Mari L. Groves

Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord

Significance Outcomes for individuals with central nervous system (CNS) malignancies remain abysmal. A major challenge in managing these patients is the lack of reliable biomarkers to monitor tumor dynamics. Consequently, many patients undergo invasive surgical procedures to determine disease status or experience treatment delays when radiographic testing fails to show disease progression. We show here that primary CNS malignancies shed detectable levels of tumor DNA into the surrounding cerebrospinal fluid (CSF), which could serve as a sensitive and exquisitely specific marker for quantifying tumor burden without invasive biopsies. Therefore, assessment of such tumor-derived DNA in the CSF has the potential to improve the management of patients with primary CNS tumors. Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57–88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88–100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher’s exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.

Outcomes following surgical intervention for impending and gross instability caused by multiple myeloma in the spinal column

OBJECT Multiple myeloma is the most common primary tumor of the spine and is the most common primary malignant tumor of bone. Although spinal myeloma is classically a radiosensitive lesion, clinical or radiographic signs of instability merit surgical intervention. The authors present the epidemiology, surgical indications, and outcome data of a series of consecutive cases involving 31 surgically treated patients with diagnoses of multiple myeloma and plasmacytoma of the spine (the largest such series reported to date). METHODS Surgical instability was the criterion for operative intervention in this patient cohort. The Spinal Instability Neoplastic Score (SINS) was used to make this assessment of instability. The cases were analyzed using location of the lesion, spinal levels involved, Frankel score, adjuvant therapy, functional outcome, and patient survival. RESULTS All patients undergoing surgical intervention were determined to have indeterminate or gross spinal column instability according to SINS criteria. The median survival was 78.9 months. No significant difference in survival was seen for patients with higher SINS scores or for older patients (> 55 years). There was a statistically significant difference in survival benefit observed for patients receiving chemotherapy and radiation versus radiation alone as an adjuvant to surgery (p = 0.02). CONCLUSIONS In this 10-year analysis, the authors report outcomes of surgical intervention for patients with indeterminate or gross spinal instability due to multiple myeloma and plasmacytoma of the spine with improved neurological function following surgery and low rates of instrumentation failure.

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.

A novel animal model of human breast cancer metastasis to the spine: A pilot study using intracardiac injection and luciferase-expressing cells

OBJECT Metastatic spine disease is prevalent in cancer victims; 10%-30% of the 1.2 million new patients diagnosed with cancer in the US exhibit spinal metastases. Unfortunately, treatments are limited for these patients, as disseminated disease is often refractory to chemotherapy and is difficult to treat with surgical intervention alone. New animal models that accurately recapitulate the human disease process are needed to study the behavior of metastases in real time. METHODS In this study the authors report on a cell line that reliably generates bony metastases following intracardiac injection and can be tracked in real time using optical bioluminescence imaging. This line, RBC3, was derived from a metastatic breast adenocarcinoma lesion arising in the osseous spine of a rat following intracardiac injection of MDA-231 human breast cancer cells. RESULTS Upon culture and reinjection of RBC3, a statistically significantly increased systemic burden of metastatic tumor was noted. The resultant spine lesions were osteolytic, as demonstrated by small animal CT scanning. CONCLUSIONS This cell line generates spinal metastases that can be tracked in real time and may serve as a useful tool in the study of metastatic disease in the spine.

Maintenance of bowel, bladder, and motor functions after sacrectomy

BACKGROUND CONTEXT Repeated cohort studies have consistently demonstrated a survival advantage after en bloc resection for locally aggressive primary tumors in the sacrum. A sacrectomy is often required to remove the tumor en bloc, which may necessitate the sacrifice of sacral nerves. This can potentially result in functional complications, including the impairment of gait, bowel function, or bladder function. PURPOSE To assess the bladder, bowel, and motor functions of patients after resection of a primary sacral tumor. STUDY DESIGN This was a retrospective cohort study at a single academic institution. PATIENT SAMPLE Consecutive patients who underwent an en bloc sacral tumor resection at a single institution between December 2002 and June 2012 were included. The study population comprised 73 patients. OUTCOME MEASURES Patients were classified as having had a low, middle, high, or total sacrectomy based on the level of sacral nerves sacrificed, if applicable. METHODS Patient data were collected from clinic notes and hospital records that included operative notes, lab studies, and rehabilitation notes. RESULTS Across all patients, there was no change in bowel function after sacrectomy, whereas bladder and motor functions returned to preoperative (pre-op) levels at 3 and 6 months, respectively. Higher level sacrectomies were associated with worse bowel (p<.001), bladder (p<.001), and motor (p=.027) functions 12 months postoperatively (post-op). At 1 year, none of the six patients with a high or total sacrectomy had intact bladder function and 14.3% (N=7) had intact bowel function. Of patients with a middle sacrectomy, 62.5% (N=8) had intact bladder function and 71.4% (N=7) had intact bowel function at 1 year. Of patients with a low sacrectomy, 91.7% (N=12) had intact bladder function and 91.7% (N=12) had intact bowel function. CONCLUSIONS Preoperative bladder, bowel, and motor functions, level of sacral tumor involvement, and corresponding level of sacrectomy were the greatest predictors of long-term bladder, bowel, and motor functions. There were no statistically significant changes in bladder, bowel, or motor functions from pre-op to 6 months post-op, and therefore, pre-op functional status was predictive of long-term function.

Automatic Localization of Target Vertebrae in Spine Surgery: Clinical Evaluation of the LevelCheck Registration Algorithm

Study Design. A 3-dimensional-2-dimensional (3D-2D) image registration algorithm, “LevelCheck,” was used to automatically label vertebrae in intraoperative mobile radiographs obtained during spine surgery. Accuracy, computation time, and potential failure modes were evaluated in a retrospective study of 20 patients. Objective. To measure the performance of the LevelCheck algorithm using clinical images acquired during spine surgery. Summary of Background Data. In spine surgery, the potential for wrong level surgery is significant due to the difficulty of localizing target vertebrae based solely on visual impression, palpation, and fluoroscopy. To remedy this difficulty and reduce the risk of wrong-level surgery, our team introduced a program (dubbed LevelCheck) to automatically localize target vertebrae in mobile radiographs using robust 3D-2D image registration to preoperative computed tomographic (CT) scan. Methods. Twenty consecutive patients undergoing thoracolumbar spine surgery, for whom both a preoperative CT scan and an intraoperative mobile radiograph were available, were retrospectively analyzed. A board-certified neuroradiologist determined the “true” vertebra levels in each radiograph. Registration of the preoperative CT scan to the intraoperative radiograph was calculated via LevelCheck, and projection distance errors were analyzed. Five hundred random initializations were performed for each patient, and algorithm settings (viz, the number of robust multistarts, ranging 50–200) were varied to evaluate the trade-off between registration error and computation time. Failure mode analysis was performed by individually analyzing unsuccessful registrations (>5 mm distance error) observed with 50 multistarts. Results. At 200 robust multistarts (computation time of ∼26 s), the registration accuracy was 100% across all 10,000 trials. As the number of multistarts (and computation time) decreased, the registration remained fairly robust, down to 99.3% registration accuracy at 50 multistarts (computation time ∼7 s). Conclusion. The LevelCheck algorithm correctly identified target vertebrae in intraoperative mobile radiographs of the thoracolumbar spine, demonstrating acceptable computation time, compatibility with routinely obtained preoperative CT scans, and warranting investigation in prospective studies. Level of Evidence: N/A

Intramedullary spinal cord tumor resection.

The authors present a case of a 27-year-old patient who presented with spastic gait and worsening difficulty walking over a 6 month period. Spinal MR imaging revealed a heterogeneously enhancing intramedullary spinal cord tumor (IMSCT) with associated syrinx in the cervical spine. The lesion was resected through posterior en bloc laminotomy, durotomy, and microscopic resection of the intramedullary component followed by laminoplasty reconstruction. Surgical resections with a goal of gross total resection can significantly improve overall survival and progression free survival in patients with low-grade IMSCT. The procedure is presented in an edited, high-definition format with accompanying narrative. The video can be found here: http://youtu.be/Ui9bn82PtP8 .

Factors associated with improved outcomes following decompressive surgery for prostate cancer metastatic to the spine.

BACKGROUND Metastatic spinal cord compression from prostate cancer is a debilitating disease causing neurological deficits, mechanical instability, and intractable pain. Surgical management may improve quality of life. OBJECTIVE To define postoperative outcomes and explore associations with prolonged survival for patients with metastatic prostate cancer. METHODS Retrospective chart reviews were performed of all patients undergoing spinal surgery for metastatic cancer from June 1, 2002 to August 31, 2011. Patient demographics, surgical details, adjuvant therapies, outcomes, complications, and postoperative survival were reviewed. RESULTS Twenty-seven patients with prostate cancer underwent surgery at a median age of 65 years (range, 46-82 years). After surgery, 93% of patients had preserved or improved neurological status, 56% of nonambulatory patients recovered ambulation, 43% of incontinent patients recovered continence, and 23% experienced complications. Postoperative Frankel grades were significantly improved by at least 1 letter grade at 1 month (P = .03). The median analgesic and steroid usage was significantly lower up to 3 months and 6 months postoperatively, respectively (P = .007, .005). Median survival following surgery was 10.2 months, and patients with castration-resistant prostate cancer had a shorter median survival than those with hormone-naïve disease (9.8 vs 40 months). Better preoperative performance status was an independent predictor of survival (P = .02). Younger age (P = .005) and instrumentation greater than 7 spinal levels (P = .03) were associated with complications. CONCLUSION Spinal surgery for prostate metastases improves neurological function and decreases analgesic requirements. Our findings support surgical intervention for carefully selected patients, and knowledge of preoperative hormone sensitivity and performance status may help with risk stratification.

Characterization of intratumor magnetic nanoparticle distribution and heating in a rat model of metastatic spine disease: Laboratory investigation

OBJECT The goal of this study was to optimize local delivery of magnetic nanoparticles in a rat model of metastatic breast cancer in the spine for tumor hyperthermia while minimizing systemic exposure. METHODS A syngeneic mammary adenocarcinoma was implanted into the L-6 vertebral body of 69 female Fischer rats. Suspensions of 100-nm starch-coated iron oxide magnetic nanoparticles (micromod Partikeltechnologie GmbH) were injected into tumors 9 or 13 days after implantation. For nanoparticle distribution studies, tissues were harvested from a cohort of 36 rats, and inductively coupled plasma mass spectrometry and histopathological studies with Prussian blue staining were used to analyze the samples. Intratumor heating was tested in 4 anesthetized animals with a 20-minute exposure to an alternating magnetic field (AMF) at a frequency of 150 kHz and an amplitude of 48 kA/m or 63.3 kA/m. Intratumor and rectal temperatures were measured, and functional assessments of AMF-exposed animals and histopathological studies of heated tumor samples were examined. Rectal temperatures alone were tested in a cohort of 29 rats during AMF exposure with or without nanoparticle administration. Animal studies were completed in accordance with the protocols of the University Animal Care and Use Committee. RESULTS Nanoparticles remained within the tumor mass within 3 hours of injection and migrated into the bone at 6, 12, and 24 hours. Subarachnoid accumulation of nanoparticles was noted at 48 hours. No evidence of lymphoreticular nanoparticle exposure was found on histological investigation or via inductively coupled plasma mass spectrometry. The mean intratumor temperatures were 43.2°C and 40.6°C on exposure to 63.3 kA/m and 48 kA/m, respectively, with histological evidence of necrosis. All animals were ambulatory at 24 hours after treatment with no evidence of neurological dysfunction. CONCLUSIONS Locally delivered magnetic nanoparticles activated by an AMF can generate hyperthermia in spinal tumors without accumulating in the lymphoreticular system and without damaging the spinal cord, thereby limiting neurological dysfunction and minimizing systemic exposure. Magnetic nanoparticle hyperthermia may be a viable option for palliative therapy of spinal tumors.

Epidemiologic, functional, and oncologic outcome analysis of spinal sarcomas treated surgically at a single institution over 10 years

BACKGROUND CONTEXT Spinal sarcomas are aggressive tumors that originate from the cells of mesechymal origin, specifically fat, cartilage, bone, and muscle. They are high-grade lesions, and treatment of spinal sarcomas can involve chemotherapy, radiation therapy, and surgery. In the appendicular skeleton, sarcomas are often treated with amputation, however, in the spinal column, surgical resection poses a unique set of challenges. PURPOSE To better understand the optimal treatment regimens and the impact of en bloc or intralesional resection on patient outcome. STUDY DESIGN A cohort of 25 sarcoma patients treated at a single medical institution between 2002 and 2012 was reviewed. PATIENT SAMPLE AND OUTCOME MEASURES Patients were classified by tumor type for subgroup analysis, including chondrosarcoma, osteosarcoma, and other malignant spinal sarcomas. Demographic data for review included patient age, tumor type, tumor location, surgery type, exposure to chemotherapy, and radiation therapy. METHODS Survival statistics and Kaplan-Meier curves were calculated using GraphPad Prism 5.0. The threshold for statistical significance was set at p<.05. Unpaired, two-tailed, equal variance t tests were performed for statistical analyses in Microsoft Excel 2010. RESULTS Twenty-five patients with spinal sarcomas were treated over the 10-year period. Diagnosis included chondrosarcoma (n=9), osteosarcoma (n=4), and other sarcomas (n=12). Mean age at the time of diagnosis was 42 years. Pain was present at the time of diagnosis in 92% patients. Median survival after surgery was 59.5 months for chondrosarcoma, undefined for other sarcomas, and 16.8 months for osteosarcoma. Median survival after en bloc resection was undefined. Median survival after intralesional resection was 17.8 months. The difference in median survival between en bloc and intralesional resection was statistically significant (p=.049). CONCLUSIONS The authors report the largest cohort of patients with spinal sarcoma. Median survival in this cohort was the longest for patients with sarcomas of varying pathologies. Median survival was longer for chondrosarcoma. En bloc resection demonstrated a survival advantage over intralesional resection. Long-term follow-up is needed for patients with spinal sarcoma to establish definitive survival data.