Purpose: Previous gene transfection studies have shown that the accumulation of human ribonucleotide reductase small subunit M2 (hRRM2) enhances cellular transformation, tumorigenesis, and malignancy potential. The latest identified small subunit p53R2 has 80% homology to hRRM2. Here, we investigate the role of p53R2 in cancer invasion and metastasis. Experimental Design: The immunohistochemistry was conducted on a tissue array including 49 primary and 59 metastatic colon adenocarcinoma samples to determine the relationship between p53R2 expression and metastasis. A Matrigel invasive chamber was used to sort the highly invasive cells and to evaluate the invasion potential of p53R2. Results: Univariate and multivariate analyses revealed that p53R2 is negatively related to the metastasis of colon adenocarcinoma samples (odds ratio, 0.23; P < 0.05). The decrease of p53R2 is associated with cell invasion potential, which was observed in both p53 wild-type (KB) and mutant (PC-3 and Mia PaCa-2) cell lines. An increase in p53R2 expression by gene transfection significantly reduced the cellular invasion potential to 54% and 30% in KB and PC-3 cells, respectively, whereas inhibition of p53R2 by short interfering RNA resulted in a 3-fold increase in cell migration. Conclusions: Opposite regulation of hRRM2 and p53R2 in invasion potential might play a critical role in determining the invasion and metastasis phenotype in cancer cells. The expression level of ribonucleotide reductase small subunits may serve as a biomarker to predict the malignancy potential of human cancers in the future.Ribonucleoside diphosphate reductase (RR) plays an essential role in converting ribonucleoside diphosphate to 2 ¶-deoxyribonucleoside diphosphate. In a RR holoenzyme, large a and small h subunits form an a 2 h 2 heterotetramer that is required for RR activity (1). In humans, one large subunit (M1) and two small subunits (hRRM2 and p53R2) of RR have been identified (2). The large subunit M1 (hRRM1) contains substrate and allosteric effector sites that control the RR holoenzyme activity and substrate specificity (3 -5). The RR small subunits form two equivalent dinuclear iron centers that stabilize the tyrosyl free radical required for the initiation of electron transformation during catalysis (3,6). RR is essential as it provides deoxynucleotide triphosphate (dNTP) for DNA synthesis and DNA repair. The expression, subcellular localization, and function of RR are highly regulated (7). Because RR plays a critical role in DNA synthesis, it represents an important target for cancer therapy.Two RR small subunits, p53R2 and hRRM2, have an 80% similarity in protein sequence (2). An in vitro assay showed that recombinant p53R2 protein, as well as hRRM2, interacts with hRRM1 to form a holoenzyme with the ability to convert CDP to dCDP (8, 9). The diiron-dityrosyl radical cluster was identified as the RR activity center, located on the common binding pockets of p53R2 and hRRM2 (10). Using a synthetic heptapeptide to inhibit RR activity, p53R2...

Radiation necrosis is a devastating complication following radiation to the central nervous system. The purpose of this study was to perform a comprehensive analysis of cases in the literature using bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as treatment for radiation necrosis. A MEDLINE/PubMed search of articles about the use of bevacizumab for radionecrosis treatment yielded 16 studies published between 2007 and 2012. Data was summarized according to patient characteristics, treatment received and outcomes measured. A total of 71 unique cases were identified that met the inclusion criteria. The median age at the time of treatment with bevacizumab was 47 years. The most common tumors treated were glioblastoma (31 %), anaplastic glioma (14 %), and metastatic brain tumors (15 %). The median time from ending radiotherapy to starting treatment with bevacizumab was 11 months and the median follow up time after bevacizumab treatment was 8 months. The median number of cycles of bevacizumab was administered was 4, and the median dosage of bevacizumab was 7.5 mg/kg. The median time elapsed between cycles of bevacizumab was 2 weeks. Overall, pre and post treatment imaging revealed a median decrease in T1 contrast enhancement of 63 %, and a 59 % median decrease in T2/FLAIR signal abnormality. Treatment with bevacizumab resulted in a significant radiographic response for patients with radionecrosis. The median dosage of bevacizumab of 7.5 mg/kg for four cycles every 2 weeks should be considered as a treatment option in this patient population.

Background: Clinical variables—age, family history, genetics—are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. Methods: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n=3,279; 2,163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. Results: Median age at last follow-up/prostate cancer death were 78.0 (IQR: 72.3–84.1) and 81.4 (75.4–86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95%CI 2.78–4.17]), family history (HR 1.72 [1.46–2.03]), alcohol (HR 1.74 [1.40–2.15]), diabetes (HR 0.53 [0.37–0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99–2.97]), family history (HR 1.73 [1.48–2.03]), alcohol (HR 1.45 [1.19–1.76]), diabetes (HR 0.62 [0.42–0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer ( p <10 −15 ). Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.

Radiation oncology (RO) is a dynamic and rapidly changing field. Residents are uniquely positioned to identify issues relevant to graduate medical education and the future workforce. As the elected members of the Executive Committee for the Association of Residents in Radiation Oncology (ARRO), we communicate with the larger RO community about the issues that residents identify as being the most pressing. ARRO recently sent a brief survey to registered American Society for Radiation Oncology (ASTRO) members-in-training (N Z 710) asking them to rank in order any (or all) of 14 specified issues that "concern[ed them] as radiation oncologist[s]." Responses were received from 179 individuals from April 4th through May 10th (response rate Z 25.2%). The top 3 concerning issues (Fig. 1), by rank order, were the job market (91%), the American Board of Radiology (ABR) qualifying (written) examinations (85%), and residency expansion (84%). Other issues identified by trainees included oral boards, declining reimbursement, variability in training programs, and fellowship expansion. Additional free-text concerns were submitted by 90 trainees. The top 2 themes included clinical relevance of board certification examinations (n Z 17) and trust in leadership (n Z 11). Here, we will briefly discuss the top 3 issues. Job Market The principal concern identified by residents was the job market (Fig. 1). Not only did 91% of residents rank the job market as "a concerning issue," but 72% ranked it as 1 of the

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