Citations

Odontogenic ghost cell carcinoma (OGCC) is a rare and aggressive tumor wherein optimal treatment remains uncertain. We report the first pediatric metastatic OGCC case treated with multimodal therapy: surgery, adjuvant chemoradiation, and adjuvant immunotherapy. Adjuvant therapy was utilized due to locally advanced disease with pathologic features indicative of high recurrence risk. This multimodal approach was modeled after management of primary head and neck cancer, where adjuvant chemoradiation and immunotherapy are associated with improved outcomes. Our patient is alive and disease free at 14 months indicating a potentially positive role for multimodal therapy in the management of OGCC.

AbstractObjectivesChest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR‐proADM) in prediction of mortality and major adverse cardiac events (MACE).MethodsThis was a subanalysis of the CHOPIN study, a 16‐center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6‐month all‐cause mortality and the secondary endpoint was 30‐day and 6‐month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.ResultsMR‐proADM performed similarly to troponin (cTnI; c‐statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR‐proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6‐month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR‐proADM, history of coronary artery disease (CAD), and hypertension were predictors of short‐term MACE, while history of CAD, hypertension, cTnI, and MR‐proADM were predictors of long‐term MACE.ConclusionsIn patients with chest pain, MR‐proADM predicts mortality and MACE in all‐comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses‐generating and future prospective studies to identify its utility in risk stratification should be considered.

OBJECT Motocross racing is a popular sport; however, its impact on the growing/developing pediatric spine is unknown. Using a retrospective cohort model, the authors compared the degree of advanced degenerative findings in young motocross racers with findings in age-matched controls. METHODS Patients who had been treated for motocross-related injury at the authors' institution between 2000 and 2007 and had been under 18 years of age at the time of injury and had undergone plain radiographic or CT examination of any spinal region were eligible for inclusion. Imaging was reviewed in a blinded fashion by 3 physicians for degenerative findings, including endplate abnormalities, loss of vertebral body height, wedging, and malalignment. Acute pathological segments were excluded. Spine radiographs from age-matched controls were similarly reviewed and the findings were compared. RESULTS The motocross cohort consisted of 29 riders (mean age 14.7 years; 82% male); the control cohort consisted of 45 adolescents (mean age 14.3 years; 71% male). In the cervical spine, the motocross cohort had 55 abnormalities in 203 segments (average 1.90 abnormalities/patient) compared with 20 abnormalities in 213 segments in the controls (average 0.65/patient) (p = 0.006, Student t-test). In the thoracic spine, the motocross riders had 51 abnormalities in 292 segments (average 2.04 abnormalities/patient) compared with 25 abnormalities in 299 segments in the controls (average 1.00/patient) (p = 0.045). In the lumbar spine, the motocross cohort had 11 abnormalities in 123 segments (average 0.44 abnormalities/patient) compared with 15 abnormalities in 150 segments in the controls (average 0.50/patient) (p = 0.197). CONCLUSIONS Increased degenerative changes in the cervical and thoracic spine were identified in adolescent motocross racers compared with age-matched controls. The long-term consequences of these changes are unknown; however, athletes and parents should be counseled accordingly about participation in motocross activities.

OBJECT Off-road motorcycling is a very popular sport practiced by countless people worldwide. Despite its popularity, not much has been published on the severity and distribution of central nervous system–related injuries associated with this activity in the pediatric population. The purpose of this study was to confirm, characterize, and document the rate of head and spine injuries associated with off-road motorcycling in this population. METHODS All patients aged 18 years or less who were treated for a motorbike injury at the authors' institution (a Level 1 regional trauma center) between 2000 and 2007 were identified through in-house surgical and trauma registries. Type, mechanism, and severity of CNS-related injuries were assessed, including: incidence of traumatic brain injury (TBI), loss of consciousness (LOC), Glasgow Coma Scale (GCS) score, head CT findings, neurological deficits, spinal fractures, cervical strain, and use of protective gear, including helmets. RESULTS During the 8-year period of study, 298 accidents were evaluated in 248 patients. The patients' mean age at the time of injury was 14.2 ± 2.7 years. Head injury or TBI was identified in 60 (20.1%) of 298 cases (involving 58 of 248 patients). Fifty-seven cases were associated with LOC, and abnormalities were identified on head CT in 10 patients; these abnormalities included skull fractures and epidural, subdural, subarachnoid, and intraparenchymal hemorrhages. The GCS score was abnormal in 11 cases and ranged from 3 to 15, with an overall mean of 14.5. No patients required cranial surgery. Helmet use was confirmed in 43 (71.6%) of the cases involving TBI. Spine fractures were identified in 13 patients (4.3%) and 5 required surgical fixation for their injury. CONCLUSIONS The authors found a high occurrence of head injuries following pediatric off-road motorcycle riding or motocross accidents despite the use of helmets. Additionally, this study severely underestimates the rate of mild TBIs in this patient population. Our data indicate that motocross is a high-risk sport despite the use of protective gear. Riders and parents should be counseled accordingly about the risks prior to participation.

OBJECT Action motorsports, including motocross, have been gaining popularity among children and adolescents, raising concerns for increased risk of concussions in participating youth. The authors undertook this study to test the following hypotheses: 1) that there is a high rate of concussion symptoms associated with a number of preventable or adjustable risk factors, and 2) that a high percentage of these symptoms are not be reported to adults and medical personnel. METHODS The authors identified all motocross riders under the age of 18 at a regional racetrack during the riding season between May and October 2010. The participants completed questionnaires pertaining to demographic characteristics and variables associated with motocross. The questionnaire results were compared with the incidence of self-reported concussion symptoms. RESULTS Two hundred two riders were identified who met the criteria for participation in the study, and 139 of them completed the study questionnaire. Of these 139 riders, 67 (48%) reported at least 1 concussion symptom during the season. The majority of riders (98%) reported “always” wearing a helmet, and 72% received professional help with fitting of their helmets. Proper helmet fitting was associated with a 41% decreased risk of concussion symptoms (RR 0.59, 95% CI 0.44–0.81, p < 0.01). Sixty-six riders (47%) reported having received sponsor support for motocross participation. Sponsor support conferred a relative risk for concussion symptoms of 1.48 (95% CI 1.05–2.08, p = 0.02). CONCLUSIONS Nearly half of all motocross competitors under the age of 18 reported concussion symptoms. Preventive measures are necessary to limit the negative impact from concussions. The risk of concussive injury can be decreased for pediatric motocross riders if they receive professional help with proper helmet fitting and through implementation of stricter guidelines regarding sponsorship.

Abstract TCR engagement by peptide-MHC class I (pMHC) ligands induces a conformational change (Δc) in CD3 (CD3Δc) that contributes to T cell signaling. We found that when this interaction took place between primary T lineage cells and APCs, the CD8 coreceptor was required to generate CD3Δc. Interestingly, neither enhancement of Ag binding strength nor Src kinase signaling explained this coreceptor activity. Furthermore, Ag-induced CD3Δc was developmentally attenuated by the increase in sialylation that accompanies T cell maturation and limits CD8 activity. Thus, both weak and strong ligands induced CD3Δc in preselection thymocytes, but only strong ligands were effective in mature T cells. We propose that CD8 participation in the TCR/pMHC interaction can physically regulate CD3Δc induction by “translating” productive Ag encounter from the TCR to the CD3 complex. This suggests one mechanism by which the developmentally regulated variation in CD8 sialylation may contribute to the developmental tuning of T cell sensitivity.

Abstract Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-α. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.

Abstract Purpose: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short 1-week manufacture protocol to determine the feasibility, safety, and antitumor efficacy of this double cell therapy. Experimental Design: A clinical trial (NCT00910650) adoptively transferring MART-1 T-cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide-pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and reinfused with (n = 10) or without (n = 3) prior cryopreservation. Results: A total of 14 patients with metastatic melanoma were enrolled and 9 of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1–specific T cells peaked within 2 weeks of ACT, indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1–specific T cells in the blood as compared with cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using noncryopreserved T cells. Conclusion: Double cell therapy with ACT of TCR-engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. Clin Cancer Res; 20(9); 2457–65. ©2014 AACR.