Alessandro Luzzati

Oncosurgical results of multilevel thoracolumbar en-bloc spondylectomy and reconstruction with a carbon composite vertebral body replacement system.

Study Design. Retrospective clinical study for patients receiving multilevel en-bloc spondylectomy resection for sarcomas and solitary metastases of the thoracolumbar spine. Objective. Assess the clinical and radiologic outcome after multilevel en-bloc spondylectomy and reconstruction. Summary of Background Data. Monolevel en-bloc spondylectomies have proven their oncosurgical effectiveness while reports on multilevel resections for extracompartmental tumor localizations are rare. Methods. Patients treated by multilevel en-bloc spondylectomy and restoration with a carbon composite vertebral body replacement system were investigated. Patient charts, and clinical follow-up investigations were analyzed for histopathological tumor origin, preoperative symptoms, surgical peri- and postoperative data, applied adjuvant therapies, as well as the course of disease. Solitary metastases time until occurrence and prognostic scores were evaluated (Tomita/Tokuhashi Score). CT-scans were performed and analyzed at follow up. Oncological status was evaluated including local recurrence rates, cumulative disease specific, and metastases-free survival. Results. Multilevel (2–5 segments) en-bloc spondylectomy of the thoracolumbar spine was performed in 20 patients (15 sarcomas and 5 solitary spinal metastases 9 male/11 female, mean age at surgery: 54 ± 15 years.). Wide and marginal surgical margins were achieved in 7 and 13 patients, respectively. Mean follow-up period was 25.0 (9–53) months. Thirteen patients received adjuvant therapy. No implant breakage or loosening was observed. Local recurrence occurred in one patient. Thirteen of the 18 surviving patients showed no evidence of the disease, two died of systemic disease. Conclusion. Multilevel en-bloc spondylectomy offers a radical resection option for extracompartmental tumor involvement. It provides oncologically adequate resection margins with low local recurrence. However, the procedures are complex; the patients stress is high and metastatic disease developed in one-third of patients. A judicious patient selection and a realistic feasibility evaluation must precede the decision for surgery. Reconstruction using a carbon composite cage system showed low complication rates and offers advantages for oncosurgical procedures.

Mobile spine chordoma: results of 166 patients from the AOSpine Knowledge Forum Tumor database

OBJECT A chordoma is an indolent primary spinal tumor that has devastating effects on the patients life. These lesions are chemoresistant, resistant to conventional radiotherapy, and moderately sensitive to proton therapy; however, en bloc resection remains the preferred treatment for optimizing patient outcomes. While multiple small and largely retrospective studies have investigated the outcomes following en bloc resection of chordomas in the sacrum, there have been few large-scale studies on patients with chordomas of the mobile spine. The goal of this study was to review the outcomes of surgically treated patients with mobile spine chordomas at multiple international centers with respect to local recurrence and survival. This multiinstitutional retrospective study collected data between 1988 and 2012 about prognosis-predicting factors, including various clinical characteristics and surgical techniques for mobile spine chordoma. Tumors were classified according to the Enneking principles and analyzed in 2 treatment cohorts: Enneking-appropriate (EA) and Enneking-inappropriate (EI) cohorts. Patients were categorized as EA when the final pathological assessment of the margin matched the Enneking recommendation; otherwise, they were categorized as EI. METHODS Descriptive statistics were used to summarize the data (Student t-test, chi-square, and Fisher exact tests). Recurrence and survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and multivariate Cox proportional hazard modeling. RESULTS A total of 166 patients (55 female and 111 male patients) with mobile spine chordoma were included. The median patient follow-up was 2.6 years (range 1 day to 22.5 years). Fifty-eight (41%) patients were EA and 84 (59%) patients were EI. The type of biopsy (p < 0.001), spinal location (p = 0.018), and if the patient received adjuvant therapy (p < 0.001) were significantly different between the 2 cohorts. Overall, 58 (35%) patients developed local recurrence and 57 (34%) patients died. Median survival was 7.0 years postoperative: 8.4 years postoperative for EA patients and 6.4 years postoperative for EI patients (p = 0.023). The multivariate analysis showed that the EI cohort was significantly associated with an increased risk of local recurrence in comparison with the EA cohort (HR 7.02; 95% CI 2.96-16.6; p < 0.001), although no significant difference in survival was observed. CONCLUSIONS EA resection plays a major role in decreasing the risk for local recurrence in patients with chordoma of the mobile spine.

Microenvironmental stimuli affect Endothelin-1 signaling responsible for invasiveness and osteomimicry of bone metastasis from breast cancer

The present study was undertaken to clarify the function(s) of Endothelin-1 and its receptors ETAR and ETBR in osteolytic-bone metastasis from breast cancer, and their regulation by hepatocyte and transforming growth factors (HGF, TGF-β) and hypoxia. The aim was to evaluate the adaptability of bone metastasis to microenvironmental stimuli through Endothelin-1-mediated epithelial-mesenchymal transition (EMT), or the reverse process MET, and through osteomimicry possible key features for bone colonization. We compared low (MCF-7) and high (MDA-MB231) invasive-breast carcinoma cells, and 1833-bone metastatic clone, with human pair-matched primary breast-carcinomas and bone metastases. Parental MDA-MB231 and the derived 1833-clone responded oppositely to the stimuli. In 1833 cells, TGF-β and hypoxia increased Endothelin-1 release, altogether reducing invasiveness important for engraftment, while Endothelin-1 enhanced MDA-MB231 cell invasiveness. The Endothelin-1-autocrine loop contributed to the cooperation of intracellular-signaling pathways and extracellular stimuli triggering MET in 1833 cells, and EMT in MDA-MB231 cells. Only in 1833 cells, HGF negatively influenced transactivation and release of Endothelin-1, suggesting a temporal sequence of these stimuli with an initial role of HGF-triggered Wnt/β-catenin pathway in metastatization. Then, Endothelin-1/ETAR conferred MET and osteomimetic phenotypes, with Runt-related transcription factor 2 activation and metalloproteinase 9 expression, contributing to colonization and osteolysis. Findings with human pair-matched primary ductal carcinomas and bone metastases gave a translational significance to the molecular study. Endothelin-1, ETAR and ETBR correlated with the acquisition of malignant potential, because of high expression already in the in situ carcinoma. These molecular markers might be used as predictive index of aggressive behavior and invasive/metastatic phenotype.

Surgical Management of Spinal Chondrosarcomas

Study Design. An ambispective cohort study. Objective. The aim of this study was to determine whether the application of the Enneking classification in the management of spinal chondrosarcomas influences local recurrence and survival. Summary of Background Data. Primary spinal chondrosarcomas are rare. Best available evidence is based on small case series, thus making it difficult to determine optimal management and risk factors for local recurrence and survival. Methods. The AOSpine Knowledge Forum Tumor developed a multicenter ambispective database of surgically treated patients with spinal chondrosarcoma. Patient data pertaining to demographics, diagnosis, treatment, cross-sectional survival, and local recurrence were collected. Tumors were classified according to the Enneking classification. Patients were divided into two cohorts: Enneking appropriate (EA) and Enneking inappropriate (EI). They were categorized as EA when the final pathological assessment of the margin matched the Enneking recommendation, and otherwise, they were categorized as EI. Results. Between 1987 and 2011, 111 patients (37 female; 74 male) received surgical treatment for a primary spinal chondrosarcoma at a mean age of 47.4 ± 15.8 years. Patients were followed for a median period of 3.1 years (range = 203 d–18.7 yrs). Median survival for the entire cohort was 8.4 years postoperative. After 10 years postoperative, 36 (32%) patients died and 37 (35%) patients suffered a local recurrence. Twenty-three of these 37 patients who suffered a local recurrence died. Sixty (58%) patients received an EA procedure while 44 (42%) received an EI procedure. EI patients had a higher hazard ratio for local recurrence than those who received an EA procedure (P = 0.052). Local recurrence was strongly associated with chondrosarcoma-related death (risk ratio = 3.6, P < 0.010). Conclusion. This is the largest multicenter cohort of spinal chondrosarcomas. EA surgical management appeared to correlate with a decreased risk of local recurrence, yet no relationship with survival was found. Where possible, surgeons should strive to achieve EA margins to minimize the risk of local recurrence. Level of Evidence: 4

An evidence-based medicine model for rare and often neglected neoplastic conditions

OBJECT The National Institutes of Health recommends strategies to obtain evidence for the treatment of rare conditions such as primary tumors of the spine (PTSs). These tumors have a low incidence and are pathologically heterogeneous, and treatment approaches are diverse. Appropriate evidence-based care is imperative. Failure to follow validated oncological principles may lead to unnecessary mortality and profound morbidity. This paper outlines a scientific model that provides significant evidence guiding the treatment of PTSs. METHODS A four-stage approach was used: 1) planning: data from large-volume centers were reviewed to provide insight; 2) recruitment: centers were enrolled and provided the necessary infrastructure; 3) retrospective stage: existing medical records were reviewed and completed with survival data; and 4) prospective stage: prospective data collection has been implemented. The AOSpine Knowledge Forum Tumor designed six modules: demographic, clinical, diagnostic, therapeutic, local recurrence, survival, and perioperative morbidity data fields and provided funding. RESULTS It took 18 months to implement Stages 1-3, while Stage 4 is ongoing. A total of 1495 tumor cases were captured and diagnosed as one of 18 PTS histotypes. In addition, a PTS biobank network has been created to link clinical data with tumor pathology and molecular analysis. CONCLUSIONS This scientific model has not only aggregated a large amount of PTS data, but has also established an international collaborative network of spine oncology centers. Access to large volumes of data will generate further research to guide and enhance PTS clinical management. This model could be applied to other rare neoplastic conditions. Clinical trial registration no.: NCT01643174 (ClinicalTrials.gov).

Spinal hemangiomas: results of surgical management for local recurrence and mortality in a multicenter study.

Study Design. Multicenter, ambispective observational study. Objective. To quantify local recurrence and mortality rates after surgical treatment of symptomatic spinal hemangiomas and identify prognostic variables for local disease control. Summary of Background Data. Spinal hemangiomas are the most common primary tumors of the spine and are generally benign and usually asymptomatic. Because of the rarity of symptomatic spinal hemangiomas, optimal surgical treatment remains unclear. Methods. AOSpine Knowledge Forum Tumor Investigators created a multicenter database of primary spinal tumors including demographics, presentation, diagnosis, treatment, survival, and recurrence data. Tumors were classified according to Enneking and Weinstein-Boriani-Biagini. Descriptive statistics were summarized and time to mortality and recurrence was determined. Results. Between 1996 and 2012, 68 patients (mean age = 51 yr, SD = 16) underwent surgical treatment of a spinal hemangioma. Epidural disease was present in 55% of patients (n = 33). Pain and neurological compromise were presenting symptoms in 82% (n = 54) and 37% (n = 24) of patients, respectively. Preoperative embolization was performed in 35% of patients (n = 23), 10% (n = 7) had adjuvant radiotherapy, and 81% (n = 55) underwent posterior-alone surgery. The local recurrence rate was 3% (n = 2). Mortality secondary to spinal hemangioma was not observed (mean follow-up = 3.9 yr, SD = 3.8). Conclusion. This is the largest multicenter surgical cohort of spinal hemangiomas. Symptomatic spinal hemangiomas are a benign tumor despite frequently presenting with epidural disease and neurological compromise. Thus, formal en bloc resection is not required, and excellent rates of local control and long-term survival can result from aggressive intralesional resection during index surgery. Level of Evidence: 3

Osteosarcoma of the spine: prognostic variables for local recurrence and overall survival, a multicenter ambispective study.

OBJECTIVE Primary spinal osteosarcomas are rare and aggressive neoplasms. Poor outcomes can occur, as obtaining marginal margins is technically demanding; further Enneking-appropriate en bloc resection can have significant morbidity. The goal of this study is to identify prognostic variables for local recurrence and mortality in surgically treated patients diagnosed with a primary osteosarcoma of the spine. METHODS A multicenter ambispective database of surgically treated patients with primary spine osteosarcomas was developed by AOSpine Knowledge Forum Tumor. Patient demographic, diagnosis, treatment, perioperative morbidity, local recurrence, and cross-sectional survival data were collected. Tumors were classified in 2 cohorts: Enneking appropriate (EA) and Enneking inappropriate (EI), as defined by pathology margin matching Enneking-recommended surgical margins. Prognostic variables were analyzed in reference to local recurrence and survival. RESULTS Between 1987 and 2012, 58 patients (32 female patients) underwent surgical treatment for primary spinal osteosarcoma. Patients were followed for a mean period of 3.5 ± 3.5 years (range 0.5 days to 14.3 years). The median survival for the entire cohort was 6.7 years postoperative. Twenty-four (41%) patients died, and 17 (30%) patients suffered a local recurrence, 10 (59%) of whom died. Twenty-nine (53%) patients underwent EA resection while 26 (47%) patients underwent EI resection with a postoperative median survival of 6.8 and 3.7 years, respectively (p = 0.048). EI patients had a higher rate of local recurrence than EA patients (p = 0.001). Patient age, previous surgery, biopsy type, tumor size, spine level, and chemotherapy timing did not significantly influence recurrence and survival. CONCLUSIONS Osteosarcoma of the spine presents a significant challenge, and most patients die in spite of aggressive surgery. There is a significant decrease in recurrence and an increase in survival with en bloc resection (EA) when compared with intralesional resection (EI). The effect of adjuvant and neoadjuvant chemotherapeutics, as well as method of biopsy, requires further exploration.

Long-term outcomes in primary spinal osteochondroma: A multicenter study of 27 patients

OBJECT Clinical outcomes in patients with primary spinal osteochondromas are limited to small series and sporadic case reports. The authors present data on the first long-term investigation of spinal osteochondroma cases. METHODS An international, multicenter ambispective study on primary spinal osteochondroma was performed. Patients were included if they were diagnosed with an osteochondroma of the spine and received surgical treatment between October 1996 and June 2012 with at least 1 follow-up. Perioperative prognostic variables, including patient age, tumor size, spinal level, and resection, were analyzed in reference to long-term local recurrence and survival. Tumor resections were compared using Enneking appropriate (EA) or Enneking inappropriate surgical margins. RESULTS Osteochondromas were diagnosed in 27 patients at an average age of 37 years. Twenty-two lesions were found in the mobile spine (cervical, thoracic, or lumbar) and 5 in the fixed spine (sacrum). Twenty-three cases (88%) were benign tumors (Enneking tumor Stages 1-3), whereas 3 (12%) exhibited malignant changes (Enneking tumor Stages IA-IIB). Sixteen patients (62%) underwent en bloc treatment-that is, wide or marginal resection-and 10 (38%) underwent intralesional resection. Twenty-four operations (92%) followed EA margins. No one received adjuvant therapy. Two patients (8%) experienced recurrences: one in the fixed spine and one in the mobile spine. Both recurrences occurred in latent Stage 1 tumors following en bloc resection. No osteochondroma-related deaths were observed. CONCLUSIONS In the present study, most patients underwent en bloc resection and were treated as EA cases. Both recurrences occurred in the Stage 1 tumor cohort. Therefore, although benign in character, osteochondromas still require careful management and thorough follow-up.

Four- and five- level en bloc spondylectomy for malignant spinal tumors.

Study Design. Retrospective study. Objective. To report results of 4- and 5-level en bloc spondylectomy (EBS) in the treatment of malignant spinal tumors. Summary of Background Data. EBS is widely used to avoid local recurrence in the treatment of spinal malignant tumors. Four- and 5-level EBS are aggressive procedures associated with complications and morbidity. Methods. We conducted a retrospective study of all patients treated with minimum 4-level EBS. Patient and surgical data were noted. Radiographs, magnetic resonance images, and computed tomographic scans were studied for local recurrence, graft, and instrumentation failures at subsequent follow-up. Type of excision was classified into intralesional, marginal, and wide margins. Complications were divided into major or minor and were further classified as intraoperative, early, and late postoperative. At the last follow-up, the patients were classified as alive with no evidence of local or systemic disease, alive with evidence of local or systemic disease or both, dead with evidence of local disease, or systemic disease or both, and dead without evidence of local and systemic disease. Results. Nine patients were identified who required a minimum 4-level en bloc resection. Five males and 4 females. Average age was 41.66 years (11–66). There were 8 primary malignant tumors: 3 chordomas, 3 osteosarcomas, 1 chondrosarcoma, 1 primary lung tumor and 1 metastatic alveolar soft part sarcoma. Six were operated with 4-level en bloc and 3 with 5 levels. The mean surgical time was 713 minutes and estimated blood loss was 4.5 L. Mean follow-up was 27.7 months (8–84). At the last follow-up, 6 patients were alive with no evidence of local or systemic disease, 1 alive with evidence of systemic disease, 1 dead with evidence of local disease, or systemic disease or both, and 1 DNLS. Only 1 (11%) patient had a local recurrence. Three patients with Frankel D had full neurological recovery. Histopathological assessment showed marginal margins in 7 patients and wide in 2. There were 9 major and 9 minor complications in 7 patients. Five of 7 patients (71%) with complications, had fully recovered from their complications at the last follow-up. Conclusion. Multilevel EBS, can be offered to a patient to prevent local recurrence of disease. Even in experienced hands, the risks of intra- and postoperative complications are high (78%). However, most of the patients with complications, recovered completely (71%). Although the surgery itself may prove beneficial, patients should be well informed regarding the morbidity associated with it. Level of Evidence: 4

High SPARC Expression Starting from Dysplasia, Associated with Breast Carcinoma, Is Predictive for Bone Metastasis without Enhancement of Plasma Levels

In order to become established in the skeleton, metastatic cells disseminating from the breast carcinoma need to acquire organ-specific traits. There are no effective predictors for who will develop bone metastasis to guide long-term predictive therapy. Our purpose was to individuate events critical for bone colonization to make a molecular classification of breast carcinoma useful for bone-metastasis outcome. In dysplasia adjacent to carcinoma and in pair-matched specimens of bone metastasis we examined SPARC expression and localization as well as Endothelin 1/ETAR signals by immunohistochemistry, and the evaluation of plasma levels of SPARC by ELISA was also performed. In patients with breast carcinoma metastasizing to bone, SPARC and Endothelin 1/ETAR axis were highly expressed from dysplasia until bone metastasis, but the SPARC plasma level was as low as that of normal women, in contrast to patients that never develop bone metastasis, suggesting that circulating SPARC was counter adhesive. Altogether, the early identification of SPARC/Endothelin 1/ETAR in dysplastic lesions would be important to devise therapies preventing metastasis engraftment, since often carcinoma cells spread to distant organs at the time or even before patients present with cancer.