silencing brachyury induces growth arrest in a chordoma cell line, we now seek to identify its downstream target genes. Here we use an integrated functional genomics approach involving shRNA-mediated brachyury knockdown, gene expression microarray, ChIP-seq experiments, and bioinformatics analysis to achieve this goal. We confirm that the T-box binding motif of human brachyury is identical to that found in mouse, Xenopus, and zebrafish development, and that brachyury acts primarily as an activator of transcription. Using human chordoma samples for validation purposes, we show that brachyury binds 99 direct targets and indirectly influences the expression of 64 other genes, thereby acting as a master regulator of an elaborate oncogenic transcriptional network encompassing diverse signalling pathways including components of the cell cycle, and extracellular matrix components. Given the wide repertoire of its active binding and the relative specific localization of brachyury to the tumour cells, we propose that an RNA interference-based gene therapy approach is a plausible therapeutic avenue worthy of investigation.