Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8 T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8 T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.

To examine the changes in birth cohort prevalence rates and severity of congenital heart disease, we studied children with congenital heart disease born to blacks, whites, and Mexican-Americans in Dallas County from 1971 through 1984. Diagnoses were made by pediatric cardiologists' clinical evaluations, echocardiography, catheterization, surgery, or autopsy. During this study period, 2,509 of 379,561 liveborn infants were diagnosed, a prevalence rate of 6.6/1000. The rates for whites was significantly higher than for blacks or Mexican-Americans -7.2/1,000, 5.6/1,000, and 5.911,000, respectively. The rate for severe cases requiring cardiac catheterization or surgery or undergoing autopsy was 3.111,000 and did not differ among the three groups. The time trend for rates of congenital heart disease suggested an apparent increase in prevalence rate during the 1970s; however, the prevalence rate of severe forms remained relatively stable. This indicates that the apparent rise in prevalence could be accounted for by an increase in detection of mild cases. These findings were interpreted as reflecting a greater tendency for pediatricians to refer asymptomatic children with significant heart murmurs to a pediatric cardiologist. (Circulation 1990;81:137-142) C ongenital heart disease (CHD) is a leading cause of death during the first year of life. Malformations of the cardiovascular system are also associated with significant medical morbidity, which requires use of costly medical facilities. Children with CHD use 25-30% of the beds in most large pediatric intensive care units and, therefore, consume a large fraction of pediatric health care resources. To plan future health care needs, epidemiologic data are needed regarding changes in prevalence and severity of CHD. The surveillance systems for birth defects conducted by the Centers for Disease Control have indicated a more than twofold increase in the most common form of CHD, ventricular septal defect, between-1970 and 1977.1 To examine the changes in prevalence rates and severity of CHD, we gathered epidemiologic data on children with CHD who were born in a well-defined geographic area during a specific time period. The

Purpose: A region on chromosome 8q24 was recently identified as a novel prostate cancer risk locus. Inherited variation in this region is associated with prostate cancer risk in the general population (21-58%), and specific alleles show a strong association in African-American men. This study was designed to evaluate associations between 8q24 risk alleles and clinical variables, such as pathologic stage, age at diagnosis, and recurrence, in a case series of African-American men.Experimental Design: Peripheral blood DNA samples from 114 African-American men with prostate cancer, including 106 who had undergone radical prostatectomy, were genotyped for six single-nucleotide polymorphisms on three 8q24 regions. The presence of these single-nucleotide polymorphisms was compared with clinicopathologic and follow-up data after radical prostatectomy.Results: The mean age of diagnosis and follow-up time were 57.4 (±8.9) years and 49.1 (±31.6) months, respectively. Patients carrying the Broad11934905 A risk allele, which is specific for African ancestry, were more likely to have a higher pathologic stage (pT 3-4 ) than individuals with the wild type (odds ratio, 4.48; 95% confidence interval, 1.42-14.14; P = 0.011). A trend toward increased frequency of and shorter time to biochemical recurrence was noted in patients with this risk allele on Kaplan-Meier unadjusted survival analysis (P = 0.076).Conclusions: The Broad11934905 polymorphism at 8q24, which is only found in people of African ancestry, is associated with an increase in non-organ-confined prostate cancer at prostatectomy. In addition, for those with this risk allele, there is a trend toward early biochemical recurrence that requires validation in larger studies. Cancer Epidemiol Biomarkers Prev; 19(1); 1-8. ©2010 AACR.