31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Epidemiology and disposition of burn injuries among infants presenting to a tertiary-care pediatric emergency department

Objective: The objective of the study was to study the etiology of and factors determining the emergency department disposition of infants sustaining burn injuries. Methods: A retrospective chart review was performed on all patients 12 months or younger with a burn injury presenting to our emergency department over a 5-year period. We collected the chief complaint and diagnosis, patient demographics, and circumstances surrounding the burn injury from the emergency department charts. Univariable statistics, multiple imputation, and multivariable regression were performed to determine differences between races and factors leading to admission. Results: During the study period, 344 patients meeting inclusion criteria were treated in our emergency department. Scalds (53.2%) and contact burns (39.8%) were the most common causes of burns among the study group. Significant differences were observed between races for mechanism of burn, interhospital transport, and total body surface area affected (P \u3c 0.05). White patients were more likely to have higher body surface affected and to be transferred from another facility (P \u3c 0.05). Increased severity of burn, burns located on the hand, and concern for abuse resulted in higher likelihood of admission (P \u3c 0.01). No significant differences in disposition or mechanism of burn were present between English-speaking and non-English-speaking patients. Conclusions: Although most infant burns in our emergency department are due to scalds, burn injuries due to contact with household objects are common. Race plays a significant role in mechanism and severity of burn sustained. Increased severity of burn, concern for abuse, and burn to the hand were all associated with increased odds of admission. Copyright © 2011 by Lippincott Williams & Wilkins

Association between upper extremity fractures and weight status in children

Objectives: Our objective was to determine the odds of having an increased weight status among children with upper extremity fracture (UEF) compared with 3 control groups without fractures. Methods: This is a secondary analysis of data from the Pediatric Risk of Admission (PRISA and PRISA II) data sets. Patients without chronic illness between the ages of 5 to 14 years were included in the following groups: (1) UEF study group, (2) upper extremity nonfracture injured control group, (3) minor-head-injured control group, and (4) noninjured probability control group. Weight for age/sex percentiles was used to evaluate weight status. The proportions of patients with weight for age/sex greater than the 50th, 85th, and 95th percentiles were determined. Logistic regression was used to generate odds ratios comparing the UEF group with each control group stratified by age. Results: This analysis included 308 patients in the 5- to 9-year age group and 207 patients in the 10- to 14-year age group. The odds of having a weight greater than the 50th percentile for age/sex were significantly increased among children with UEF aged 5 to 9 years compared with all control groups. There were no significant differences in the corresponding odds ratios for children with UEF aged 10 to 14 years compared with controls. Conclusions: These findings may be related to differential injury mechanisms, mobility patterns, or underlying patient vulnerability to fracture based on weight status and bone qualities in prepubescent versus pubescent populations. Further investigation should explore fracture epidemiology and fracture risk in children stratified by age. © 2011 by Lippincott Williams & Wilkins

Prevalence of vitamin D insufficiency in African American children with forearm fractures: A preliminary study

Objectives: Forearm fractures account for a significant proportion of childhood injuries and seem to be increasing in incidence. Poor vitamin D status increases overall fracture risk in infants with rickets and adults with osteoporosis. Children with vitamin D insufficiency (serum 25-hydroxy vitamin D level \u3c20ng/mL) have decreased bone mineral density (BMD) compared with children having normal vitamin D status. The relationship between vitamin D status and childhood forearm fracture has not been investigated. Methods: This prospective study enrolled African American children, aged 5 to 9 years, with a forearm fracture. Bone health evaluation included measurement of serum 25-hydroxy vitamin D level and BMD by dual energy x-ray absorptiometry scan. Univariable analyses were used to test the associations between fracture status and the independent variables, serum vitamin D level and BMD. Results: Vitamin D levels were available for 17 cases. The mean (±SD) 25-hydroxy vitamin D level was 20.1 (±7.3) ng/mL with a range of 10 to 38ng/mL. The mean of this group was at the cut point for vitamin D insufficiency. Ten cases (59%) were vitamin D insufficient. Dual energy x-ray absorptiometry scan results for these patients were consistent with normal bony mineralization for age. Conclusions: A significant proportion of African American children with fractures in our study have vitamin D insufficiency. Analysis of serum 25-hydroxy vitamin D levels and BMD in additional cases and controls will determine the significance of these findings. Clinical Relevance: Vitamin D insufficiency may play a previously unrecognized role in childhood fractures. Strong consideration should be given to routine vitamin D testing in African American children with forearm fractures. Copyright © 2010 by Lippincott Williams & Wilkins

The association between fracture rates and neighborhood characteristics in Washington, DC, children

Effects of neighborhood contextual features have been found for many diseases, including bone fractures in adults. Our study objective was to evaluate the association between neighborhood characteristics and pediatric bone fracture rates. We hypothesized that neighborhood indices of deprivation would be associated with higher fracture rates. Pediatric bone fracture cases treated at a tertiary, academic, urban pediatric emergency department between 2003 – 2006 were mapped to census block groups using geographical information systems software. Fracture rates were calculated as fractures per 1,000 children in each census block. Exploratory factor analysis of socioeconomic indicators was performed using 2000 census block data. Factor scores were used to predict odds of bone fracture at the individual level while adjusting for mean age, gender composition, and race/ethnicity composition at census block level using our sample data. We analyzed 3764 fracture visits in 3557 patients representing 349 distinct census blocks groups. Fracture rates among census blocks ranged from 0 to 207 per 1,000 children/study period. Logistic regression modeling identified two factors (race/education and large families) associated with increased fracture risk. Census variables reflecting African American race, laborer/service industry employment, long term block group residence and lower education levels strongly loaded on the race/education factor. The large families factor indicated the children-to-families ratio within the block group. The poverty factor was not independently associated with fracture risk. Thus, neighborhood characteristics are associated with risk for fractures in children. These results can help inform translational efforts to develop targeted strategies for bone fracture prevention in children

Bone mineral density and vitamin D status among African American children with forearm fractures

OBJECTIVE: To determine whether African American children with forearm fractures have decreased bone mineral density and an increased prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D level ≤20 ng/mL) compared with fracture-free control patients. METHODS: This case-control study in African American children, aged 5 to 9 years, included case patients with forearm fracture and control patients without fracture. Evaluation included measurement of bone mineral density and serum 25-hydroxyvitamin D level. Univariable and multivariable analyses were used to test for associations between fracture status and 2 measures of bone health (bone mineral density and 25-hydroxyvitamin D level) while controlling for other potential confounders. RESULTS: The final sample included 76 case and 74 control patients. There were no significant differences between case and control patients in age, gender, parental education level, enrollment season, outdoor play time, height, or mean dietary calcium nutrient density. Cases were more likely than control patients to be overweight (49.3% vs 31.4%, P = .03). Compared with control patients, case patients had lower whole body z scores for bone mineral density (0.62 ± 0.96 vs 0.98 ± 1.09; adjusted odds ratio 0.38 [0.20-0.72]) and were more likely to be vitamin D deficient (47.1% vs 40.8%; adjusted odds ratio 3.46 [1.09-10.94]). CONCLUSIONS: These data support an association of lower bone mineral density and vitamin D deficiency with increased odds of forearm fracture among African American children. Because suboptimal childhood bone health also negatively impacts adult bone health, interventions to increase bone mineral density and correct vitamin D deficiency are indicated in this population to provide short-term and long-term benefits. Copyright © 2012 by the American Academy of Pediatrics

Bone mineral density and vitamin D status among African American children with forearm fractures

OBJECTIVE: To determine whether African American children with forearm fractures have decreased bone mineral density and an increased prevalence of vitamin D deficiency (serum 25-hydroxyvitamin D level ≤20 ng/mL) compared with fracture-free control patients. METHODS: This case-control study in African American children, aged 5 to 9 years, included case patients with forearm fracture and control patients without fracture. Evaluation included measurement of bone mineral density and serum 25-hydroxyvitamin D level. Univariable and multivariable analyses were used to test for associations between fracture status and 2 measures of bone health (bone mineral density and 25-hydroxyvitamin D level) while controlling for other potential confounders. RESULTS: The final sample included 76 case and 74 control patients. There were no significant differences between case and control patients in age, gender, parental education level, enrollment season, outdoor play time, height, or mean dietary calcium nutrient density. Cases were more likely than control patients to be overweight (49.3% vs 31.4%, P = .03). Compared with control patients, case patients had lower whole body z scores for bone mineral density (0.62 ± 0.96 vs 0.98 ± 1.09; adjusted odds ratio 0.38 [0.20-0.72]) and were more likely to be vitamin D deficient (47.1% vs 40.8%; adjusted odds ratio 3.46 [1.09-10.94]). CONCLUSIONS: These data support an association of lower bone mineral density and vitamin D deficiency with increased odds of forearm fracture among African American children. Because suboptimal childhood bone health also negatively impacts adult bone health, interventions to increase bone mineral density and correct vitamin D deficiency are indicated in this population to provide short-term and long-term benefits. Copyright © 2012 by the American Academy of Pediatrics