Revision surgery for tumors of the thoracic and lumbar spine: causes, prevention, and treatment strategy.

INTRODUCTION: Revision surgery in spine tumor surgery can offer peculiar challenges given the severity of the majority of these lesions and the complexity of surgical procedures that are required. MATERIALS AND METHODS AND RESULTS: Based on literature review and on personal experience, surgical site infection, cerebrospinal fluid leakage, tumor recurrence and hardware failures are some of the possible causes of surgical revision in this set of patients. CONCLUSIONS: The aim of this study is to evaluate the most frequent complications that can lead to revision in spine tumor patients, to provide suggestions on how to prevent these events and to offer reasonable strategies to properly plan and perform a revision surgery. These slides can be retrieved under Electronic Supplementary Material.

Thermal-ablation of vertebral metastases prevents adverse events in patients with differentiated thyroid carcinoma.

PURPOSE: To evaluate a strategy that used thermal-ablation of vertebral metastases (VM) to prevent vertebral related events (VRE) in patients with differentiated thyroid cancer (DTC). METHODS: This single center study retrospectively reviewed records and post-operative imaging of all DTC patients treated with thermal-ablation for asymptomatic VMs. Rate of local tumor control at first post-operative imaging, 12 and 24 months after thermal-ablation and rate of VREs at 12 and 24 months among the treated VMs were reported. New VMs that occurred during the follow-up and were not considered for additional thermal-ablation were moniroted and VREs were reported. RESULTS: Thermal-ablation was used to achieve local control of 41 VMs in 28 patients. Median post-treatment follow-up was 22 months [range: 12-80] and the mean delay for first post-operative imaging was 2 months [range: 0.6-7.5]. Local control at first post-operative imaging, 12 and 24 months was achieved in 87.8%, 82.9% and 75.6%, respectively. Among the treated VMs the rates of VRE was 7.3% at 2 years, significantly lower if local control was achieved at first post-operative imaging than if it was not (0% vs 30%, p = 0.011, OR = 0.184 [95%CI = 0.094-0.360]). After thermal-ablation procedures, 19 news VMs occurred in 11 patients (39.2%) with a median interval of 8 months [range 1-26] and remained untreated. Among these untreated VMs, the rate of VREs at 2 years was significantly higher compared to the treated VMs: (36.8% vs. 7.3%, p = 0.008, OR = 0.135, [95%CI = 0.030-0.607]). CONCLUSION: local tumor control of VMs using thermal-ablation decreases the risk of VREs in DTC patients.

CX3CL1/fractalkine enhances prostate cancer spinal metastasis by activating the Src/FAK pathway.

Chemokines serve important roles in the development of cancer. C-X3-C motif chemokine ligand 1 (CX3CL1) has been demonstrated to promote metastases in different types of tumors. The authors' previous studies demonstrated that the CX3CL1 (also termed fractalkine)/steroid receptor coactivator (Src)/focal adhesion kinase (FAK) signaling pathway is associated with spinal metastasis. In the present study, it was observed that CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1) was overexpressed in prostate cancer tissues with spinal metastasis compared with primary tumors. Overexpression of CX3CR1 induced cell proliferation, migration and invasion, and inhibited cellular apoptosis. However, repression of CX3CR1 reduced cell proliferation, migration and invasion, and increased cellular apoptosis. In addition, the Src/FAK pathway was activated by CX3CL1, which depends on the Tyr992 residue of epidermal growth factor receptor (EGFR) for phosphorylation. The inhibitors of these kinases repressed the cell migration induced by CX3CL1 or CX3CR1 overexpression. Furthermore, overexpression of CX3CR1 induced the spinal metastasis of prostate cancer in an in vivo mouse model. Therefore, CX3CL1 and its regulation of the EGFR, Src and FAK pathways may be potential targets for the early prevention of spinal metastasis in prostate cancer.

ICAM1 depletion reduces spinal metastasis formation in vivo and improves neurological outcome.

INTRODUCTION: Clinical treatment of spinal metastasis is gaining in complexity while the underlying biology remains unknown. Insufficient biological understanding is due to a lack of suitable experimental animal models. Intercellular adhesion molecule-1 (ICAM1) has been implicated in metastasis formation. Its role in spinal metastasis remains unclear. It was the aim to generate a reliable spinal metastasis model in mice and to investigate metastasis formation under ICAM1 depletion. MATERIAL AND METHODS: B16 melanoma cells were infected with a lentivirus containing firefly luciferase (B16-luc). Stable cell clones (B16-luc) were injected retrogradely into the distal aortic arch. Spinal metastasis formation was monitored using in vivo bioluminescence imaging/MRI. Neurological deficits were monitored daily. In vivo selected, metastasized tumor cells were isolated (mB16-luc) and reinjected intraarterially. mB16-luc cells were injected intraarterially in ICAM1 KO mice. Metastasis distribution was analyzed using organ-specific fluorescence analysis. RESULTS: Intraarterial injection of B16-luc and metastatic mB16-luc reliably induced spinal metastasis formation with neurological deficits (B16-luc:26.5, mB16-luc:21 days, p<0.05). In vivo selection increased the metastatic aggressiveness and led to a bone specific homing phenotype. Thus, mB16-luc cells demonstrated higher number (B16-luc: 1.2±0.447, mB16-luc:3.2±1.643) and increased total metastasis volume (B16-luc:2.87±2.453 mm3, mB16-luc:11.19±3.898 mm3, p<0.05) in the spine. ICAM1 depletion leads to a significantly reduced number of spinal metastasis (mB16-luc:1.2±0.84) with improved neurological outcome (29 days). General metastatic burden was significantly reduced under ICAM1 depletion (control: 3.47×10(7)±1.66×10(7); ICAM-1-/-: 5.20×10(4)±4.44×10(4), p<0.05 vs. control) CONCLUSION: Applying a reliable animal model for spinal metastasis, ICAM1 depletion reduces spinal metastasis formation due to an organ-unspecific reduction of metastasis development.

A survival score for patients with metastatic spinal cord compression from prostate cancer.

BACKGROUND: This study aimed to develop and validate a survival scoring system for patients with metastatic spinal cord compression (MSCC) from prostate cancer. PATIENTS AND METHODS: Of 436 patients, 218 patients were assigned to the test group and 218 patients to the validation group. Eight potential prognostic factors (age, performance status, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time developing motor deficits) plus the fractionation regimen were retrospectively investigated for associations with survival. Factors significant in the multivariate analysis were included in the survival score. The score for each significant prognostic factor was determined by dividing the 6-month survival rate (%) by 10. The total score represented the sum of the scores for each factor. The prognostic groups of the test group were compared to the validation group. RESULTS: In the multivariate analysis of the test group, performance status, ambulatory status, other bone metastases, visceral metastases, and interval from cancer diagnosis to radiotherapy were significantly associated with survival. Total scores including these factors were 20, 21, 22, 24, 26, 28, 29, 30, 31, 32, 33, 35, 37, or 39 points. In the test group, the 6-month survival rates were 6.5% for 20-24 points, 44.6% for 26-33 points, and 95.8% for 35-39 points (p < 0.0001). In the validation group, the 6-month survival rates were 7.4%, 45.4%, and 94.7%, respectively (p < 0.0001). CONCLUSIONS: Because the survival rates of the validation group were almost identical to the test group, this score can be considered valid and reproducible.

Spinocellular carcinoma from warts in a HPV infection natural history lasting 49 years. Virus strategy or host choice? Implications for researches and therapeutic vaccines.

There is a very strong evidence that progression (also to cancer) in variable percentages of cases infected by HPV, HBV, HCV, and HIV depends on host immune response. A large number of observations demonstrate that virus set up a postulated "active strategy" to modify host reactions or to avoid it. But in all those infections it also seems that antigen load (viral RNA or DNA), chronic activation of immune response and time elapsing from the primary infection play a pivotal role in determining clearing or persisting outcomes. My wife's HPV and cancer natural history, lasting 49 years, started at the age of 10 years with facial warts and progressed to CIN 2/3, cervical in situ carcinoma, perineal warts, perianal carcinoma, inguinal lymph nodes, and invasion of bones and muscular structures, until death is paradigmatic: a progressive immune failure was detected in her scaling up all those clinical features, ending in a massive apoptosis of her lymphocytes collected by leukapheresis and cultured with HPV antigens E6/E7, with the aim of obtaining antigen presenting cells and CD8+ specific T lymphocytes. From this experience, a concept of "host choice to reach a tolerance (mainly by a Tregs mediated anergy) or symbiotic-like state" arises, underlining all the affected host's immune-responses to virus persistence (and to consequent tumors). It might be then postulated as the hallmark of a long-term host/parasites co-evolution, and considered a "normal" reaction when the host faces overwhelming numbers of non-self cancer cells (high antigen loads) preceded by persistent virus infections (chronic activation). This happens in patients who do not clear HPV or other viruses soon enough after infection. These observations may lead to a better understanding of many phenomena that are actually difficult to explain or still are open questions. The auto-limiting host's immune-responses are likely to be aimed to avoid risks arising mainly in the protection of "self" (autoimmunity), to prolong its own survival (balance with the virus), to avoid the risk of producing uncontrolled cells (dangerous outcomes). Finally, the postulated negative implications for therapeutic vaccines in cervical cancer, as they really seem to not work till now might be ascribed just to the cited host immune-specific state itself, through an activation induced cell death, elicited by recall antigens (E6/E7 in the case of my wife). Also this latter hypothesis, as well as the previous ones may be of some value to better account for clinical behaviors and researches.

Inhibition of neurotrophin receptor p75 intramembran proteolysis by gamma-secretase inhibitor reduces medulloblastoma spinal metastasis.

Medulloblastoma (MB) is the most devastating and common pediatric brain tumor. Tumor cells invading into surrounding tissue and disseminating through cerebrospinal fluid make treatment extremely difficult. Identifying the mechanisms of MB cells is therefore imperative for the development of novel treatments. A research group demonstrated recently that the multifunctional signaling protein neurotrophin receptor p75(NTR) is a central regulator for glioma invasion. γ-secretase mediated processing of the p75(NTR) is a major contributor to the highly invasive nature of malignant gliomas. In this study we examine the p75(NTR) expression and processing in medulloblastoma cells. Results show that p75(NTR) is a critical regulator of medulloblastoma spinal metastasis. γ-secretase inhibitor, which blocks p75(NTR) proteolytic processing, significantly abrogates p75(NTR) induced medulloblastoma migration and invasion in vitro and in vivo. This data suggests that p75(NTR) is also an important therapeutic target for MB. γ-secretase inhibitor may be a potentially effective clinical application for the treatment of medulloblastoma spinal metastasis.

A biochemical mechanism for resistance of intervertebral discs to metastatic cancer: Fas ligand produced by disc cells induces apoptotic cell death of cancer cells.

Metastatic spinal cancer is characterized by the maintenance of normal disc structure until the vertebral body is severely destroyed by cancer cells. Anatomic features of the discs have been thought to be the main factor which confer the discs their resistance to metastatic cancer. However, little is known about the biochemical mechanism to prevent or attenuate the local infiltration of cancer cells into the discs. The purpose of this study was to investigate whether Fas ligand (FasL) produced by disc cells can kill Fas-bearing breast cancer cells by Fas and FasL interaction. Two human breast cancer cells (MCF-7 and MDA-MB-231) were obtained and cultured (1 x 10(6) cells/well), and the expression of Fas was investigated by western blot analysis. Annulus fibrosus cells were isolated and cultured, and the presence of FasL was quantified in the supernatants of three different numbers of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) by ELISA assay. The MCF-7 and MDA-MB-231 cancer cells were cultured with supernatants of annulus fibrosus cells for 48 h. As controls, MCF-7 and MDA-MB-231 cancer cells were also cultured by themselves for 48 h. Finally, we determined and quantified the apoptosis rates of MCF-7 and MDA-MB-231 cancer cells by Annexin V-FITC and PI and TUNEL at 48 h, respectively. The expression of Fas was identified in MCF-7 and MDA-MB-231 cancer cells. The mean concentrations of FasL in supernatants of annulus fibrosus cells (1x, 2x, and 4 x 10(6) cells/well) were 10.8, 29.6, and 56.4 pg/mL, respectively. After treatment with the supernatant of three different numbers of annulus fibrosus cells, the mean apoptosis rate of MCF-7 cancer cells was increased (2.8%, P < 0.01; 6.7%, P < 0.001; 31.0%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (1.1%). The mean apoptosis rate of MDA-MB-231 cancer cells was also increased (5.7%, P < 0.01; 11.1%, P < 0.001; 25.3%, P < 0.001) in a dose-dependent manner of FasL compared to that of control (2.1%). TUNEL also demonstrated direct evidence of apoptosis of MCF-7 and MDA-MB-231 cancer cells. Our results demonstrate that Fas-bearing cancer cells undergo apoptosis by FasL produced by disc cells, which may be considered as a potential biochemical explanation for the disc's resistance to metastatic cancer.

Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice.

Mice heterozygous for Trp53 are radiation-sensitive and cancer-prone, spontaneously developing a variety of cancer types. Osteosarcomas in the spine lead to paralysis, while lymphomas lead rapidly to death, distinct events that provide objective measures of latency. The effects of a single low-dose (10 or 100 mGy), low-dose-rate (0.5 mGy/min) (60)Co gamma irradiation on lymphoma or spinal osteosarcoma frequency and latency, defined as time of death or of onset of paralysis, respectively, were examined. Compared to spontaneous lymphomas or to spinal osteosarcomas leading to paralysis in unexposed mice, an exposure of 7-8-week-old Trp53(+/-) mice to 10 or 100 mGy had no significant effect on tumor frequency, indicating no effect on tumor initiation. All tumors are therefore assumed to be of spontaneous origin. However, a 10-mGy exposure reduced the risk of both lymphomas and spinal osteosarcomas by significantly increasing tumor latency, indicating that the main in vivo effect of a low-dose exposure is a reduction in the rate at which spontaneously initiated cells progress to malignancy. The effect of this adaptive response persisted for the entire life span of all the animals that developed these tumors. Exposure to 100 mGy delayed lymphoma latency longer than the 10-mGy exposure. However, the 100-mGy dose increased spinal osteosarcoma risk by decreasing overall latency compared to unexposed control mice. That result suggested that this higher dose was in a transition zone between reduced and increased risk, but that the dose at which the transition occurs varies with the tumor type.

Evaluation of radiation carcinogenesis risk in vertebral hemangioma treated by radiotherapy.

The purpose of this study is to report carcinogenesis risk factor evaluation in vertebral hemangioma patients treated by radiotherapy. Between 1975 and 1995, 29 patients received 20-30 Gy total irradiation dose using conventional fractionation scheme. All the patients had measurements with thermoluminescent dosimeters (TLD 100 ), placed on multiple randophantom sites in vivo within the irradiated volume, to verify irradiation accuracy and calculate carcinogenesis risk factor. Twenty nine still-alive patients who had a minimum 6-year and maximum 26-year follow-up (median 14.34 years) have been evaluated by carcinogenic radiation risk factor on the basis of tissue weighting factors as defined by International Commission on Radiological Protection Publication 60. Reasonable pain relief has been obtained in all 29 patients. Calculated mean carcinogenesis risk factor is 0.6% for single irradiation portals and 0.9% for double irradiation portals in the whole group, whilst no secondary cancer has been detected. Radiotherapy is an effective treatment modality in relieving pain of vertebral hemangioma patients. Estimated secondary cancer risk factor for this benign neoplasm irradiation is not as high as can be feared.

Cervical subluxation after surgery and irradiation of childhood ependymoma.

Aggressive resection followed by postoperative radiation therapy directed at the tumor bed characterizes the treatment of childhood infratentorial ependymoma. Tumor resection often requires access to the upper portion of the cervical spinal canal, which places the patient at risk of complications, including destabilization. Two cases of cervical subluxation after surgery and irradiation for infratentorial ependymoma are presented and discussed to identify factors that may be responsible for this uncommon treatment complication. Cervical laminotomies, multiple surgeries, postoperative infection and the addition of radiation therapy may be contributory. Because second resection will be an important component of the next generation of cooperative group studies for infratentorial tumors, the incidence and severity of this treatment-related complication should be documented and efforts should be made to image the upper portion of the cervical spine during routine follow-up.

Systemic immunotoxin treatment inhibits formation of human breast cancer metastasis and tumor growth in nude rats.

Adjuvant chemotherapy in breast cancer patients has had limited success, which is possibly because of lack of effect on non-proliferating cells accompanied by the emergence of drug-resistant cell clones. Since immunotoxins (ITs) are known to exert proliferation-independent cytotoxicity, we investigated the efficacy of systemically administered anti-carcinoma ITs in nude rat models, simulating micrometastatic disease. The monoclonal antibodies MOC31, BM7 and 425.3, which recognize epithelial glycoprotein 2, MUC-1 mucin and the epidermal growth factor receptor, chemically conjugated to Pseudomonas exotoxin A (PE), inhibited protein synthesis of the 2 breast cancer cell lines at concentrations of 0.3-0.4 ng/ml, except for BM7-PE, which was less efficacious (65 ng/ml). In the MA-11 model in nude rats, a single i. v. dose of 20 microg MOC31-PE prevented development of metastasis in the spinal cord in 11/19 (58%) of the animals. Similarly, 425.3-PE treatment gave 6/9 (66%) long-term survivors. In rats injected intracardially or intratibially with MT-1 cells, treatment with 425. 3-PE prevented metastasis in 4/10 (40%) and intratibial tumor growth in 17/18 (94%) of the rats. Importantly, an equimolar dose of free 425.3 (antibody) was ineffective, whereas PE alone was toxic. With BM7-PE, 5/17 (29%) cures were obtained in the intratibial model. The results demonstrate that systemic short-term treatment with non-toxic doses of the 3 ITs tested can effectively inhibit the development of experimental breast cancer metastasis and/or local tumor growth in bone. The results support the development of the ITs towards clinical evaluation for possible use as short-term adjuvant therapy in patients at high risk of early relapse.

Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: a clinical and molecular study.

OBJECTIVE: To delineate the clinical phenotype, molecular basis, and implications for screening in patients and families with multiple schwannomas not generally involving the cranium. METHODS: As part of a United Kingdom clinical and genetic study of type 2 neurofibromatosis (NF2) patients and families with multiple schwannomas who do not fulfil diagnostic criteria for NF2 have been identified. The clinical phenotype was studied in the extended families and molecular analysis was carried out at the NF2 gene locus on chromosome 22. RESULTS: Patterns of inheritance in five families with schwannomatosis are consistent with inheritance of an autosomal dominant gene. The consistency of phenotype, with relative sparing of the cranium, is constant in these families. However, families which initially seem to be indicative of schwannomatosis may develop into classic NF2 as shown by a sixth family. Many of the tumours found in these families were referred to as "neurofibroma" when they were clearly schwannomas. This difference in classification has major implications for the relative risk of each particular type of neurofibromatosis and neuropathological review may be important in some cases. Genetic linkage analysis in the two largest families is entirely consistent with primary involvement of the NF2 gene. CONCLUSIONS: Variant forms of neurofibromatosis have presented a dilemma in classification and determination of recurrence risks in families. Previous reports have suggested that schwannomatosis is a sporadic non-hereditary condition. Patients with multiple schwannomas are likely to have a variant form of NF2 and up to a 50% risk of passing on a gene predisposing to multiple schwannoma.

Radiation treatment of prostate bone metastases and the biological considerations.

This contribution on the biology and management of bone metastases from prostatic cancer is divided into three parts. The first details a study conducted at Stanford University on the prevention of bone metastases in the lumbar spine, in patients in whom the lumbar spine has been irradiated coincidental to the radiation treatment of the paraaortic lymph nodes. The incidence of metastases was significantly reduced in 71 patients in whom the apparently normal lumbar spine was irradiated, as compared to the incidence of metastases in 65 patients who received no lumbar irradiation. The implications of these observations on developing strategies for early, or preemptive, irradiation for bone metastases are discussed. In the second part, the optimum radiation dose and fractionation scheme for the palliation of overt bone metastases is addressed. Drawing largely from the work of Arcangeli et al., a total dose of 40-50 Gy*, fractionated at 2 Gy per day, seems to be the regimen of choice for enduring pain relief for most patients with prostatic metastases to bone. Finally, the recent utilization of strontium-89 in the palliation of advanced bone metastases is addressed. *The Gy is the current international unit of radiation. 1Gy = 100 Rad; 1cGy (centigray) = 1 Rad.

The role of prophylactic spinal irradiation in localized intracranial ependymoma.

A review of the clinical literature on ependymoma, published between 1969 and 1989, was carried out to assess the influence of tumor grade and site, tumor control at the primary site, and extent of irradiation on the incidence of spinal seeding after initial treatment. The pooled data show that the incidence of seeding was 8.4% (7/83) for high grade tumors and 4.5% (6/132) for low grade tumors. Seeding occurred more frequently in infratentorial tumors than in supratentorial tumors. For high grade tumors the incidence was 0% (0/26) for supratentorial and 15.7% (6/38) for infratentorial lesions; for low grade tumors the respective incidence was 2.7% (1/37) and 5.5% (4/73). Spinal seeding was 9.5% (15/157) in the event of failure at the primary site compared to 3.3% (4/122) when local control was achieved. The development of spinal metastases was not influenced by the extent of irradiation. For high grade tumors the incidence was 9.4% (5/53) with spinal irradiation and 6.7% (2/30) without prophylactic treatment; for low grade tumors the respective values were 9.3% (4/43) and 2.2% (2/89). These results indicate that tumor grade, tumor localization, and control of the tumor at the primary site are all factors which may influence the risk of spinal seeding. On the present evidence spinal metastases are not prevented by prophylactic spinal irradiation, regardless of tumor grade and site.

Reduction of spinal metastases after preemptive irradiation in prostatic cancer.

For this study, 136 patients treated at Stanford University Hospital for prostatic cancer between 1971 and 1980 were selected for review. The patients had received no prior therapy, and had no evidence of bone metastases at time of radiation treatment based on radiographic studies and bone scan. Of this group, 71 patients received extended-field irradiation (paraaortic and pelvic fields), and 65 patients received pelvic irradiation. The pelvic field was treated to 50 Gy and the paraaortic field received 45 Gy to 60 Gy. All patients subsequently underwent routine follow-up examinations and studies at Stanford University Hospital: 1,513 follow-up X rays, bone scans, and CT-scans were analyzed for site-specific recurrence. The follow-up ranged from 14 months to 16 yrs from the time of initial treatment, with a mean follow-up of 7 yrs. Lower extremities and ribs were found to be the most common sites of bone metastases. Irradiation of the lumbar spine to a dose of 35 to 60 Gy, coincidental to irradiation of the paraaortic lymph nodes prevented or delayed the development of lumbar spine metastases. The potential mechanism and clinical implications are discussed.