KIR and HLA Loci Are Associated with Hepatocellular Carcinoma Development in Patients with Hepatitis B Virus Infection: A Case-Control Study

BACKGROUND: Natural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. However, the role of NK cells in the process of HBV-associated hepatocellular carcinoma (HCC) development has not been addressed. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes. METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether KIR and HLA genes could influence the risk of HBV-associated HCC development, 144 HBV-infected patients with HCC and 189 well-matched HBV infectors with chronic hepatitis or cirrhosis as non-HCC controls were enrolled in this study. The presence of 12 loci of KIR was detected individually. HLA-A, -B, -C loci were genotyped with high-resolution. HLA-C group 1 homozygote (OR = 2.02; p = 0.005), HLA-Bw4-80I (OR = 2.67; p = 2.0E-04) and combination of full-length form and 22 bp-deleted form of KIR2DS4 (KIR2DS4/1D) (OR = 1.89; p = 0.017) were found associated with HCC incidence. When the combined effects of these three genetic factors were evaluated, more risk factors were observed correlating with higher odds ratios for HCC incidence (P trend = 7.4E-05). Because all the risk factors we found have been reported to result in high NK cell functional potential by previous studies, our observations suggest that NK cell activation may contribute to HBV-associated HCC development. CONCLUSIONS/SIGNIFICANCE: In conclusion, this study has identified significant associations that suggest an important role for NK cells in HCC incidence in HBV-infected patients. Our study is useful for HCC surveillance and has implications for novel personalized therapy strategy development aiming at HCC prevention in HBV-infected patients

Radiation doses to normal tissues and organs outside the target volume during radiotherapy

Public Health Codes more and more require that any information relevant to the estimation of the high doses delivered within the target volumes and low doses delivered outside should be recorded. In this context, the availability for each radiotherapy patient of the magnitude of the unavoidable low doses delivered outside the target-volumes becomes an important issue. However, to date, Treatment Planning Systems (TPS) are not designed for this issue. Therefore, we have developed a new version of the ISOgray TPS which can provide, in addition to the doses distributions in the fields, the magnitude of the doses to distant healthy tissues in the course of common radiotherapeutic procedures. Our strategy involves 3 modules: A library of adjustable whole-body patient models in treatment position which allows different patient anatomies to be simulated; A multi-sources beam model, which allows the description of the irradiation field to be extended to the whole body; A dose calculation engine producing the distributions of doses in the fields and in any organ outside. This paper describes the principles of the system and provides data on doses distributions to distant organs for various common radiotherapeutic procedures. At this stage of development, the agreement of measured and calculated doses reaches ±3% in the radiation field and is better than ±15% outside. In the case of a 17 years aged girl treated for Hodgkin's disease using two 6MV opposite photon beams, when a dose of 20 Gy was delivered to the target volume, outside the beam, the dose to the brain was 0.37 Gy (1.85% of the tumor dose), the kidney 0.06 Gy (0.30%) and the ovaries below 0.02 Gy (<0.1%). Although the development of our system is still in progress, these preliminary results are encouraging. Allowing the realization of whole-body dose evaluations for each patient in the course of radiation therapy treatment planning, our approach must provide relevant information required to meet the current requirements of patient radiation protection and radiation therapy benefit-risk management purposes. The systematic evaluation of low doses outside the radiation therapy fields creates new opportunities in quality assurance of radiation therapy and prospective studies of long-term risks of radiation modern radiotherapeutic procedures