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1.  Prevalence of diabetes mellitus in patients with newly evaluated papillary thyroid cancer 
Thyroid Research  2014;7:7.
Background
This study investigates whether diabetes mellitus is a risk factor for the development of papillary thyroid cancer, using an age-, gender-, and race-matched analysis.
Methods
We retrospectively reviewed the charts of 1559 patients with newly evaluated thyroid cancer over a 4-year period at our institution and identified 1313 patients (84%) with papillary thyroid carcinoma. Characteristics of patients with diabetes versus those without diabetes were compared with a chi-square test for categorical variables and the Wilcoxon Rank Sum test for numeric variables. The prevalence of diabetes among patients with papillary thyroid carcinoma at our institution was compared (using an age-, gender-, and race-matched analysis) with that expected based on data from the continuous National Health and Nutrition Examination Survey (NHANES) from the same time period.
Results
For patients with papillary thyroid carcinoma, the median age was 47 years; 74% were female; 83% were white; and the prevalence of diabetes was 8%. Among those with diabetes, 92% had type 2 diabetes, and 24% were treated with insulin. Risk factors for diabetes included age and race. The prevalence of diabetes among patients with papillary thyroid carcinoma of all ages versus that among patients from NHANES of all ages was not significantly different (RR 1.07, CI 0.88 - 1.28). The prevalence of diabetes among patients with papillary thyroid cancer who were 44 years of age or younger versus that among patients from NHANES who were 44 years of age or younger, however, was significantly increased (RR 2.32, CI 1.37 - 3.66). There was no significant difference when subgroup analysis was performed by gender or race.
Conclusions
We found an increased prevalence of diabetes in patients with papillary thyroid carcinoma who were 44 years of age or younger.
doi:10.1186/1756-6614-7-7
PMCID: PMC4167256  PMID: 25237398
Diabetes mellitus; Papillary thyroid cancer; NHANES; Risk factor
2.  Electroretinogram Monitoring of Dose-Dependent Toxicity after Ophthalmic Artery Chemosurgery in Retinoblastoma Eyes: Six Year Review 
PLoS ONE  2014;9(1):e84247.
Purpose
To report electroretinogram responses of retinoblastoma children under anesthesia before and after treatment with chemotherapeutic drugs (melphalan, topotecan, carboplatin) delivery by ophthalmic artery chemosurgery (OAC).
Methods
A cohort study of 81 patients with retinoblastoma treated with OAC. All patients treated with OAC at our center through May 2012 for whom the requisite ERG data were available are included in the analysis. This study recorded the ERG 30 Hz flicker amplitude response changes from baseline, at 3 and 12 months following OAC treatment completion. Both univariate and multivariate linear regression models were evaluated, with generalized estimating equations to correct for correlations within patients. Independent numerical variables included maximum doses and cumulative doses of melphalan, topotecan and carboplatin.
Results
By univariate analysis, both melphalan and topotecan appear to be associated with changes in ERG amplitude at both 3 and 12 months; but for the most part, these changes are minimal and likely clinically insignificant. By multivariate analysis, maximum and cumulative melphalan have a modest, temporary effect on the ERG amplitude change, which is apparent at 3 months but no longer evident at 12 months after completing treatment. By multivariate analysis, topotecan and carboplatin do not appear to adversely effect the change in ERG response.
Conclusion
Melphalan has the strongest, and carboplatin the weakest association with reduction in ERG response amplitudes; but for the most part, these changes are minimal and likely clinically insignificant. These conclusions apply only over the dose ranges used here, and should be applied with caution.
doi:10.1371/journal.pone.0084247
PMCID: PMC3896342  PMID: 24465398
3.  A Comprehensive Comparison of the Continual Reassessment Method to the Standard 3 + 3 Dose Escalation Scheme in Phase I Dose-Finding Studies 
Background
An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.
Purpose
This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.
Methods
The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.
Results
CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (≤5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20–25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.
Limitations
We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.
Conclusions
We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.
doi:10.1177/1740774508096474
PMCID: PMC2637378  PMID: 18827039
4.  Estimating the empirical Lorenz curve and Gini coefficient in the presence of error with nested data 
Statistics in medicine  2008;27(16):3191-3208.
SUMMARY
The Lorenz curve is a graphical tool that is widely used to characterize the concentration of a measure in a population, such as wealth. It is frequently the case that the measure of interest used to rank experimental units when estimating the empirical Lorenz curve, and the corresponding Gini coefficient, is subject to random error. This error can result in an incorrect ranking of experimental units which inevitably leads to a curve that exaggerates the degree of concentration (variation) in the population. We consider a specific data configuration with a hierarchical structure where multiple observations are aggregated within experimental units to form the outcome whose distribution is of interest. Within this context, we explore this bias and discuss several widely available statistical methods that have the potential to reduce or remove the bias in the empirical Lorenz curve. The properties of these methods are examined and compared in a simulation study. This work is motivated by a health outcomes application that seeks to assess the concentration of black patient visits among primary care physicians. The methods are illustrated on data from this study.
doi:10.1002/sim.3151
PMCID: PMC3465674  PMID: 18172873
concentration; distribution; inequality; hierarchical data
5.  Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2 
Journal of Clinical Oncology  2010;28(14):2404-2410.
Purpose
Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation.
Patients and Methods
In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed.
Results
Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance.
Conclusion
The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.
doi:10.1200/JCO.2009.24.2495
PMCID: PMC2881721  PMID: 20368571
6.  Prevalence of Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node Biopsy or Axillary Dissection: Patient Perceptions and Precautionary Behaviors 
Journal of Clinical Oncology  2008;26(32):5220-5226.
Purpose
Sentinel lymph node (SLN) biopsy was adopted for the staging of the axilla with the assumption that it would reduce the risk of lymphedema in women with breast cancer. This study was undertaken to examine patient perceptions of lymphedema and use of precautionary behaviors several years after axillary surgery.
Patients and Methods
Nine hundred thirty-six women who underwent SLN biopsy (SLNB) alone or SLNB followed by axillary lymph node dissection (SLNB/ALND) between June 1, 1999, and May 30, 2003, were evaluated at a median of 5 years after surgery. Patient-perceived lymphedema and avoidant behaviors were assessed through interview and administered a validated instrument, and compared with arm measurements.
Results
Current arm swelling was reported in 3% of patients who received SLNB alone versus 27% of patients who received SLNB/ALND (P < .0001), as compared with 5% and 16%, respectively, with measured lymphedema. Only 41% of patients reporting arm swelling had measured lymphedema, and 5% of patients reporting no arm swelling had measured lymphedema. Risk factors associated with reported arm swelling were greater body weight (P < .0001), higher body mass index (P < .0001), infection (P < .0001), and injury (P = .007) in the ipsilateral arm since surgery. Patients followed more precautions if they had measured or perceived lymphedema.
Conclusion
Body weight, infection, and injury are significant risk factors for perceiving lymphedema. There is significant discordance between the presence of measured and patient-perceived lymphedema. When compared to SLNB/ALND, SLNB-alone results in a significantly lower rate of patient-perceived arm swelling 5 years postoperatively, and is perceived by fewer women than are measured to have it.
doi:10.1200/JCO.2008.16.3766
PMCID: PMC2652092  PMID: 18838708
7.  Prevalence of Lymphedema in Women With Breast Cancer 5 Years After Sentinel Lymph Node Biopsy or Axillary Dissection: Objective Measurements 
Journal of Clinical Oncology  2008;26(32):5213-5219.
Purpose
Sentinel lymph node biopsy was adopted for the staging of the axilla with the assumption that it would reduce the risk of lymphedema in women with breast cancer. The aim of this study was to determine the long-term prevalence of lymphedema after SLN biopsy (SLNB) alone and after SLNB followed by axillary lymph node dissection (SLNB/ALND).
Patients and Methods
At median follow-up of 5 years, lymphedema was assessed in 936 women with clinically node-negative breast cancer who underwent SLNB alone or SLNB/ALND. Standardized ipsilateral and contralateral measurements at baseline and follow-up were used to determine change in ipsilateral upper extremity circumference and to control for baseline asymmetry and weight change. Associations between lymphedema and potential risk factors were examined.
Results
Of the 936 women, 600 women (64%) underwent SLNB alone and 336 women (36%) underwent SLNB/ALND. Patients having SLNB alone were older than those having SLNB/ALND (56 v 52 years; P < .0001). Baseline body mass index (BMI) was similar in both groups. Arm circumference measurements documented lymphedema in 5% of SLNB alone patients, compared with 16% of SLNB/ALND patients (P < .0001). Risk factors associated with measured lymphedema were greater body weight (P < .0001), higher BMI (P < .0001), and infection (P < .0001) or injury (P = .02) in the ipsilateral arm since surgery.
Conclusion
When compared with SLNB/ALND, SLNB alone results in a significantly lower rate of lymphedema 5 years postoperatively. However, even after SLNB alone, there remains a clinically relevant risk of lymphedema. Higher body weight, infection, and injury are significant risk factors for developing lymphedema.
doi:10.1200/JCO.2008.16.3725
PMCID: PMC2652091  PMID: 18838709
8.  Frequency and Distinctive Spectrum of KRAS Mutations in Never Smokers with Lung Adenocarcinoma 
Purpose:
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.
Results:
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).
Conclusions:
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.
doi:10.1158/1078-0432.CCR-08-0646
PMCID: PMC2754127  PMID: 18794081
9.  A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase I dose-finding studies 
Background
An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.
Purpose
This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.
Methods
The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.
Results
CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (≤5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20−25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.
Limitations
We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.
Conclusions
We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.
doi:10.1177/1740774508096474
PMCID: PMC2637378  PMID: 18827039
10.  VARIATIONS AMONG HIGH VOLUME SURGEONS IN THE RATE OF COMPLICATIONS AFTER RADICAL PROSTATECTOMY: FURTHER EVIDENCE THAT TECHNIQUE MATTERS 
The Journal of urology  2005;173(6):2099-2103.
Purpose
A strong association between surgeon, hospital volume and postoperative morbidity of radical prostatectomy has been demonstrated. While better outcomes are associated with high volume surgeons, the degree of variation in outcomes among surgeons has not been fully examined.
Materials and Methods
Using a linked database from Surveillance, Epidemiology and End Results registries and federal Medicare claims data, we analyzed outcomes of consecutive patients treated with radical prostatectomy between 1992 and 1996. We focused on variations in several measures of morbidity (perioperative complications, late urinary complications and long-term incontinence) among patients of high volume surgeons, defined as those with 20 or more patients in the study period. After adjusting for hospital, surgeon volume and case mix, we examined the extent to which variations in the rates of adverse outcomes differed among surgeons for all 3 end points.
Results
Of the 999 surgeons 16% (159) performed 48.7% (5,238) of the 10,737 radical prostatectomies during the study. The 30-day mortality rate was 0.5%, the major postoperative complication rate was 28.6%, late urinary complications 25.2% (major events 16%) and long-term incontinence 6.7%. For all 3 morbidity outcomes the variation among surgeons in the rate of complications was significantly greater than that expected by chance (p =0.001 for each) after adjustment of covariates. Furthermore, surgeons with better (or worse) than average results with regard to 1 outcome were likely to have better (or worse, respectively) results with regard to the other2 outcome measures.
Conclusions
Morbidity end points that directly affect quality of life showed significant variability among high volume providers. Surgeons who performed well in 1 area (eg postoperative complications) performed well in others. These results further suggest that variations in surgical technique and postoperative care lead to variations in outcomes after radical prostatectomy, indicating that outcomes of this operation are sensitive to small differences in performance.
doi:10.1097/01.ju.0000158163.21079.66
PMCID: PMC1855289  PMID: 15879851
outcome and process assessment; prostatectomy; complications; urinary incontinence; workload

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