Citations

As there is evidence that ligamentous laxity is affected by the female hormones, we hypothesized that hormonal changes occurring during pregnancy could have a therapeutic role in preventing the development of a joint contracture. Knee joint contractures were created in pregnant and nonpregnant rats. After 2 wk of immobilization, the degree of contracture was measured with structural properties of the medial collateral and anterior cruciate ligaments and the pubic symphysis. Although not statistically significant, there was a general trend toward reduced contracture in pregnant compared with nonpregnant rats. Cutting the posterior capsule significantly decreased contracture for both the pregnant and nonpregnant groups, confirming the contribution of capsular structures to contracture. Ultimate loads of the medial collateral and anterior cruciate ligaments significantly decreased after immobilization compared with control, but there was no significant effect due to pregnancy. Stiffness and ultimate load of the pubic symphysis were not significantly different between pregnant and nonpregnant groups. The trend toward reduced contracture with pregnancy points toward a possible therapeutic role for female hormones in the prevention of postoperative and/or posttraumatic joint contracture.

Significance We have identified a lethal subtype of gastric cancer (GC) that is characterized by high levels of clonal heterogeneity and TP53 (tumor protein P53) mutation. We have also uncovered key novel mutations in the targetable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair and identified BRCA2 (breast cancer 2, early onset) mutations as new genetic markers to predict better survival for GC. Our study represents a novel approach for GC personalized medicine and identified novel clinical actionable therapies for GC therapy.

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.

Background: Femoral nerve block (FNB) has become a popular method of postoperative analgesia for anterior cruciate ligament (ACL) reconstruction in pediatric and adolescent patients. Successful rehabilitation after surgery involves return of quadriceps and hamstring strength. Purpose: To compare knee strength and function 6 months after ACL reconstruction in pediatric and adolescent patients who received FNB versus patients with no nerve block. Study Design: Cohort study; Level of evidence, 3. Methods: Patients 18 years or younger who underwent primary ACL reconstruction between 2000 and 2010 at a single institution were identified. If the patient was skeletally immature, a transphyseal ACL reconstruction was performed. Of these patients, 68% underwent reconstruction with a patellar tendon autograft, and in 32% of patients a hamstring autograft was utilized. There were 124 patients who met the study inclusion criteria, including 62 in the FNB group (31 males, 31 females) and 62 patients in the control group (25 males, 37 females). All study patients participated in a comprehensive rehabilitation program that included isokinetic strength and functional testing at 6 months postoperatively. Results: Univariate analysis showed a significantly higher deficit at 6 months in the FNB group with respect to fast isokinetic extension strength (17.6% vs 11.2%; P = .01) as well as fast (9.9% vs 5.7%; P = .04) and slow (13.0% vs 8.5%; P = .03) isokinetic flexion strength. There was no difference in slow isokinetic extension strength deficit between the 2 groups (FNB, 22.3% vs control, 18.7%; P = .20). With respect to function, there were no differences in deficit for vertical jump (FNB, 9.4% vs control, 11.3%; P = .30), single hop (7.6% vs 7.5%; P = .96), or triple hop (8.0% vs 6.6%; P = .34) between the 2 groups. A significantly higher percentage of patients in the control group met functional and isokinetic criteria for return to sports at 6 months (90.2% vs 67.7%; odds ratio, 4.37; P = .002). Conclusion: Pediatric and adolescent patients treated with FNB for postoperative analgesia after ACL reconstruction had significant isokinetic deficits in knee extension and flexion strength at 6 months when compared with patients who did not receive a nerve block. Patients without a block were 4 times more likely to meet criteria for clearance to return to sports at 6 months.

Abstract Multiple sclerosis is an inflammatory, demyelinating disease of the CNS of presumed autoimmune origin. Of all the genetic factors linked with multiple sclerosis, MHC class II molecules have the strongest association. Generation of HLA class II transgenic (Tg) mice has helped to elucidate the role of HLA class II genes in chronic inflammatory and demyelinating diseases. We have shown that the human HLA-DRB1*0301 gene predisposes to proteolipid protein (PLP)–induced experimental autoimmune encephalomyelitis (EAE), whereas HLA-DQβ1*0601 (DQ6) was resistant. We also showed that the DQ6 molecule protects from EAE in DRB1*0301.DQ6 double-Tg mice by producing anti-inflammatory IFN-γ. HLA-DQβ1*0302 (DQ8) Tg mice were also resistant to PLP91–110–induced EAE, but production of proinflammatory IL-17 exacerbated disease in DRB1*0301.DQ8 mice. To further confirm the role of IFN-γ in protection, we generated DRB1*0301.DQ8 mice lacking IFN-γ (DRB1*0301.DQ8.IFN-γ−/−). Immunization with PLP91–110 peptide caused atypical EAE in DRB1*0301.DQ8.IFN-γ−/− mice characterized by ataxia, spasticity, and dystonia, hallmarks of brain-specific disease. Severe brain-specific inflammation and demyelination in DRB1*0301.DQ8.IFN-γ−/− mice with minimal spinal cord pathology further confirmed brain-specific pathology. Atypical EAE in DRB1*0301.DQ8.IFN-γ−/− mice was associated with increased encephalitogenicity of CD4 T cells and their ability to produce greater levels of IL-17 and GM-CSF compared with DRB1*0301.DQ8 mice. Further, areas with demyelination showed increased presence of CD68+ inflammatory cells, suggesting an important role for monocytes/microglia in causing brain pathology. Thus, our study supports a protective role for IFN-γ in the demyelination of brain through downregulation of IL-17/GM-CSF and induction of neuroprotective factors in the brain by monocytes/microglial cells.

Abstract Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was &gt; 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if &lt; 10% (AI sensitive) the patient completed 16 to 18 weeks of neoadjuvant AI treatment. Co-primary endpoints were: 1) to confirm that the pathological complete response (pCR) rate to standard NCCN chemotherapy in the AI resistant population is in the range of 20% (similar to ER− disease). This required the observation of least 4/35 pCRs; 2) whether patients were willing to accept a recommendation of no chemotherapy when the preoperative endocrine prognostic index score was zero (PEPI-0) (pStage 1 or 2A, Ki67&lt;2.7% and ER+) since, according to the PEPI model, these patients have such a low relapse risk that chemotherapy is unlikely to be of value (Ellis, M JNCI 100:1380–8, 2008). Feasible was defined as &lt;10% PEPI-0 cases receiving adjuvant chemotherapy. Secondary endpoints included a determination of the distribution of intrinsic subtypes in the AI sensitive and resistant groups (using a research use only assay). Results: 51 patients (21%) had 2 to 4 week Ki67&gt;10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 &lt;10%, of these 176 had PEPI score information. 65 had a PEPI-0 (37%), of which 61 (94%) reported a treatment plan that did not include adjuvant chemotherapy. The AI resistant group had a significantly higher frequency of baseline high-risk intrinsic subtypes (LumB: 26, HER2-E: 2 versus LumA: 7) at baseline than the AI sensitive group (LumB: 40, HER2-E: 0 versus LumA: 66) Fishers exact test p = 7.16E−6. Additional molecular data will be presented at the meeting. Conclusion. A Ki67 value &gt;10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.

Objectives: Femoral nerve blockade has become a popular method of postoperative analgesia for anterior cruciate ligament (ACL) reconstruction in pediatric and adolescent patients. Successful rehabilitation after ACL reconstruction involves return of quadriceps and hamstring strength and dynamic knee stability. The objective of this study was to compare strength and function six months after ACL reconstruction in pediatric and adolescent patients who received a femoral nerve block versus a control group of patients with no nerve block. Methods: A search of our institutional database was performed to identify patients 17 years of age or younger who underwent primary ACL reconstruction between 2001 and 2010. Revision ACL surgeries and previous contralateral and ipsilateral knee surgeries were excluded. Based on institutional protocol, the patients participated in a comprehensive rehabilitation program and underwent isokinetic strength testing (slow and fast activation) and functional testing (vertical jump, single hop, triple hop) at six months after ACL reconstruction. Results: There were 127 patients that met the inclusion criteria, including 63 patients in the NB group (32 males, 31 females) and 64 patients in the control group (26 males, 38 females). There were no significant differences between the NB group and the control group with respect to age (15.7 ± 1.4 vs. 15.5 ± 1.4, p = 0.26), sex (p = 0.29), BMI (23.7 ± 3.6 vs. 23.8 ± 3.6, p = 0.91), or type of graft used (67% patellar tendon autograft, 33% hamstring autograft vs. 70% patellar tendon autograft, 30% hamstring autograft, p = 0.85). Univariate analysis showed a significantly higher deficit at six months in the NB group with respect to fast isokinetic extension strength (17.6% vs. 11.3%, p = 0.008), as well as fast (12.8% vs. 8.3%, p = 0.029) and slow (9.9% vs. 5.5%, p = 0.029) isokinetic flexion strength. There was no difference in slow extension isokinetic strength deficit between the two groups (NB 22.1% vs. control 18.9%, p = 0.246).. With respect to function, there were no differences in deficit for vertical jump (NB 9.3% vs. control 11.3%, p = 0.267), single hop (NB 7.5% vs. control 7.6%, p = 0.970), or triple hop (NB 7.9% vs. control 6.5%, p = 0.375) between the two groups. A higher percentage of patients in the control group met criteria for return to sports at six months. (88.9% vs. 68.3%, p = 0.008). Conclusion: Pediatric and adolescent patients treated with a femoral nerve block for postoperative pain control after ACL reconstruction had significant isokinetic deficits in knee extension (quadriceps) and flexion (hamstring) strength at six months when compared to patients who did not receive a nerve block. No differences in the results of functional testing were observed between the two groups. A significantly higher percentage of patients in the group who did not receive a block were cleared to return to sports at six months following ACL reconstruction.