Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.
We have applied image analysis methods in the assessment of human kidney perfusion based on 3D dynamic contrast-enhanced (DCE) MRI data. This approach consists of 3D non-rigid image registration of the kidneys and fuzzy C-mean classification of kidney tissues. The proposed registration method reduced motion artifacts in the dynamic images and improved the analysis of kidney compartments (cortex, medulla, and cavities). The dynamic intensity curves show the successive transition of the contrast agent through kidney compartments. The proposed method for motion correction and kidney compartment classification may be used to improve the validity and usefulness of further model-based pharmacokinetic analysis of kidney function.
The volume of diagnostic imaging studies performed in the United States is rapidly increasing resulting from an increase in the number of patients as well as an increase in the volume of studies per patient. Concurrently, the number and complexity of images in each patient data set are also increasing. Nuclear medicine physicians and radiologists are required to master an ever-expanding knowledge base whereas the hours available to master this knowledge base and apply it to specific tasks are steadily shrinking. The convergence of an expanding knowledge base and escalating time constraints increases the likelihood of physician errors. The problem is particularly acute for low-volume studies such as MAG3 diuresis renography where many imagers may have had limited training or experience. To address this problem, renal decision support systems (DSS) are being developed to assist physicians evaluate suspected obstruction in patients referred for diuresis renography. Categories of DSS include neural networks, case-based reasoning, expert systems and statistical systems; RENEX and CART are examples of renal DSS currently in development. RENEX (renal expert) uses a set of rules obtained from human experts to analyze a knowledge base of expanded quantitative parameters obtained from diuresis MAG3 scintigraphy whereas CART (classification and regression tree analysis) is a statistical method that grows and prunes a decision tree based on an analysis of these quantitative parameters in a training data set. RENEX can be queried to provide the reasons for its conclusions. Initial data show that the interpretations provided by RENEX and CART are comparable to the interpretations of a panel of experts blinded to clinical information. This project should serve as a benchmark for the scientific comparison and collaboration of these 2 fields of medical decision-making. Moreover, we anticipate that these DSS will better define the essential interpretative criteria, foster standardized interpretation, teach trainees to better interpret renal scans, enhance diagnostic accuracy and provide a methodology applicable to other diagnostic problems in radiology and medicine.
Background
To dosimetrically evaluate the effect of reduced margin radiotherapy on hippocampal dose for glioblastoma multiforme (GBM) patients.
Methods
GBM patients enrolled on the Radiation Therapy Oncology Group (RTOG) 0825 trial at our institution were identified. Standard RTOG 0825 expansions were 2 cm + 3-5 mm from the gross tumor volume (GTV) to the clinical tumor volume (CTV) and from the CTV to the planning tumor volume (PTV), respectively. These same patients also had reduced margin tumor volumes generated with 8 mm (GTV to CTV) + 3 mm (CTV to PTV) expansions. Individual plans were created for both standard and reduced margin structures. The dose-volume histograms were statistically compared with a paired, two-tailed Student’s t-test with a significance level of p < 0.05.
Results
A total of 16 patients were enrolled on RTOG 0825. The reduced margins resulted in statistically significant reductions in hippocampal dose at all evaluated endpoints. The hippocampal Dmax was reduced from a mean of 61.4 Gy to 56.1 Gy (8.7%), D40% was reduced from 49.9 Gy to 36.5 Gy (26.9%), D60% was reduced from 32.7 Gy to 18.7 Gy (42.9%) and the D80% was reduced from 27.3 Gy to 15.3 Gy (44%).
Conclusions
The use of reduced margin PTV expansions in the treatment of GBM patients results in significant reductions in hippocampal dose. Though the exact clinical benefit of this reduction is currently unclear, this study does provide support for a future prospective trial evaluating the neurocognitive benefits of reduced margin tumor volumes in the treatment of GBM patients.
Keywords: Glioblastoma multiforme; GBM; Hippocampus
Purpose
Solid tumors can be resistant or develop resistance to radiotherapy. The purpose of this study is to explore whether microRNA-302 is involved in radioresistance and can be exploited as a sensitizer to enhance sensitivity of breast cancer cells to radiation therapy.
Methods
MiR-302 expression levels in radioresistant cell lines were analyzed in comparison with their parent cell lines. Furthermore, we investigated whether enforced expression of miR-302 sensitized radioresistant breast cancer cells to ionizing radiation in vitro and in vivo.
Results
MiR-302 was downregulated in irradiated breast cancer cells. Additionally, the expression levels of miR-302a were inversely correlated with those of AKT1 and RAD52, two critical regulators of radioresistance. More promisingly, miR-302a sensitized radioresistant breast cancer cells to radiation therapy in vitro and in vivo and reduced the expression of AKT1 and RAD52.
Conclusion
Our findings demonstrated that decreased expression of miR-302 confers radioresistance and restoration of miR-302 baseline expression sensitizes breast cancer cells to radiotherapy. These data suggest that miR-302 is a potential sensitizer to radiotherapy.
Recently, TROG 02.01 results showed that in stage III melanoma patients with nodal metastasis, adjuvant radiation to lymph node basin after nodal dissection improves lymph node field relapse without an overall survival (OS) benefit. However, this trial was neither designed nor powered to detect an OS difference. In the present study, we analyzed patients in the National Cancer Database (NCDB) with stage III melanoma with pathologically involved nodes and compared survival outcomes of adjuvant radiation and no-radiation cohorts. Inclusion criteria were as follows: age at least 18 years; diagnosed 2003-2011; surgery to regional lymph nodes; pathologically involved lymph nodes; and American Joint Committee on Cancer stage (IIIA-C). We used propensity score matching analysis to compare the OS of patients with similar baseline demographic, clinical, and pathologic characteristics who received adjuvant radiation and no adjuvant radiation. Overall, 912 patients were analyzed with an average age at diagnosis of 54.4 years and a median follow-up time of 5.5 years. In this cohort, the 5-year OS was 69.0, 51.1, and 30.6% for stage IIIA, IIIB, and IIIC, respectively. On propensity score-adjusted multivariate analysis, we found that adjuvant radiation had no statistically significant impact on OS (hazard ratio: 1.09, 95% confidence interval: 0.75-1.58, P=0.640). Furthermore, age older than 60 years, number of nodes, increasing pathologic stage, and absence of immunotherapy correlated with worse OS. In this NCDB analysis, we found that the adjuvant radiotherapy for node-positive, stage III melanoma patients did not improve OS. This is consistent with TROG 02.01; however, there may be patient selection bias not accounted for by the NCDB.
Background Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. Methods Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. Results Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm2) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm2), P =.01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P =.009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P =.01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. Conclusions In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation.
Background: To investigate the impact of proton radiotherapy (PBT) on overall survival (OS) and evaluate PBT usage trends for patients with gliomas in the National Cancer Data Base (NCDB). Methods: Patients with a diagnosis of World Health Organization (WHO) Grade I-IV glioma treated with definitive radiation therapy (RT) between the years of 2004-13 were identified. Patients were stratified based on WHO Grade and photon radiotherapy (XRT) vs. PBT. Univariate (UVA) and multivariable analysis (MVA) with OS were performed by Cox proportional hazards model and log-rank tests. Propensity score (PS) weighting was utilized to account for differences in patient characteristics and to minimize selection bias. Results: There were a total of 49,405 patients treated with XRT and 170 patients treated with PBT. Median follow-up time was 62.1 months. On MVA, the following factors were associated with receipt of PBT (all p < 0.05): WHO Grade I-II gliomas, treatment at an academic/research program, west geographic facility location, and surgical resection. After PS weighting, all patients treated with PBT were found to have superior median and 5 year survival than patients treated with XRT: 45.9 vs. 29.7 months (p = 0.009) and 46.1 vs. 35.5% (p = 0.0160), respectively. Conclusions: PBT is associated with improved OS compared to XRT for patients with gliomas. This finding warrants verification in the randomized trial setting in order to account for potential patient imbalances not adequately captured by the NCDB, such as tumor molecular characteristics and patient performance status. Importance of the Study: This is the first study that compares the outcomes of patients treated with photon based radiotherapy vs. proton based radiotherapy for patients with gliomas. In this retrospective analysis, the results demonstrate that proton therapy is associated with improved outcomes which support ongoing prospective, randomized clinical trials comparing the two modalities in patients with gliomas.
by
Benjamin Fischer-Valuck;
Jeff M. Michalski;
Jessika A. Contreras;
Randall Brenneman;
John P. Christodouleas;
Christopher D. Abraham;
Eric H. Kim;
Vivek K. Arora;
Arnold D. Bullock;
Ruben Carmona;
Robert S. Figenshau;
Robert Grubb III;
Eric M. Knoche;
Russell K. Pachynski;
Joel Picus;
Bruce J. Roth;
Paul Sargos;
Gerald L. Andriole;
Hiram A. Gay;
Brian C. Baumann
Introduction: Squamous cell carcinoma (SqCC) is the second most common histology of primary bladder cancer, but still very limited information is known about its treatment outcomes. Most bladder cancer trials have excluded SqCC, and the current treatment paradigm for localized SqCC is extrapolated from results in urothelial carcinoma (UC). In particular, there is limited data on the efficacy of definitive chemo-radiotherapy (CRT). In this study, we compare overall survival outcomes between SqCC and UC patients treated with definitive CRT. Materials/methods: We queried the National Cancer Database (NCDB) for muscle-invasive (cT2-T4 N0 M0) bladder cancer patients diagnosed from 2004 to 2013 who underwent concurrent CRT. Propensity matching was performed to match patients with SqCC to those with UC. OS was analyzed using the Kaplan-Meier survival method, and the log-rank test and Cox regression were used for analyses. Results: 3332 patients met inclusion criteria of which 79 (2.3%) had SqCC. 73.4% of SqCC patients had clinical T2 disease compared to 82.5% of UC patients. Unadjusted median OS for SqCC patients was 15.6 months (95% CI, 11.7-19.6) versus 29.1 months (95% CI, 27.5-30.7) for those with UC (P < 0.0001). On multivariable analysis, factors associated with worse OS included: SqCC histology [HR: 1.53 (95% CI, 1.19-1.97); P = 0.001], increasing age [HR: 1.02 (95% CI, 1.02-1.03); P < 0.0001], increasing clinical T-stage [HR: 1.21 (95% CI, 1.13-1.29); P < 0.0001], and Charlson-Deyo comorbidity index [HR: 1.26 (95% CI, 1.18-1.33); P < 0.0001]. Seventy-seven SqCC patients were included in the propensity-matched analysis (154 total patients) with a median OS for SqCC patients of 15.1 months (95% CI, 11.1-18.9) vs. 30.4 months (95% CI, 19.4-41.4) for patients with UC (P = 0.013). Conclusions: This is the largest study to-date assessing survival outcomes for SqCC of the bladder treated with CRT. In this study, SqCC had worse overall survival compared to UC patients. Histology had a greater impact on survival than increasing T-stage, suggesting that histology should be an important factor when determining a patient's treatment strategy and that treatment intensification in this subgroup may be warranted.