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1.  Diffusion tensor tractography of the arcuate fasciculus in patients with brain tumors: Comparison between deterministic and probabilistic models 
The purpose of this study was to compare the deterministic and probabilistic tracking methods of diffusion tensor white matter fiber tractography in patients with brain tumors.
Materials and Methods
We identified 29 patients with left brain tumors <2 cm from the arcuate fasciculus who underwent pre-operative language fMRI and DTI. The arcuate fasciculus was reconstructed using a deterministic Fiber Assignment by Continuous Tracking (FACT) algorithm and a probabilistic method based on an extended Monte Carlo Random Walk algorithm. Tracking was controlled using two ROIs corresponding to Broca’s and Wernicke’s areas. Tracts in tumoraffected hemispheres were examined for extension between Broca’s and Wernicke’s areas, anterior-posterior length and volume, and compared with the normal contralateral tracts.
Probabilistic tracts displayed more complete anterior extension to Broca’s area than did FACT tracts on the tumor-affected and normal sides (p < 0.0001). The median length ratio for tumor: normal sides was greater for probabilistic tracts than FACT tracts (p < 0.0001). The median tract volume ratio for tumor: normal sides was also greater for probabilistic tracts than FACT tracts (p = 0.01).
Probabilistic tractography reconstructs the arcuate fasciculus more completely and performs better through areas of tumor and/or edema. The FACT algorithm tends to underestimate the anterior-most fibers of the arcuate fasciculus, which are crossed by primary motor fibers.
PMCID: PMC4199232  PMID: 25328583
Diffusion Tensor Imaging; DTI; Tractography; Probabilistic; FACT; Arcuate Fasciculus; Brain Tumors
2.  Allergies and Risk of Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Case-Control Consortium 
American Journal of Epidemiology  2013;178(5):691-700.
In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.
PMCID: PMC3755648  PMID: 23820785
allergic rhinitis; case-control studies; hypersensitivity; pancreatic neoplasms
3.  Toxicity and outcomes of thoracic re-irradiation using stereotactic body radiation therapy (SBRT) 
Patients treated for a thoracic malignancy carry a significant risk of developing other lung lesions. Locoregional control of intrathoracic recurrences is challenging due to the impact of prior therapies on normal tissues. We examined the safety and efficacy of thoracic re-irradiation using high-precision image-guided stereotactic body radiation therapy (SBRT).
Records of 39 patients with prior intra-thoracic conventionally fractionated radiation therapy (RT) who underwent SBRT for a subsequent primary, recurrent or metastatic lung tumor from 11/2004 to 7/2011 were retrospectively reviewed.
Median dose of prior RT was 61 Gy (range 30–80 Gy). Median biologically effective prescription dose (α/β = 10) (BED10) of SBRT was 70.4 Gy (range 42.6-180 Gy). With a median followup of 12.6 months among survivors, 1- and 2-year actuarial local progression-free survival (LPFS) were 77% and 64%, respectively. Median recurrence-free (RFS) and overall survival (OS) were 13.8 and 22.0 months, respectively. Patients without overlap of high-dose regions of the primary and re-irradiation plans were more likely to receive a BED10 ≥100 Gy, which was associated with higher LPFS (hazard ratio, [HR] = 0.18, p = 0.04), RFS ([HR] = 0.31, p = 0.038) and OS ([HR] = 0.25, p = 0.014). Grade 2 and 3 pulmonary toxicity was observed in 18% and 5% of patients, respectively. Other grade 2–4 toxicities included chest wall pain in 18%, fatigue in 15% and skin toxicity in 5%. No grade 5 events occurred.
SBRT can be safely and successfully administered to patients with prior thoracic RT. Dose reduction for cases with direct overlap of successive radiation fields results in acceptable re-treatment toxicity profile.
PMCID: PMC3651392  PMID: 23617949
Lung re-irradiation; SBRT; Pulmonary toxicity; BED
4.  Time Course and Predictors for Cancer-Related Fatigue in a Series of Oropharyngeal Cancer Patients Treated with Chemoradiation Therapy 
The Oncologist  2012;17(4):569-576.
Cancer-related fatigue (CRF) is an underestimated phenomenon and is prevalent in head and neck cancer patients. Results on aspects of the time course of CRF and its correlation with pain as well as the impact of pain on CRF are discussed.
Learning Objectives
After completing this course, the reader will be able to: Discuss the incidence of cancer-related fatigue and the impact it has on cancer patients.Evaluate clinical correlates of cancer-related fatigue and describe possible interventions.Explain the time course of cancer-related fatigue before, during, and post-treatment and the effect treatment has on patients for years after treatment.
This article is available for continuing medical education credit at
Cancer-related fatigue (CRF) is a highly prevalent and underestimated symptom in cancer patients. This study aims to analyze CRF solely in a cohort of oropharyngeal cancer patients who underwent treatment with radiotherapy (RT).
In January 2008 to June 2010, 87 consecutive oropharyngeal carcinoma patients underwent definitive RT. Concurrent chemotherapy was used for 94% of patients. The median prescription dose to the planning target volume of the gross or clinical tumor volume was 70 Gy for definitive cases (n = 84) and 66 Gy for postoperative cases (n = 3), both delivered over 6.5 weeks. A normalized 12-point numeric rating scale assessed CRF from patient visits before, during, and after RT.
The median follow-up of living patients was 14 months. Fatigue peaked 1–2 weeks post-RT and remained higher than baseline for up to 2 years post-RT in 50% of patients. The average fatigue score at the time of completion of therapy or maximum thereafter up to 1 year post-RT was significantly worse than baseline. Patients who experienced pain had a trend toward significance with association for a higher maximum difference in fatigue from baseline. Karnofsky performance status score, weight change, and mood disorders did not correlate with CRF.
Fatigue was a common treatment-related symptom in this uniform cohort of patients with oropharyngeal cancer. RT was highly correlated with worsening of CRF. Pain control has the potential to help mitigate CRF in patients experiencing pain, and will need to be confirmed using larger datasets.
PMCID: PMC3336831  PMID: 22398160
Oropharynx; Fatigue; Pain; Radiotherapy; Cancer; Chemotherapy; Head and neck; Pain
5.  The Influence of UGT 1A6 Variants and Aspirin Use in a Randomized Trial of Celecoxib for Prevention of Colorectal Adenoma 
Aspirin and celecoxib prevent colorectal adenoma recurrence. Genetic variants in the UGT1A6 enzyme are associated with delayed aspirin metabolism and greater chemopreventive efficacy. We examined the effect of combining aspirin and celecoxib in relation to UGT1A6 T181A and R184S variants among 1,647 patients in the Adenoma Prevention with Celecoxib (APC) trial who were stratified according to the use of low-dose aspirin after removal of adenomas and randomized to placebo, 200 mg-twice-daily, or 400 mg-twice-daily celecoxib for 3 years. Patients underwent follow-up colonoscopies at 1 and 3 years to assess on-treatment efficacy. At 5 years, 538 patients underwent a colonoscopy to assess risk of recurrence after treatment was discontinued for at least 1 year. During treatment, the relative risk (RR) of recurrent adenoma was 0.68 (95%CI,0.59–0.79) for 200 mg-twice-daily celecoxib and 0.54 (95%CI,0.46–0.64) for 400 mg-twice-daily celecoxib compared with placebo. Aspirin use was not independently associated with recurrent adenoma (RR, 0.98, 95%CI,0.86–1.15). These results did not vary according to UGT1A6 genotype. However, among those with a variant UGT1A6 genotype on aspirin, the RR of adenoma was 1.60 (95%CI,0.81–3.15) after withdrawal of 200 mg-twice-daily and 1.98 (95%CI,1.06–3.70) after withdrawal of 400 mg-twice-daily celecoxib compared to withdrawal of placebo. In contrast, there was no increased risk associated with discontinuing celecoxib among any other groups. Concurrent use of low-dose aspirin does not influence the efficacy of celecoxib in adenoma prevention. However, discontinuing celecoxib among aspirin-using individuals that initially developed adenoma despite a UGT1A6 variant genotype resulted in rapid re-emergence of disease.
PMCID: PMC3252487  PMID: 22030088
Adenoma; celecoxib; UGT1A6; inflammation; chemoprevention
6.  Statin Use and Colorectal Adenoma Risk: Results from the Adenoma Prevention with Celecoxib (APC) Trial 
Statins are widely prescribed for cardiovascular disease prevention, and also commonly used in patients at high risk for colorectal cancer (CRC). We report the results of a planned secondary analysis of the relationship between statin use and colorectal adenoma risk in a large chemoprevention trial.
The Adenoma Prevention with Celecoxib (APC) trial randomized 2035 adenoma patients to receive placebo (679 patients), 200 mg celecoxib twice daily (685 patients), or 400 mg celecoxib twice daily (671 patients). The study collected complete medical history and medication use data, and performed colonoscopic surveillance to 5 years after study enrollment. Effects of statin use on newly detected adenomas and cardiovascular adverse events were analyzed as time-dependent variables by multivariable Cox regression.
Statins were used by 36% (N=730) of APC trial participants. When adjusted for covariates including cardioprotective aspirin use, age, and sex, participants on the placebo arm who used statins at any time had no benefit over 5 years compared to never users (Risk Ratio (RR) 1.24; 95% confidence interval (CI) (0.99-1.56); p=0.065). Statin use for >3 years increased adenoma risk over 5 years (RR 1.39; 95%CI 1.04-1.86; p=0.024). For all comparisons of patients treated with celecoxib, adenoma detection rates for statin users and non-users were equivalent. Consistent with their use in patients at high risk, cardiovascular serious adverse events were more common among statin users.
For patients at high risk of CRC, statins do not protect against colorectal neoplasms and may even increase the risk of developing colorectal adenomas.
PMCID: PMC2990920  PMID: 20403998
colon; adenomas; NSAIDs; chemoprevention; statins
7.  Cytochrome P450 2C9 Variants Influence Response to Celecoxib for Prevention of Colorectal Adenoma 
Gastroenterology  2009;136(7):2127-2136.e1.
Background & Aims
Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib.
We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (≥1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg, twice-daily) or high-dose (400 mg, twice-daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years.
Among 1660 patients, 21% were CYP2C9*2 and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (0.56–0.76) for the low-dose and 0.54 (0.46–0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 0.30–0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 0.57–1.21) or wild-type (RR, 0.89; 0.72–1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes, but only with the high dose among patients with variant genotypes.
The greater efficacy of high-dose celecoxib, compared with the low dose, in preventing colorectal adenoma appears confined to individuals with slow-metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib.
PMCID: PMC2693443  PMID: 19233181
8.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma 
KRAS mutations are found in ~ 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib.
Experimental Design:
We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas.
KRAS mutational analysis was performed on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12/81; 95% CI 8%-24%) of tumors from never smokers. Similarly, 22% (69/316; 95% CI 17%-27%) of tumors from former smokers, and 25% (21/85; 95% CI 16%-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G→A) rather than the transversion mutations known to be smoking related (G→T or G→C; p<0.0001).
Based upon our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.
PMCID: PMC2754127  PMID: 18794081

Results 1-8 (8)