Second cancers following treatment for retinoblastoma

Improvements in treatment over the past century have greatly increased survival for retinoblastoma, a rare childhood tumour of the eye, caused by mutations of the RB1 tumour suppressor gene. However, as survival for retinoblastoma has improved, those with the hereditary form of the disease (RB1 germline mutation) have elevated risks of developing additional cancers, mostly bone and soft tissue sarcomas and melanoma. Despite advances in understanding of second cancer risks following treatment for retinoblastoma, key research questions remained including 1) risks of common adult onset cancers, some of which have somatic mutations in the RB1 pathway and are associated with ionizing radiation; 2) persistence of increased risks of bone and soft tissue sarcomas into adulthood; 3) clarification of risks of second cancers following chemotherapy to treat retinoblastoma and 4) role of genetic susceptibility to second cancers following retinoblastoma. In response to these questions, a large cohort of 1852 long-term survivors of retinoblastoma was assembled to evaluate systematically the risk of second cancers. The work described in this thesis, which comprises six major studies, that have used this cohort to identify a higher risk than previously assumed of lung cancer; confirmed the increased risk of second cancers in survivors with a RB1 germline mutation and past radiotherapy; documented for the first time that risk of soft tissue sarcomas varied by subtype; demonstrated that mortality from second cancers exceeded that from retinoblastoma; provided new information on variation in second cancer risk by family history of retinoblastoma; and clarified that chemotherapy in addition to radiotherapy for retinoblastoma confers a higher risk for second cancers compared with radiotherapy alone. These studies collectively have provided risk data that can be used to inform survivors and their health care providers to facilitate screening or surveillance and early identification of second cancers

Hydration versus N-acetylcysteine for protection of renal function in patients with renal insufficiency undergoing percutaneous coronary intervention

A Clarion Call for Large-Scale Collaborative Studies of Pediatric Proton Therap

Cancer risks following diagnostic and therapeutic radiation exposure in children

The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life

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