Metformin and the risk of endometrial cancer: a case-control analysis

OBJECTIVE To explore the risk of endometrial cancer in relation to metformin and other antidiabetic drugs. METHODS We conducted a case-control analysis to explore the association between use of metformin and other antidiabetic drugs and the risk of endometrial cancer using the UK-based General Practice Research Database (GPRD). Cases were women with an incident diagnosis of endometrial cancer, and up to 6 controls per case were matched in age, sex, calendar time, general practice, and number of years of active history in the GPRD prior to the index date. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated and results were adjusted by multivariate logistic regression analyses for BMI, smoking, a recorded diagnosis of diabetes mellitus, and diabetes duration. RESULTS A total of 2554 cases with incident endometrial cancer and 15,324 matched controls were identified. Ever use of metformin compared to never use of metformin was not associated with an altered risk of endometrial cancer (adj. OR 0.86, 95% CI 0.63-1.18). Stratified by exposure duration, neither long-term (≥25 prescriptions) use of metformin (adj. OR 0.79, 95% CI 0.54-1.17), nor long-term use of sulfonylureas (adj. OR 0.96, 95% CI 0.65-1.44), thiazolidinediones (≥15 prescriptions; adj. OR 1.22, 95% CI 0.67-2.21), or insulin (adj. OR 1.05 (0.79-1.82) was associated with the risk of endometrial cancer. CONCLUSION Use of metformin and other antidiabetic drugs were not associated with an altered risk of endometrial cancer.

Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis

PURPOSE Patients with Alzheimer's disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy. METHODS We conducted a follow-up study with a nested case-control analysis using the United Kingdom-based General Practice Research Database (GPRD). We identified patients aged ≥65 years with an incident diagnosis of AD or VD between 1998 and 2008 and a matched comparison group of dementia-free patients. Conditional logistic regression was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) of developing seizures/epilepsy in patients with AD or VD, stratified by age at onset and duration of dementia as well as by use of antidementia drugs. KEY FINDINGS Among 7,086 cases with AD, 4,438 with VD, and 11,524 matched dementia-free patients, we identified 180 cases with an incident diagnosis of seizures/epilepsy. The IRs of epilepsy/seizures for patients with AD or VD were 5.6/1,000 person-years (py) (95% CI 4.6-6.9) and 7.5/1,000 py (95% CI 5.7-9.7), respectively, and 0.8/1,000 py (95% CI 0.6-1.1) in the dementia-free group. In the nested case-control analysis, patients with longer standing (≥3 years) AD had a slightly higher risk of developing seizures or epilepsy than those with a shorter disease duration, whereas in patients with VD the contrary was observed. SIGNIFICANCE Seizures or epilepsy were substantially more common in patients with AD and VD than in dementia-free patients. The role of disease duration as a risk factor for seizures/epilepsy seems to differ between AD and VD.

Development of a Bayesian Joint Logistic Model to Better Study the Association between Haplotypes and Disease

In 2011, there will be an estimated 1,596,670 new cancer cases and 571,950 cancer-related deaths in the US. With the ever-increasing applications of cancer genetics in epidemiology, there is great potential to identify genetic risk factors that would help identify individuals with increased genetic susceptibility to cancer, which could be used to develop interventions or targeted therapies that could hopefully reduce cancer risk and mortality. In this dissertation, I propose to develop a new statistical method to evaluate the role of haplotypes in cancer susceptibility and development. This model will be flexible enough to handle not only haplotypes of any size, but also a variety of covariates. I will then apply this method to three cancer-related data sets (Hodgkin Disease, Glioma, and Lung Cancer). I hypothesize that there is substantial improvement in the estimation of association between haplotypes and disease, with the use of a Bayesian mathematical method to infer haplotypes that uses prior information from known genetics sources. Analysis based on haplotypes using information from publically available genetic sources generally show increased odds ratios and smaller p-values in both the Hodgkin, Glioma, and Lung data sets. For instance, the Bayesian Joint Logistic Model (BJLM) inferred haplotype TC had a substantially higher estimated effect size (OR=12.16, 95% CI = 2.47-90.1 vs. 9.24, 95% CI = 1.81-47.2) and more significant p-value (0.00044 vs. 0.008) for Hodgkin Disease compared to a traditional logistic regression approach. Also, the effect sizes of haplotypes modeled with recessive genetic effects were higher (and had more significant p-values) when analyzed with the BJLM. Full genetic models with haplotype information developed with the BJLM resulted in significantly higher discriminatory power and a significantly higher Net Reclassification Index compared to those developed with haplo.stats for lung cancer. Future analysis for this work could be to incorporate the 1000 Genomes project, which offers a larger selection of SNPs can be incorporated into the information from known genetic sources as well. Other future analysis include testing non-binary outcomes, like the levels of biomarkers that are present in lung cancer (NNK), and extending this analysis to full GWAS studies.

Who is likely to develop persistent low back pain? A longitudinal analysis of prognostic occupational factors

OBJECTIVE: Occupational low back pain (LBP) is considered to be the most expensive form of work disability, with the socioeconomic costs of persistent LBP exceeding the costs of acute and subacute LBP by far. This makes the early identification of patients at risk of developing persistent LBP essential, especially in working populations. The aim of the study was to evaluate both risk factors (for the development of persistent LBP) and protective factors (preventing the development of persistent LBP) in the same cohort. PARTICIPANTS: An inception cohort of 315 patients with acute to subacute or with recurrent LBP was recruited from 14 health practitioners (twelve general practitioners and two physiotherapists) across New Zealand. METHODS: Patients with persistent LBP at six-month follow-up were compared to patients with non-persistent LBP looking at occupational, psychological, biomedical and demographic/lifestyle predictors at baseline using multiple logistic regression analyses. All significant variables from the different domains were combined into a one predictor model. RESULTS: A final two-predictor model with an overall predictive value of 78% included social support at work (OR 0.67; 95%CI 0.45 to 0.99) and somatization (OR 1.08; 95%CI 1.01 to 1.15). CONCLUSIONS: Social support at work should be considered as a resource preventing the development of persistent LBP whereas somatization should be considered as a risk factor for the development of persistent LBP. Further studies are needed to determine if addressing these factors in workplace interventions for patients suffering from acute, subacute or recurrent LBP prevents subsequent development of persistent LBP.

The Application of Comorbidity Indices to Predict Early Postoperative Outcomes After Laparoscopic Roux-en-Y Gastric Bypass: A Nationwide Comparative Analysis of Over 70,000 Cases

BACKGROUND: Patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB) often have substantial comorbidities, which must be taken into account to appropriately assess expected postoperative outcomes. The Charlson/Deyo and Elixhauser indices are widely used comorbidity measures, both of which also have revised algorithms based on enhanced ICD-9-CM coding. It is currently unclear which of the existing comorbidity measures best predicts early postoperative outcomes following LRYGB. METHODS: Using the Nationwide Inpatient Sample, patients 18 years or older undergoing LRYGB for obesity between 2001 and 2008 were identified. Comorbidities were assessed according to the original and enhanced Charlson/Deyo and Elixhauser indices. Using multivariate logistic regression, the following early postoperative outcomes were assessed: overall postoperative complications, length of hospital stay, and conversion to open surgery. Model performance for the four comorbidity indices was assessed and compared using C-statistics and the Akaike's information criterion (AIC). RESULTS: A total of 70,287 patients were included. Mean age was 43.1 years (SD, 10.8), 81.6 % were female and 60.3 % were White. Both the original and enhanced Elixhauser indices modestly outperformed the Charlson/Deyo in predicting the surgical outcomes. All four models had similar C-statistics, but the original Elixhauser index was associated with the smallest AIC for all of the surgical outcomes. CONCLUSIONS: The original Elixhauser index is the best predictor of early postoperative outcomes in our cohort of patients undergoing LRYGB. However, differences between the Charlson/Deyo and Elixhauser indices are modest, and each of these indices provides clinically relevant insight for predicting early postoperative outcomes in this high-risk patient population.

Organ donation in Switzerland - an analysis of factors associated with consent rate

BACKGROUND AND AIM Switzerland has a low post mortem organ donation rate. Here we examine variables that are associated with the consent of the deceased's next of kin (NOK) for organ donation, which is a prerequisite for donation in Switzerland. METHODS AND ANALYSIS During one year, we registered information from NOK of all deceased patients in Swiss intensive care units, who were approached for consent to organ donation. We collected data on patient demographics, characteristics of NOK, factors related to the request process and to the clinical setting. We analyzed the association of collected predictors with consent rate using univariable logistic regression models; predictors with p-values <0.2 were selected for a multivariable logistic regression. RESULTS Of 266 NOK approached for consent, consent was given in 137 (51.5%) cases. In multivariable analysis, we found associations of consent rates with Swiss nationality (OR 3.09, 95% CI: 1.46-6.54) and German language area (OR 0.31, 95% CI: 0.14-0.73). Consent rates tended to be higher if a parent was present during the request (OR 1.76, 95% CI: 0.93-3.33) and if the request was done before brain death was formally declared (OR 1.87, 95% CI: 0.90-3.87). CONCLUSION Establishing an atmosphere of trust between the medical staff putting forward a request and the NOK, allowing sufficient time for the NOK to consider donation, and respecting personal values and cultural differences, could be of importance for increasing donation rates. Additional measures are needed to address the pronounced differences in consent rates between language regions.

Predicting 3-year mortality after percutaneous coronary intervention: updated logistic clinical SYNTAX score based on patient-level data from 7 contemporary stent trials

OBJECTIVES This study aimed to update the Logistic Clinical SYNTAX score to predict 3-year survival after percutaneous coronary intervention (PCI) and compare the performance with the SYNTAX score alone. BACKGROUND The SYNTAX score is a well-established angiographic tool to predict long-term outcomes after PCI. The Logistic Clinical SYNTAX score, developed by combining clinical variables with the anatomic SYNTAX score, has been shown to perform better than the SYNTAX score alone in predicting 1-year outcomes after PCI. However, the ability of this score to predict long-term survival is unknown. METHODS Patient-level data (N = 6,304, 399 deaths within 3 years) from 7 contemporary PCI trials were analyzed. We revised the overall risk and the predictor effects in the core model (SYNTAX score, age, creatinine clearance, and left ventricular ejection fraction) using Cox regression analysis to predict mortality at 3 years. We also updated the extended model by combining the core model with additional independent predictors of 3-year mortality (i.e., diabetes mellitus, peripheral vascular disease, and body mass index). RESULTS The revised Logistic Clinical SYNTAX models showed better discriminative ability than the anatomic SYNTAX score for the prediction of 3-year mortality after PCI (c-index: SYNTAX score, 0.61; core model, 0.71; and extended model, 0.73 in a cross-validation procedure). The extended model in particular performed better in differentiating low- and intermediate-risk groups. CONCLUSIONS Risk scores combining clinical characteristics with the anatomic SYNTAX score substantially better predict 3-year mortality than the SYNTAX score alone and should be used for long-term risk stratification of patients undergoing PCI.

Incidence of and risk factors for severe hypoglycaemia in treated type 2 diabetes mellitus patients in the UK - a nested case-control analysis

AIMS To assess incidence rates (IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs. METHODS Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time. Using multivariate conditional logistic regression analyses, we adjusted for potential confounders. RESULTS Of 130,761 patients with newly treated type 2 diabetes (mean age 61.7 ± 13.0 years), 690 (0.5%) had an incident episode of severe hypoglycaemia recorded [estimated IR 11.97 (95% confidence interval, CI, 11.11-12.90) per 10,000 person-years (PYs)]. The IR was markedly higher in insulin users [49.64 (95% CI, 44.08-55.89) per 10,000 PYs] than in patients not using insulin [8.03 (95% CI, 7.30-8.84) per 10,000 PYs]. Based on results of the nested case-control analysis increasing age [≥ 75 vs. 20-59 years; adjusted odds ratio (OR), 2.27; 95% CI, 1.65-3.12], cognitive impairment/dementia (adjusted OR, 2.00; 95% CI, 1.37-2.91), renal failure (adjusted OR, 1.34; 95% CI, 1.04-1.71), current use of sulphonylureas (adjusted OR, 4.45; 95% CI, 3.53-5.60) and current insulin use (adjusted OR, 11.83; 95% CI, 9.00-15.54) were all associated with an increased risk of severe hypoglycaemia. CONCLUSIONS Severe hypoglycaemia was recorded in 12 cases per 10,000 PYs. Risk factors for severe hypoglycaemia included increasing age, renal failure, cognitive impairment/dementia, and current use of insulin or sulphonylureas.

Cardiopulmonary Bypass has No Significant Impact on Survival in Patients Undergoing Nephrectomy and Level III-IV Inferior Vena Cava Thrombectomy. A Multi-Institutional Analysis.

PURPOSE The impact of cardiopulmonary bypass in level III-IV tumor thrombectomy on surgical and oncologic outcomes is unknown. We determine the impact of cardiopulmonary bypass on overall and cancer specific survival, as well as surgical complication rates and immediate outcomes in patients undergoing nephrectomy and level III-IV tumor thrombectomy with or without cardiopulmonary bypass. MATERIALS AND METHODS We retrospectively analyzed 362 patients with renal cell cancer and with level III or IV tumor thrombus from 1992 to 2012 at 22 U.S. and European centers. Cox proportional hazards models were used to compare overall and cancer specific survival between patients with and without cardiopulmonary bypass. Perioperative mortality and complication rates were assessed using logistic regression analyses. RESULTS Median overall survival was 24.6 months in noncardiopulmonary bypass cases and 26.6 months in cardiopulmonary bypass cases. Overall survival and cancer specific survival did not differ significantly in both groups on univariate analysis or when adjusting for known risk factors. On multivariate analysis no significant differences were seen in hospital length of stay, Clavien 1-4 complication rate, intraoperative or 30-day mortality and cancer specific survival. Limitations include the retrospective nature of the study. CONCLUSIONS In our multi-institutional analysis the use of cardiopulmonary bypass did not significantly impact cancer specific survival or overall survival in patients undergoing nephrectomy and level III or IV tumor thrombectomy. Neither approach was independently associated with increased mortality on multivariate analysis. Greater surgical complications were not independently associated with the use of cardiopulmonary bypass.

An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia.

OBJECTIVE Recent small single-center data indicate that the current hemodynamic parameters used to diagnose critical limb ischemia are insensitive. We investigated the validity of the societal guidelines-recommended hemodynamic parameters against core laboratory-adjudicated angiographic data from the multicenter IN.PACT DEEP (RandomIzed AmPhirion DEEP DEB vs StAndard PTA for the treatment of below the knee Critical limb ischemia) Trial. METHODS Of the 358 patients in the IN.PACT DEEP Trial to assess drug-eluting balloon vs standard balloon angioplasty for infrapopliteal disease, 237 had isolated infrapopliteal disease with an available ankle-brachial index (ABI), and only 40 of the latter had available toe pressure measurements. The associations between ABI, ankle pressure, and toe pressure with tibial runoff, Rutherford category, and plantar arch were examined according to the cutoff points recommended by the societal guidelines. Abnormal tibial runoff was defined as severely stenotic (≥70%) or occluded and scored as one-, two-, or three-vessel disease. A stenotic or occluded plantar arch was considered abnormal. RESULTS Only 14 of 237 patients (6%) had an ABI <0.4. Abnormal ankle pressure, defined as <50 mm Hg if Rutherford category 4 and <70 mm Hg if Rutherford category 5 or 6, was found only in 37 patients (16%). Abnormal toe pressure, defined as <30 mm Hg if Rutherford category 4 and <50 mm Hg if Rutherford category 5 or 6, was found in 24 of 40 patients (60%) with available measurements. Importantly, 29% of these 24 patients had an ABI within normal reference ranges. A univariate multinomial logistic regression found no association between the above hemodynamic parameters and the number of diseased infrapopliteal vessels. However, there was a significant paradoxic association where patients with Rutherford category 6 had higher ABI and ankle pressure than those with Rutherford category 5. Similarly, there was no association between ABI and pedal arch patency. CONCLUSIONS The current recommended hemodynamic parameters fail to identify a significant portion of patients with lower extremity ulcers and angiographically proven severe disease. Toe pressure has better sensitivity and should be considered in all patients with critical limb ischemia.

Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis

OBJECTIVES Improvement of skin fibrosis is part of the natural course of diffuse cutaneous systemic sclerosis (dcSSc). Recognising those patients most likely to improve could help tailoring clinical management and cohort enrichment for clinical trials. In this study, we aimed to identify predictors for improvement of skin fibrosis in patients with dcSSc. METHODS We performed a longitudinal analysis of the European Scleroderma Trials And Research (EUSTAR) registry including patients with dcSSc, fulfilling American College of Rheumatology criteria, baseline modified Rodnan skin score (mRSS) ≥7 and follow-up mRSS at 12±2 months. The primary outcome was skin improvement (decrease in mRSS of >5 points and ≥25%) at 1 year follow-up. A respective increase in mRSS was considered progression. Candidate predictors for skin improvement were selected by expert opinion and logistic regression with bootstrap validation was applied. RESULTS From the 919 patients included, 218 (24%) improved and 95 (10%) progressed. Eleven candidate predictors for skin improvement were analysed. The final model identified high baseline mRSS and absence of tendon friction rubs as independent predictors of skin improvement. The baseline mRSS was the strongest predictor of skin improvement, independent of disease duration. An upper threshold between 18 and 25 performed best in enriching for progressors over regressors. CONCLUSIONS Patients with advanced skin fibrosis at baseline and absence of tendon friction rubs are more likely to regress in the next year than patients with milder skin fibrosis. These evidence-based data can be implemented in clinical trial design to minimise the inclusion of patients who would regress under standard of care.

An analysis of two methods for the classification of stage of readiness to obtain repeat mammography screening

Background and purpose: Breast cancer continues to be a health problem for women, representing 28 percent of all female cancers and remaining one of the leading causes of death for women. Breast cancer incidence rates become substantial before the age of 50. After menopause, breast cancer incidence rates continue to increase with age creating a long-lasting source of concern (Harris et al., 1992). Mammography, a technique for the detection of breast tumors in their nonpalpable stage when they are most curable, has taken on considerable importance as a public health measure. The lifetime risk of breast cancer is approximately 1 in 9 and occurs over many decades. Recommendations are that screening be periodic in order to detect cancer at early stages. These recommendations, largely, are not followed. Not only are most women not getting regular mammograms, but this circumstance is particularly the case among older women where regular mammography has been proven to reduce mortality by approximately 30 percent. The purpose of this project was to increase our understanding of factors that are associated with stage of readiness to obtain subsequent mammograms. A secondary purpose of this research was to suggest further conceptual considerations toward the extension of the Transtheoretical Model (TTM) of behavior change to repeat screening mammography. ^ Methods. A sample (n = 1,222) of women 50 years and older in a large multi-specialty clinic in Houston, Texas was surveyed by mail questionnaire regarding their previous screening experience and stage of readiness to obtain repeat screening. A computerized database, maintained on all women who undergo mammography at the clinic, was used to identify women who are eligible for the project. The major statistical technique employed to select the significant variables and to examine the man and interaction effects of independent variables on dependent variables was polychotomous stepwise, logistic regression. A prediction model for each stage of readiness definition was estimated. The expected probabilities for stage of readiness were calculated to assess the magnitude and direction of significant predictors. ^ Results. Analysis showed that both ways of defining stage of readiness for obtaining a screening mammogram were associated with specific constructs, including decisional balance and processes of the change. ^ Conclusions. The results of the present study demonstrate that the TTM appears to translate to repeat mammography screening. Findings in the current study also support finding of previous studies that suggest that stage of readiness is associated with respondent decisional balance and the processes of change. ^

Colorectal cancer screening: Racial/ethnic and gender disparities in a population-based cross-sectional analysis of the United States

Gender and racial/ethnic disparities in colorectal cancer screening (CRC) has been observed and associated with income status, education level, treatment and late diagnosis. According to the American Cancer Society, among both males and females, CRC is the third most frequently diagnosed type of cancer and accounts for 10% of cancer deaths in the United States. Differences in CRC test use have been documented and limited to access to health care, demographics and health behaviors, but few studies have examined the correlates of CRC screening test use by gender. This present study examined the prevalence of CRC screening test use and assessed whether disparities are explained by gender and racial/ethnic differences. To assess these associations, the study utilized a cross-sectional design and examined the distribution of the covariates for gender and racial/ethnic group differences using the chi square statistic. Logistic regression was used to estimate the prevalence odds ratio and to adjust for the confounding effects of the covariates. ^ Results indicated there are disparities in the use of CRC screening test use and there were statistically significant difference in the prevalence for both FOBT and endoscopy screening between gender, χ2, p≤0.003. Females had a lower prevalence of endoscopy colorectal cancer screening than males when adjusting for age and education (OR 0.88, 95% CI 0.82–0.95). However, no statistically significant difference was reported between racial/ethnic groups, χ 2 p≤0.179 after adjusting for age, education and gender. For both FOBT and endoscopy screening Non-Hispanic Blacks and Hispanics had a lower prevalence of screening compared with Non-Hispanic Whites. In the multivariable regression model, the gender disparities could largely be explained by age, income status, education level, and marital status. Overall, individuals between the age "70–79" years old, were married, with some college education and income greater than $20,000 were associated with a higher prevalence of colorectal cancer screening test use within gender and racial/ethnic groups. ^

A space-time analysis of reported shigellosis and salmonellosis cases in Texas from 2000 to 2004

Background. The purpose of this study was to describe the risk factors and demographics of persons with salmonellosis and shigellosis and to investigate both seasonal and spatial variations in the occurrence of these infections in Texas from 2000 to 2004, utilizing time series analyses and the geographic information system digital mapping methods. ^ Methods. Spatial Analysis: MapInfo software was used to map the distribution of age-adjusted rates of reported shigellosis and salmonellosis in Texas from 2000–2004 by zip codes. Census data on above or below poverty level, household income, highest level of educational attainment, race, ethnicity, and urban/rural community status was obtained from the 2000 Decennial Census for each zip code. The zip codes with the upper 10% and lower 10% were compared using t-tests and logistic regression to determine whether there were any potential risk factors. ^ Temporal analysis. Seasonal patterns in the prevalence of infections in Texas from 2000 to 2003 were determined by performing time-series analysis on the numbers of cases of salmonellosis and shigellosis. A linear regression was also performed to assess for trends in the incidence of each disease, along with auto-correlation and multi-component cosinor analysis. ^ Results. Spatial analysis: Analysis by general linear model showed a significant association between infection rates and age, with young children aged less than 5 and those aged 5–9 years having increased risk of infection for both disease conditions. The data demonstrated that those populations with high percentages of people who attained a higher than high school education were less likely to be represented in zip codes with high rates of shigellosis. However, for salmonellosis, logistic regression models indicated that when compared to populations with high percentages of non-high school graduates, having a high school diploma or equivalent increased the odds of having a high rate of infection. ^ Temporal analysis. For shigellosis, multi-component cosinor analyses were used to determine the approximated cosine curve which represented a statistically significant representation of the time series data for all age groups by sex. The shigellosis results show 2 peaks, with a major peak occurring in June and a secondary peak appearing around October. Salmonellosis results showed a single peak and trough in all age groups with the peak occurring in August and the trough occurring in February. ^ Conclusion. The results from this study can be used by public health agencies to determine the timing of public health awareness programs and interventions in order to prevent salmonellosis and shigellosis from occurring. Because young children depend on adults for their meals, it is important to increase the awareness of day-care workers and new parents about modes of transmission and hygienic methods of food preparation and storage. ^

Enlarged tracheoesophageal puncture: A systematic review and retrospective analysis

Background. An enlarged tracheoesophageal puncture (TEP) results in aspiration around the voice prosthesis (VP) and may lead to pneumonia. The aims of this research were: (1) to conduct a systematic review and meta-analysis on enlarged TEP; (2) to analyze preoperative, perioperative, and postoperative risk factors for enlarged TEP; and (3) to evaluate control of leakage around the VP using conservative treatments and adverse events in patients with enlarged TEP.^ Methods. A systematic review was conducted (1978-2008). A summary risk estimate was calculated using a random-effects meta-analysis model. A retrospective cohort study was completed. Patients who underwent total laryngectomy and TEP at The University of Texas M. D. Anderson Cancer Center (MDACC) were included. Multiple logistic regression methods were used to assess risk factors for enlargement. Descriptive and bivariate statistics were calculated to evaluate outcomes and adverse events. Results: Twenty-seven manuscripts were included in the systematic review. The summary risk estimate of enlarged TEP/leakage around the VP was 7.2% (95% CI: 4.8%-9.6%). Temporary VP removal and TEP-site injections were the most commonly reported treatments. Neither prosthetic diameter (p=0.076) nor timing of TEP (p=0.297) significantly increased risk of enlargement per stratified analyses of published outcomes. The cumulative incidence of enlarged TEP was 18.6% (36/194, 95% CI: 13.0%-24.1%) in the MDACC cohort. Enlarged TEP occurred exclusively in irradiated patients. Adjusting for length of follow-up and timing of TEP, advanced nodal disease (ORadjusted: 4.3, 95% CI: 1.0-19.1), stricture (ORadjusted : 3.2, 95% CI: 1.2-8.6), and locoregional recurrence/distant metastasis after laryngectomy (ORadjusted: 6.2, 95% CI: 2.3-16.4) increased risk of enlarged TEP. At last follow-up, conservative methods controlled leakage around the VP in 81% (29/36) of patients. Unresolved leakage was associated with recurrent cancer (p=0.081) and TEP-site irregularity (p=0.003). Relative to those without enlargement, enlarged TEP patients had significantly higher risk of pneumonia (RR: 3.4, 95% CI: 1.9-6.2).^ Conclusions. These data establish that enlarged TEP poses serious health risks, and provide insight into medical and oncologic factors that may contribute to development of this complication. In addition, this research supports the use of conservative treatments to address leakage after enlarged TEP in lieu of complete TEP closure.^