Faculty Bibliography

Patients with cancer are frequently affected by spinal metastases. Treatment is palliative, with the principle goals of pain relief, preservation of neurologic function, and improvement in quality of life. In the past decade, we have witnessed a dramatic change in the treatment paradigms due to the development of improved surgical strategies and systemic and radiation therapy. The most important change to these paradigms has been the integration of spinal stereotactic radiosurgery (SSRS), allowing delivery of tumoricidal radiation doses with sparing of nearby organs at risk. High-dose SSRS provides durable tumor control when used either as definitive therapy or as a postoperative adjuvant therapy. Integration of SSRS has fundamentally changed the indications for and type of surgery performed for metastatic spine tumors. Although the role for surgical intervention is well established, a clear trend toward less-aggressive, often minimally invasive techniques has been observed. Targeted therapies are also rapidly changing the way cancer is being treated and have demonstrated improved survival for a number of malignancies. As these treatment decisions become more complex, a multidisciplinary approach including medical oncologists, radiation oncologists, surgeons, interventionalists, and pain specialists is required. In this article, the current evidence affecting the treatment of spinal metastases is integrated into a decision framework that considers four principal assessments of a patient's spine disease: NOMS (neurologic, oncologic, mechanical instability, and systemic disease).

OBJECTIVE An analysis of factors contributing to durable radiographic control of spinal metastases was undertaken, drawing from a large single-institution database in an attempt to elucidate indications and dose requirements for successful treatment. METHODS All patients treated at a single institution with stereotactic radiosurgery (SRS) of the spine as first-line therapy were assessed for local progression of the treated site, defined as radiographic enlargement of the treated tumor and/or biopsy-proven evidence of active tumor cells. All patients were followed with CT, PET, or MR imaging every 3-6 months until death. Treatment decisions were made by a multidisciplinary team of radiation oncologists, neurosurgeons, and neuroradiologists. Target volumes were defined according to the international consensus guidelines and were reviewed in a multidisciplinary conference. Image-guided techniques and intensity modulation were used for every case. The tumor's histological type, gross tumor volume (GTV), dose that covers 95% of the GTV (GTV D95), percentage of GTV covered by 95% of the prescribed dose (GTV V95), planning target volume (PTV), dose that covers 95% of the PTV (PTV D95), and percentage of PTV covered by 95% of the prescribed dose (PTV V95) were analyzed for significance in relation to local control, based on time to local progression. RESULTS A total of 811 lesions were treated in 657 patients between 2003 and 2015 at a single institution. The mean follow-up and overall survival for the entire cohort was 26.9 months (range 2-141 months). A total of 28 lesions progressed and the mean time to failure was 26 months (range 9.7-57 months). The median prescribed dose was 2400 cGy (range 1600-2600 cGy). Both GTV D95 and PTV D95 were highly significantly associated with local failure in univariate analysis, but GTV and PTV and histological type did not reach statistical significance. The median GTV D95 for the cohort equal to or above the GTV D95 1830 cGy cut point (high dose) was 2356 cGy, and it was 1709 cGy for the cohort of patients who received less than 1830 cGy (low dose). In terms of PTV D95, the median dose for those equal to or above the cut point of 1740 cGy (high dose) was 2233 cGy, versus 1644 cGy for those lesions below the PTV D95 cut point of 1740 cGy (low dose). CONCLUSIONS High-dose single-session SRS provides durable long-term control, regardless of the histological findings or tumor size. In this analysis, the only significant factors predictive of local control were related to the actual dose of radiation given. Although the target volumes were well treated with the intended dose, those lesions irradiated to higher doses (median GTV D95 2356 cGy, minimum 1830 cGy) had a significantly higher probability of durable local control than those treated with lower doses (median PTV D95 2232 cGy, minimum of 1740 cGy) (p < 0.001). Patients in the high-dose cohort had a 2% cumulative rate of local failure. Histological findings were not associated with local failure, suggesting that radioresistant histological types benefit in particular from radiosurgery. For patients with a favorable prognosis, a higher dose of SRS is important for long-term outcomes.

OBJECTIVE The object of this study was to determine the percentage of high-dose (1800-2600 cGy) single-fraction stereotactic radiosurgery (SF-SRS) treatments to the spine that result in peripheral nervous system (PNS) injury. METHODS All patients treated with SF-SRS for primary or metastatic spine tumors between January 2004 and May 2013 and referred to the Rehabilitation Medicine Service for evaluation and treatment of neuromuscular, musculoskeletal, or functional impairments or pain were retrospectively identified. RESULTS Five hundred fifty-seven SF-SRS treatments in 447 patients resulted in 14 PNS injuries in 13 patients. All injures resulted from SF-SRS delivered to the cervical or lumbosacral spine at 2400 cGy. The overall percentage of SF-SRS treatments resulting in PNS injury was 2.5%, increasing to 4.5% when the thoracic spine was excluded from analysis. The median time to symptom onset following SF-SRS was 10 months (range 4-32 months). The plexus (cervical, brachial, and/or lumbosacral) was affected clinically and/or electrophysiologically in 12 (86%) of 14 cases, the nerve root in 2 (14%) of 14, and both in 6 (43%) of 14 cases. All patients experienced pain and most (93%) developed weakness. Peripheral nervous system injuries were CTCAE Grade 1 in 14% of cases, 2 in 64%, and 3 in 21%. No dose relationship between SF-SRS dose and PNS injury was detected. CONCLUSIONS Single-fraction SRS to the spine can result in PNS injury with major implications for function and quality of life.

INTRODUCTION/BACKGROUND:Chiari malformation type I is defined as a descent of cerebellar tonsils below the level of the foramen magnum. The traditional treatment for symptomatic patients is foramen magnum decompression (FMD) surgery. Intraoperative neurophysiological monitoring (INM) is an established surgical adjunct, which is proposed to reduce the potential risk of various surgical procedures. Though INM has been suggested as being helpful in patient positioning and in determining the optimal surgical extent of FMD (i.e., duroplasty, laminectomy, tonsillectomy), its shortcomings include prolongation of anesthesia and surgery as well as monetary costs. Multimodality INM including transcranial-electric motor evoked potential (TcMEP) is not routinely employed in most practices. This study evaluates efficacy of multimodality INM during FMD. METHODS:This work is a retrospective analysis of prospectively collected data. Twenty-two FMD surgeries in 21 pediatric patients (aged 1-18 years) were performed at our center utilizing multimodality INM. All patients presented Chiari malformation type I, 18 of which had presented with syringomyelia, underwent posterior fossa decompression (FMD + C1 laminectomy), accompanied in some with additional cervical laminectomies, duroplasty, and partial tonsillectomies. TcMEP and somatosensory evoked potentials (SSEP) were monitored throughout the procedure including before and after positioning. INM alarms were correlated with perioperative and long-term patient outcomes. RESULTS:INM data remained stable during 19 operations. Three cases displayed significant attenuation in the monitoring signals, all concomitant with patient positioning on the surgical table. One case showed attenuation in SSEP data only, which remained attenuated following repositioning. Another displayed altered TcMEP concomitant with positioning which partially stabilized following repositioning and resolved following bony decompression. The third case showed unilateral attenuation of both TcMEP and SSEP data, which did not rectify until closure. In each of these three cases, no new neurological deficits were observed post operatively. CONCLUSIONS:Multimodality INM can be useful in FMD surgery, particularly during patient positioning. TcMEP attenuations may occur independent of SSEPs. The clinical implications of these monitoring alerts have yet to be defined. There is a need to establish an optimal, cost-effective monitoring protocol for FMD.

BACKGROUND:Conducting research on the molecular biology, immunology, and physiology of brain tumors (BTs) and primary brain tissues requires the use of viably dissociated single cells. Inadequate methods for tissue dissociation generate considerable loss in the quantity of single cells produced and in the produced cells' viability. Improper dissociation may also demote the quality of data attained in functional and molecular assays due to the presence of large quantities cellular debris containing immune-activatory danger associated molecular patterns, and due to the increased quantities of degraded proteins and RNA. RESULTS:Over 40 resected BTs and non-tumorous brain tissue samples were dissociated into single cells by mechanical dissociation or by mechanical and enzymatic dissociation. The quality of dissociation was compared for all frequently used dissociation enzymes (collagenase, DNase, hyaluronidase, papain, dispase) and for neutral protease (NP) from Clostridium histolyticum. Single-cell-dissociated cell mixtures were evaluated for cellular viability and for the cell-mixture dissociation quality. Dissociation quality was graded by the quantity of subcellular debris, non-dissociated cell clumps, and DNA released from dead cells. Of all enzymes or enzyme combinations examined, NP (an enzyme previously not evaluated on brain tissues) produced dissociated cell mixtures with the highest mean cellular viability: 93 % in gliomas, 85 % in brain metastases, and 89 % in non-tumorous brain tissue. NP also produced cell mixtures with significantly less cellular debris than other enzymes tested. Dissociation using NP was non-aggressive over time-no changes in cell viability or dissociation quality were found when comparing 2-h dissociation at 37 °C to overnight dissociation at ambient temperature. CONCLUSIONS:The use of NP allows for the most effective dissociation of viable single cells from human BTs or brain tissue. Its non-aggressive dissociative capacity may enable ambient-temperature shipping of tumor pieces in multi-center clinical trials, meanwhile being dissociated. As clinical grade NP is commercially available it can be easily integrated into cell-therapy clinical trials in neuro-oncology. The high quality viable cells produced may enable investigators to conduct more consistent research by avoiding the experimental artifacts associated with the presence dead cells or cellular debris.

BACKGROUND:The association between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) has been suggested previously, but prior studies provided contradicting findings. OBJECTIVES/OBJECTIVE:To characterize the expression profile of eight classic and non-classic aPL in patients diagnosed with MS. METHODS:Using the BioPlex 2200 immunoassay, we measured the levels of serum immunoglobulin (Ig)M and IgG isotypes of three classic aPL and five non-classic aPL in 98 subjects with MS and 237 healthy controls. RESULTS:Three non-classic aPL were significantly more prevalent among MS patients in comparison to the control group. These antibodies included IgM and IgG against phosphatidylserine-β2GPI (PS-B2), IgG prothrombin complex (PT-PT) and IgM prothrombin (PT). The positive results according to Bonferroni correction are PS-B2 IgG and PT-PT IgG. The remaining aPL profiles did not differ significantly between the two groups. CONCLUSIONS:An association between certain non-classic aPL and MS has been established. The specific role of these autoantibodies in the pathogenesis of the condition remains uncertain.

BACKGROUND:Pemphigus and bullous pemphigoid are two autoimmune diseases that have similar pathogenesis. Both have a genetic predisposition, which promotes the production of auto antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Antiphospholipid antibodies (aPL) are heterogeneous group of antibodies found in patients with autoimmune diseases and inflammatory conditions and are associated with thrombotic events. OBJECTIVE:We sought to determine the expression profile of eight non classical aPLs in ABD patients. METHODS:A cohort of 266 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for the presence of eight aPL antibodies, using the Bio-Rad BioPlex™ 2200 system. RESULTS:Phosphatidylserine-beta-2-glycoprotein-I (aPS-β2GPI) and anti prothrombin complex (aPT-PT) serum profiles were significantly more prevalent among ABD patients; 20.7% patients with ABD compared to 5.9% of control patients were positive for aPS-β2GPI IgM. In addition, aPT-PT IgM was more prevalent among ABD patients (31% vs. 14.8%). CONCLUSION/CONCLUSIONS:aPL auto antibodies are more prevalent in ABD. Any clinical association should be further determined.

BACKGROUND:The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents. Helicobacter pylori, a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti-H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. METHODS:A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies by "pylori detect" kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). RESULTS:Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophilia-associated antibodies, as well as negative associations with gastrointestinal-associated antibodies. CONCLUSIONS:Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases.

Much is known about the geoepidemiology of defined autoimmune diseases (AD); however, there is currently limited data regarding the prevalence of autoantibodies among healthy populations of different geographical areas. The aim of this study was to evaluate a large profile of autoantibodies in healthy adults from distinct global regions as well as the prevalence of anti-infectious agents antibodies in those regions. Sera samples from 557 healthy donors were obtained at six centers located in different countries (i.e., Italy, Netherlands, Israel, Mexico, Columbia, Papua New Guinea (Kitavans)). Sera were tested for the presence of antinuclear antibodies (ANA) and autoantibodies associated with thrombophilia, vasculitis, and gastrointestinal (GI) disease. Sera samples were also screened for antibodies against infectious agents (i.e., EBV, CMV, HBV, Helicobacter pylori, Treponema pallidum, and Toxoplasma gondii). Tests were performed using the BioPlex 2200 or ELISA kits (Bio-Rad Laboratories, USA). We found a significant gradient of ANA positivity among the groups: 45% of Columbians, 38% of Kitavans, 26% of Mexicans, 12% of Italians, 12% of Dutch, and 11% of Israelis were ANA positive. Geographical differences were also observed regarding the prevalence of specific autoantibodies, namely ANA: anti-dsDNA, chromatin, SmRNP, Ro/SSA, La/SSB, Scl70; GI associated: antigliadin; and thrombophilia-associated: anti-β2GP1 and prothrombin. Additionally, significant differences were observed regarding serological markers of all infectious agents screened. The observed variance between healthy ethno-geographical distinct populations in prevalence of autoantibodies may represent different genetic or environmental (e.g., prior exposure to infection) influences. Thus may illuminate possible causes of geoepidemiological differences in AD.

Mixed cryoglobulinemia (MC) syndrome is an immune complex-mediated vasculitis characterized by the clinical triad of purpura, weakness, and arthralgias, the morbidity of which is mainly related to kidney and peripheral nervous system dysfunction as well as to the development of a secondary lymphoma (Ferri et al. Autoimmun Rev 7:114-120, 2007, Lidar et al. Ann N Y Acad Sci 1173:649-657, 2009, Trejo et al. Semin Arthritis Rheum 33:19-28, 2003). MC is associated with infectious and systemic disorders, principally autoimmune and lymphoproliferative diseases. Since the 1990s, a striking association (>90%) between MC and hepatitis C virus (HCV) infection has been established (Ferri and Bombardieri 2004; Pascual et al. J Infect Dis 162:569-570, 1990). However, information regarding the etiopathogenesis of HCV-negative MC is scant (Mascia et al. Dig Liver Dis 39:61-64, 2007). We hereby present our findings, as well as previously published data, regarding the presence of antibodies against infectious agents and autoantibodies in patients with MC in an attempt to establish novel associations which may shed light on the etiopathogenesis of this disease.