Ryan Murtagh

Phase I trial of vorinostat combined with bevacizumab and CPT-11 in recurrent glioblastoma.

A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. Correlative science involving proteomic profiling of serial patient plasma samples was performed. Nineteen patients were treated. The MTD of vorinostat was established at 400 mg on days 1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. Although the MTD was established, CPT-11 dose reductions were common early in therapy. High-dose vorinostat had an improved progression-free survival and overall survival when compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for the combination of vorinostat with bevacizumab and CPT-11 has been established, although it has poor long-term tolerability. With the increased toxicities associated with CPT-11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of a phase II clinical trial.

Diffusion tensor imaging tractography in patients with intramedullary tumors: comparison with intraoperative findings and value for prediction of tumor resectability

OBJECT The aim of this retrospective study was to evaluate the predictive value of diffusion tensor (DT) imaging with respect to resectability of intramedullary spinal cord tumors and to determine the concordance of this method with intraoperative surgical findings. METHODS Diffusion tensor imaging was performed in 14 patients with intramedullary lesions of the spinal cord at different levels using a 3-T magnet. Routine MR imaging scans were also obtained, including unenhanced and enhanced T1-weighted images and T2-weighted images. Patients were classified according to the fiber course with respect to the lesion and their lesions were rated as resectable or nonresectable. These results were compared with the surgical findings (existence vs absence of cleavage plane). The interrater reliability was calculated using the kappa coefficient of Cohen. RESULTS Of the 14 patients (7 male, 7 female; mean age 49.2 +/- 15.5 years), 13 had tumors (8 ependymomas, 2 lymphomas, and 3 astrocytoma). One lesion was proven to be a multiple sclerosis plaque during further diagnostic workup. The lesions could be classified into 3 types according to the fiber course. In Type 1 (5 cases) fibers did not pass through the solid lesion. In Type 2 (3 cases) some fibers crossed the lesion, but most of the lesion volume did not contain fibers. In Type 3 (6 cases) the fibers were completely encased by tumor. Based on these results, 6 tumors were considered resectable, 7 were not. During surgery, 7 tumors showed a good cleavage plane, 6 did not. The interrater reliability (Cohen kappa) was calculated as 0.83 (p < 0.003), which is considered to represent substantial agreement. The mean duration of follow-up was 12.0 +/- 2.9. The median McCormick grade at the end of follow-up was II. CONCLUSIONS These preliminary data suggest that DT imaging in patients with spinal cord tumors is capable of predicting the resectability of the lesion. A further prospective study is needed to confirm these results and any effect on patient outcome.

Normal and Abnormal Imaging Findings in Lumbar Total Disk Replacement: Devices and Complications

Fusion, with or without laminectomy, is the standard treatment for symptomatic lumbar degenerative disk disease when conservative management has failed. Yet even radiographically verified solid fusion may be accompanied by considerable long-term problems, including recurrent low back pain, spinal stenosis, hypertrophic facet disease, pseudarthrosis, and spondylolysis and spondylolisthesis at adjacent levels. Several studies have shown a relationship between solid fusion and the development of adjacent-level disk disease, which is thought to result from increased stress on, or hypermobility of, adjacent segments. Total disk replacement (TDR) was developed as a way to restore normal mobility of the diseased segments and improve clinical outcomes by decreasing the risk of adjacent-level degenerative disease and related complications. However, like fusion, TDR is associated with various complications; some of these (eg, migration, subsidence) may occur regardless of the device used, whereas others (eg, extrusion of the polyethylene inlay, vertical fractures) are device specific. Facet arthrosis, device wear, particle disease, adjacent-level degeneration, and heterotopic ossification also have been observed after TDR, but the frequency and importance of these findings remain uncertain. Given the increasing use of lumbar TDR to treat degenerative disk disease, it is important that radiologists be familiar with the most commonly used devices and the potential complications of their use.

New Techniques in Lumbar Spinal Instrumentation: What the Radiologist Needs to Know

Lumbar spinal fusion is a commonly performed procedure, and, despite changes in cage types and fixation hardware, radiologists have, over the years, become familiar with the imaging features of typical spinal fusion and many of the complications seen in patients after surgery, including pseudoarthrosis, hardware loosening, and recurrent or residual disk herniation. Recently, however, novel approaches and devices have been developed, including advances in minimally invasive surgery, the increasing use of osteoinductive materials, and a wide variety of motion-preserving devices. These new approaches and devices manifest with characteristic imaging features and the potential for unusual and unexpected complications. Several of these devices and approaches are experimental, but many, including those devices used in lateral approaches to fusion, as well as the use of bone morphogenic protein, disk arthroplasty, and interspinous spacers, are seen with increasing frequency in daily clinical practice. Given the recent advances in spinal fusion surgery, it is important that radiologists have a basic understanding of the rationale behind these procedures, the common imaging features of the devices, and the complications associated with their use.

A Cadaveric Radiographic Analysis on the Effect of Extreme Lateral Interbody Fusion Cage Placement With Supplementary Internal Fixation on Indirect Spine Decompression

Study Design: Cadaveric Biomechanical and Radiographic Analysis. Objective: The purpose of this study was to quantify the changes in intervertebral height and lateral and central recess areas afforded by lateral interbody fusion cages with 2 supplemental forms of internal fixation in cadaveric specimens. Background Data: When conservative treatment for symptomatic lumbar stenosis fails, traditional intervention has been direct posterior decompression. The minimally invasive, lateral transpsoas approach may be a viable alternative to direct decompression by providing restoration of the foraminal and intervertebral dimensions, yet few reports have examined the anatomic and radiographic changes that occur using this technique. Methods: Computed tomography (CT) scans were taken of 18 intact lumbar (L1–S1) cadaveric specimens under a 400 N preload. Intervertebral height, foraminal areas, and canal area were measured at L3–L4 and L4–L5. Thereafter, the cadaveric specimens were instrumented with lateral cages placed in the central or posterior third of the disk space at L3–L4 and L4–L5 and either (1) lateral plate (n=9) or (2) bilateral posterior pedicle screw fixation (n=9). All constructs were again subjected to a 400 N preload, postinstrumentation CT scans were taken, and changes in intervertebral height and lateral and central recess areas were calculated. Results: There was no effect of cage placement on any radiographic metric of indirect decompression for either fusion construct. In the lateral plate and pedicle screw groups, respectively, significant increases in average posterior disk height (30.9%, 60.1%), average right (35.3%, 61.5%) and left foraminal area (48.3%, 57.8%), and average canal area (32.3%, 33.3%) were observed. Pedicle screw instrumentation afforded a significantly greater increase in average posterior disk height and foraminal area compared with the lateral plate group, though there was no difference in the average increase in canal area afforded by either form of fixation. Conclusions: The radiographic results reported here using a cadaveric model add validity to the underlying rationale described for the minimally invasive lateral approach technique. Increases in disk height, foraminal and canal areas were not dependent on cage positioning within the disk space. As intraoperative placement of a cage in the central portion of the disk is an easier and safer technique, our results suggest that central placement may be preferable in a clinical setting.

Pseudo‐Guillain‐Barre Syndrome Due to “Whippet”‐Induced Myeloneuropathy

Guillain‐Barre syndrome (GBS) is the rubric encompassing highly variable phenotypic subgroups of acute, postinfectious, immune‐mediated peripheral neuropathy. The hallmark of GBS phenomenology is a rapidly progressive ascending lower extremity weakness. GBS taxonomy includes a motor and sensory axonal neuropathy (AMSAN). Nitrous oxide (NO) abuse may create a pattern of neurological dysfunction almost identical to subacute combined degeneration. We report an adult with myeloneuropathy due to NO abuse that mimicked the presenting features of the GBS‐subtype AMSAN.

Rupture of a Cerebral Arteriovenous Malformation in a Patient Treated with Bevacizumab

To the Editor: A previously healthy 52-year-old man presented with recurrent pneumonia. A computerized tomography scan demonstrated a right upper lobe mass, multiple mediastinal adenopathy, and pleural effusion. Biopsy revealed poorly differentiated non-small cell carcinoma. Magnetic resonance imaging of the brain showed no evidence of metastasis; however, a 2.5-cm arteriovenous malformation (AVM) near the Sylvian fissure was identified. A reconstructed maximum-intensity-projection image demonstrated a tangle of vessels on the left, with large vein draining to the superior sagittal sinus (Figure 1). Paclitaxel (200 mg/ m), carboplatin (AUC 6), and bevacizumab (15 mg/kg) was administered. The first cycle of treatment was well tolerated; however, 4 days after the second cycle, the patient became obtunded and developed respiratory failure. Computed tomography scan of the brain revealed massive intracerebral hemorrhage with transfalcine herniation (Figure 2). Platelet count and coagulation parameters were within the normal ranges. Despite vigorous supportive measures, the patient died shortly thereafter. AVMs of the brain are focal abnormal conglomerations of dilated arteries and veins within brain parenchyma.1 These vessels connect directly without a capillary bed, resulting in a high pressure being imposed upon the venous portion (which frequently harbors an incompetent elastic lamina) and a tendency to rupture. Rupture of AVM is associated with 5 to 10% mortality and 30 to 50% permanent neurologic deficit rates. The prevalence of AVMs is approximately 0.01% of the general population. The risk of hemorrhage is estimated at 2 to 4% per year; however, higher risks were observed among AVMs with associated aneurysm, drainage to deep venous sinus, single draining vein, or history of previous rupture. To our knowledge, rupture of AVMs of the brain has never been linked to bevacizumab, although a bleeding tendency at the tumor site and in the gastrointestinal tract has been associated with bevacizumab treatment. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, is approved by the Food and Drug Administration for treatment of advanced non-small cell lung, breast, and colon cancer.2 Phase II study of bevacizumab in non-small cell lung cancer reported a severe or fatal hemoptysis in 31% of patients with squamous carcinomas and 2.3% of patients with nonsquamous histology.3 In a phase III study, excluding patients with brain metastasis, squamous histology or anticoagulation, the incidence of serious bleeding events was still significantly higher among patients receiving carboplatin/paclitaxel plus bevacizumab than those receiving carboplatin/paclitaxel alone.4 After marketing of the drug, cases of intracerebral hemorrhage associated with concurrent bevacizumab and anticoagulation therapy have also been reported. Bleeding tendency associated with bevacizumab is believed to result from an endothelial dysfunction and weakened supporting layers of blood vessels. Most bleeding complications are minor, including mucocutaneous Disclosure: The authors declare no conflicts of interest. Address for correspondence: Tawee Tanvetyanon, MD, 12902 Magnolia Drive, Tampa, FL. E-mail: tanvett@moffitt.usf.edu Copyright

Comparison of Unilateral versus Bilateral Kyphoplasty in Multiple Myeloma Patients and the Importance of Preoperative Planning

Study Design Retrospective comparative study and technical note. Purpose To determine if there is a difference in clinical and radiographic parameters between unilateral and bilateral kyphoplasty in a uniform cancer population and to stress the importance of preoperative planning. Overview of Literature While unipedicular kyphoplasty is gaining popularity, a few comparative studies have reported on superior kyphotic reduction with the bipedicular approach. Methods We reviewed 69 myeloma patients with 105 operated levels (51 levels were done bilaterally vs. 54 unilaterally). Pain reduction, height restoration, cement volume and complications were recorded up to three months postoperatively. A technical note to identify the skin entry point on the basis of the magnetic resonance imaging and fluoroscopy (lateral view) is being described. Results Both procedures resulted in significant pain reduction (5.4-5.6/10 points, p=0.8). There was significant height restoration after the operation (p<0.001), while there was no sustained difference between the procedures (p=0.5) up to three months postoperatively. More cement was injected in the bilateral group (4.1 mL vs. 4.9 mL, p=0.002); no difference in cement extravasation in the spinal canal was observed (p=0.5). Conclusions There was no difference in the clinical or radiological outcomes between the unilateral and bilateral approaches. Therefore, unilateral kyphoplasty may be performed whenever it is technically feasible and this may be determined preoperatively.

Effects on inadvertent endplate fracture following lateral cage placement on range of motion and indirect spine decompression in lumbar spine fusion constructs: A cadaveric study.

Background The lateral transpsoas approach to interbody fusion is gaining popularity. Existing literature suggests that perioperative vertebra-related complications include endplate breach owing to aggressive enedplate preparation and poor bone quality. The acute effects of cage subsidence on stabilization and indirect decompression at the affected level are unknown. The purpose of this study was to compare the kinematics and radiographic metrics of indirect decompression in lumbar spines instrumented with laterally placed cages in the presence of inadvertent endplate fracture, which was determined radiographically, to specimens instrumented with lateral cages with intact endplates. Methods Five levels in 5 specimens sustained endplate fracture during lateral cage implantation followed by supplementary fixation (pedicle screw/rod [PSR]: n = 1; anterolateral plate [ALP]: n = 4), as part of a larger laboratory-based study. Range of motion (ROM) in these specimens was compared with 13 instrumented specimens with intact endplates. All specimens were scanned using computed tomography (CT) in the intact, noninstrumented condition and after 2-level cage placement with internal fixation under a 400-N follower load. Changes in disc height, foraminal area, and canal area were measured and compared between specimens with intact endplates and fractured endplates. Results Subsidence in the single PSR specimen and 4 ALP specimens was 6.5 mm and 4.3 ± 2.7 mm (range: 2.2–8.3 mm), respectively. ROM was increased in the PSR and ALP specimens with endplate fracture when compared with instrumented specimens with intact endplates. In 3 ALP specimens with endplate fracture, ROM in some motion planes increased relative to the intact, noninstrumented spine. These increases in ROM were paralleled by increase in cage translations during cyclic loading (up to 3.3 mm) and an unpredictable radiographic outcome with increases or decreases in posterior disc height, foraminal area, and canal area when compared with instrumented specimens with intact endplates. Conclusions Endplate fracture and cage subsidence noted radiographically intraoperatively or in the early postoperative period may be indicative of biomechanical instability at the affected level concomitant with a lack of neurologic decompression, which may require revision surgery.

Motion Preservation Surgery in the Spine

The primary goal of motion preservation surgery in the spine is to maintain normal or near normal motion in an attempt to prevent adverse outcomes commonly seen with conventional spinal fusion, most notably the development of adjacent-level degenerative disc disease. Several different surgical approaches have been developed to preserve motion in the lumbar spine, including total disc replacement, partial disc (nucleus) replacement, interspinous spacers, dynamic stabilization devices, and total facet replacement devices. The design of devices varies greatly. The devices are created using a similar rationale but are unique in design relative to their lumbar counterparts.