Retrospective assesment of the levonorgestrel intrauterine device to treat complex atypical hyperplasia and early endometrioid endometrial cancer

Objective: The primary objective of this project was to describe the efficacy of the Levonorgestrel Intrauterine Device (LIUD) for treatment of Complex Endometrial Cancer (CAH) and Grade 1 Endometrial Cancer (G1EEC) in terms of rate of Complete Response (CR) and Partial Response (PR) after 6 months of therapy. Finally, we assessed if any clinical or pathologic features were associated with response to the LIUD. ^ Methods: This study was a retrospective case series designed to report the response rate of patients with CAH or G1EEC treated with LIUD therapy. In addition, this study has a laboratory component to assess molecular predictors of response to LIUD therapy. Retrospective data already collected from patients diagnosed with CAH or EEC grade 1 and treated with LIUD therapy at MD Anderson Cancer Center (MDACC) were used for this study. Patients from all ethnic and race groups were included. A Complete Response (CR) was defined in patients diagnosed with CAH if pathologic report at 6 months demonstrated either no evidence of hyperplasia or no atypia in the setting of simple or complex hyperplasia. Partial Response (PR) was recorded if disease downgraded to only CAH from G1EEC. No Response (NR) was recorded if pathologic report demonstrates no change (Stable Disease, SD) or progression to cancer (Progressive Disease, PD). We calculated the proportion of patients with complete response to LIUD therapy with 95% confidence interval. We compared the response rates (CR/PR vs NR) by obesity status (Obese if BMI > 40 kg/m2 vs non-obese if BMI <= 40 kg/m2) as well as other clinical and pathologic factors, such as age, uterine size (median size), and presence of exogenous progesterone effect. ^ Results: There were 39 patients diagnosed with either CAH or G1EEC treated with the LIUD. Of 39 patients, 12 did not have pathological results of biopsy at 6months time period. Of 27 evaluable patients, 17 were diagnosed with CAH and 10 with G1EEC. Overall response rate (RR) was 78% (95% CI = 62-94%) at 6 months, 18 patients had CR (4 in G1EEC; 14 in CAH), 3 patients had PR (3 in G1EEC), 3 had SD (1 in CAH; 2 in G1EEC), 3 had PD (2 in CAH; 1 in G1EEC). After histology stratification, RR at 6 months was 82.35% (14/17; 95%CI = 67.4-97.3%) in CAH and 70% (7/10; 95% CI = 41-98.4%) in G1EEC. ^ There was no difference in response (R) and no response (NR) based on BMI (p=0.56). He observed a trend showing association between age with response (p=0.1). There was no association between uterine size and response to therapy (p=0.17). We recorded strong association between exogenous progesterone effect and response. ^ Conclusion: LIUD therapy for the treatment of CAH and G1EEC may be effective and safe. Presence of exogenous progesterone effect may predict the response to LIUD therapy at earlier time points. There is need of further studies with larger sample size to explore the relationship of response with other clinical and pathologic factors^

A RANDOMIZED TRIAL OF BILEVEL POSITIVE AIRWAY PRESSURE DEVICE AND HIGH FLOW OXYGEN FOR PERSISTENT DYSPNEA IN

Background: Dyspnea is a common and distressing symptom among patients with advanced cancer. The role of bilevel positive airway pressure (BIPAP) and Vapotherm in the relief of dyspnea have not been well defined. We aimed to determine and to compare the efficacy of BIPAP and VapoTherm for cancer related dyspnea. Methods: In this randomized, open-label, crossover study, we randomly assigned advanced cancer patients with persistent dyspnea >=3/10 to either Vapotherm for 2 hours followed by BiPAP for 2 hours, or BiPAP followed by Vaptherm. A variable washout period was instituted between interventions. The primary end point was change in numeric rating scale before and after each intervention. We planned to enroll 50 patients in total. Results: Among the 803 patients screened over the last 8 months, 62 (26%) were eligible, and 16 (2%) were enrolled so far. Five patients completed the entire study successfully, 4 discontinued the study prematurely due to prolonged relief of dyspnea, and 7 dropped out for various reasons, including inability to tolerate BiPAP (N=3), anxiety (N=2), fatigue (N=1) and pain requiring opioids (N=1). The median baseline numeric rating score for dyspnea was 7/10 (interquartile range (IQR) 5-8), and the median baseline Borg score was 4/10 (3-7). Interim analysis revealed that BiPAP was associated with a median change in numeric rating score of -3 (N=10, IQR -6.3 to -1, p=0.007) and modified Borg score of -1 (N=10, IQR -3 to 0.3, p=0.058), while Vapotherm was associated with a median change in numeric rating score of -2 (N=9, IQR -3 to -1, p=0.011) and modified Borg score of -2.5 (N=8, IQR -5.5 to -0.1, p=0.051). Among the 5 individuals who completed the entire study, 2 preferred Vapotherm, 2 favored BiPAP, and 1 liked both. The respiratory rate decreased and the oxygen saturation improved with both interventions. No significant toxicities were observed. Conclusions: We were successfully able to enroll patients onto this clinic trial. Our preliminary results suggest that BiPAP and Vapotherm are highly efficacious in providing relief for patients with persistent refractory dyspnea. A direct comparison of the two interventions will be done upon study completion. Further research is necessary to confirm our findings.

The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia.

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT(1)-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.

Devices in heart failure: potential methods for device-based monitoring of congestive heart failure.

Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and therapeutic refractoriness, that have an impact on outcomes. The onset of such conditions is sometimes heralded by subtle pathophysiologic changes, and the timely identification of these changes may promote the use of preventive measures. Consequently, device-based methods could in the future have an important role in the timely identification of the subtle pathophysiologic changes associated with congestive heart failure.

Development of automated image analysis tools for verification of radiotherapy field accuracy with an electronic portal imaging device

The successful management of cancer with radiation relies on the accurate deposition of a prescribed dose to a prescribed anatomical volume within the patient. Treatment set-up errors are inevitable because the alignment of field shaping devices with the patient must be repeated daily up to eighty times during the course of a fractionated radiotherapy treatment. With the invention of electronic portal imaging devices (EPIDs), patient's portal images can be visualized daily in real-time after only a small fraction of the radiation dose has been delivered to each treatment field. However, the accuracy of human visual evaluation of low-contrast portal images has been found to be inadequate. The goal of this research is to develop automated image analysis tools to detect both treatment field shape errors and patient anatomy placement errors with an EPID. A moments method has been developed to align treatment field images to compensate for lack of repositioning precision of the image detector. A figure of merit has also been established to verify the shape and rotation of the treatment fields. Following proper alignment of treatment field boundaries, a cross-correlation method has been developed to detect shifts of the patient's anatomy relative to the treatment field boundary. Phantom studies showed that the moments method aligned the radiation fields to within 0.5mm of translation and 0.5$\sp\circ$ of rotation and that the cross-correlation method aligned anatomical structures inside the radiation field to within 1 mm of translation and 1$\sp\circ$ of rotation. A new procedure of generating and using digitally reconstructed radiographs (DRRs) at megavoltage energies as reference images was also investigated. The procedure allowed a direct comparison between a designed treatment portal and the actual patient setup positions detected by an EPID. Phantom studies confirmed the feasibility of the methodology. Both the moments method and the cross-correlation technique were implemented within an experimental radiotherapy picture archival and communication system (RT-PACS) and were used clinically to evaluate the setup variability of two groups of cancer patients treated with and without an alpha-cradle immobilization aid. The tools developed in this project have proven to be very effective and have played an important role in detecting patient alignment errors and field-shape errors in treatment fields formed by a multileaf collimator (MLC). ^

Managing the risks of medical technology: Do hazard surveillance systems provide an early warning of medical device problems?

The Food and Drug Administration (FDA) is responsible for risk assessment and risk management in the post-market surveillance of the U.S. medical device industry. One of the FDA regulatory mechanisms, the Medical Device Reporting System (MDR) is an adverse event reporting system intended to provide the FDA with advance warning of device problems. It includes voluntary reporting for individuals, and mandatory reporting for device manufacturers. ^ In a study of alleged breast implant safety problems, this research examines the organizational processes by which the FDA gathers data on adverse events and uses adverse event reporting systems to assess and manage risk. The research reviews the literature on problem recognition, risk perception, and organizational learning to understand the influence highly publicized events may have on adverse event reporting. Understanding the influence of an environmental factor, such as publicity, on adverse event reporting can provide insight into the question of whether the FDA's adverse event reporting system operates as an early warning system for medical device problems. ^ The research focuses on two main questions. The first question addresses the relationship between publicity and the voluntary and mandatory reporting of adverse events. The second question examines whether government agencies make use of these adverse event reports. ^ Using quantitative and qualitative methods, a longitudinal study was conducted of the number and content of adverse event reports regarding breast implants filed with the FDA's medical device reporting system during 1985–1991. To assess variation in publicity over time, the print media were analyzed to identify articles related to breast implant failures. ^ The exploratory findings suggest that an increase in media activity is related to an increase in voluntary reporting, especially following periods of intense media coverage of the FDA. However, a similar relationship was not found between media activity and manufacturers' mandatory adverse event reporting. A review of government committee and agency reports on the FDA published during 1976–1996 produced little evidence to suggest that publicity or MDR information contributed to problem recognition, agenda setting, or the formulation of policy recommendations. ^ The research findings suggest that the reporting of breast implant problems to FDA may reflect the perceptions and concerns of the reporting groups, a barometer of the volume and content of media attention. ^

Barriers and facilitators to nurses' acceptance of and implications for injury rates of an IV catheter safety device

This study has the purpose of determining the barriers and facilitators to nurses' acceptance of the Johnson and Johnson Protectiv®* Plus IV catheter safety needle device and implications for needlestick injuries at St. Luke's Episcopal Hospital, Houston, Texas. A one-time cross-sectional survey of 620 responding nurses was conducted by this researcher during December, 2000. The study objectives were to: (1) describe the perceived (a) organizational and individual barriers and facilitators and (b) acceptance of implementation of the IV catheter device; (2) examine the relative importance of these predictors; (3) describe (a) perceived changes in needlestick injuries after implementation of the device; (b) the reported incidence of injuries; and (c) the extent of underreporting by nurses; and (4) examine the relative importance of (a) the preceding predictors and (b) acceptance of the device in predicting perceived changes in needlestick injuries. Safety climate and training were evaluated as organizational factors. Individual factors evaluated were experience with the device, including time using it and frequency of use, and background information, including nursing unit, and length of time as a nurse in this hospital and in total nursing career. The conceptual framework was based upon the safety climate model. Descriptive statistics and multiple and logistic regression were utilized to address the study objectives. ^ The findings showed widespread acceptance of the device and a strong perception that it reduced the number of needlesticks. Acceptance was notably predicted by adequate training, appropriate time between training and device use, solid safety climate, and short length of service, in that order. A barrier to acceptance was nurses' longtime of use of previous needle technologies. Over four-fifths of nurses were compliant in always using the device. Compliance had two facilitators: length of time using device and, to a lesser extent, safety climate. Rates of compliance tended to be lower among nurses in units in which the device was frequently used. ^ High quality training and an atmosphere of caring about nurse safety stand out as primary facilitators that other institutions would need to adopt in order to achieve maximum success in implementing safety programs involving utilization of new safety devices. ^

An examination of the relationship between maternal and neighborhood-level characteristics and intrauterine growth retardation in Harris County, Texas, 1999--2001

The persistence of low birth weight and intrauterine growth retardation (IUGR) in the United States has puzzled researchers for decades. Much of the work that has been conducted on adverse birth outcomes has focused on low birth weight in general and not on IUGR. Studies that have examined IUGR specifically thus far have focused primarily on individual-level maternal risk factors. These risk factors have only been able to explain a small portion of the variance in IUGR. Therefore, recent work has begun to focus on community-level risk factors in addition to the individual-level maternal characteristics. This study uses Social Ecology to examine the relationship of individual and community-level risk factors and IUGR. Logistic regression was used to establish an individual-level model based on 155, 856 births recorded in Harris County, TX during 1999-2001. IUGR was characterized using a fetal growth ratio method with race/ethnic and sex specific mean birth weights calculated from national vital records. The spatial distributions of 114,460 birth records spatially located within the City of Houston were examined using choropleth, probability and density maps. Census tracts with higher than expected rates of IUGR and high levels of neighborhood disadvantage were highlighted. Neighborhood disadvantage was constructed using socioeconomic variables from the 2000 U.S. Census. Factor analysis was used to create a unified single measure. Lastly, a random coefficients model was used to examine the relationship between varying levels of community disadvantage, given the set of individual-level risk factors for 152,997 birth records spatially located within Harris County, TX. Neighborhood disadvantage was measured using three different indices adapted from previous work. The findings show that pregnancy-induced hypertension, previous preterm infant, tobacco use and insufficient weight gain have the highest association with IUGR. Neighborhood disadvantage only slightly further increases the risk of IUGR (OR 1.12 to 1.23). Although community level disadvantage only helped to explain a small proportion of the variance of IUGR, it did have a significant impact. This finding suggests that community level risk factors should be included in future work with IUGR and that more work needs to be conducted. ^

Contraceptive use in women by body mass index categories

The prevalence of obesity has increased sharply in the United States since the mid 1970's. Obese women who become pregnant are at increased risk of pregnancy complications for both mother and fetus. This study assessed whether women in higher body mass index (BMI) categories engage in the preventive behaviors of contraception more frequently than normal weight women. It also evaluated the type of contraception used by both obese and normal weight women. The study used cross-sectional data from 7 states participating in the Family Planning Module of the 2006 Behavioral Risk Factor Surveillance System (BRFSS). The Behavioral Risk Factor Surveillance System survey is an annual random digit dialed telephone survey of the non-institutionalized civilian population aged 18 years and older. The Family Planning Module was administered by Arizona, Kentucky, Minnesota, Missouri, Montana, Oregon, and Wisconsin. Of the 4,757 women who participated in the Family Planning Module, 2,244 (53.2%) were normal weight, 1,202 (25.6%) were overweight, and 1,072 (21.2%) were obese. The majority of these women 4,115 (86.2%) reported using some type of contraception to prevent pregnancy. Six hundred forty two women (13.8%) stated they did not use any type of contraception to prevent pregnancy. Within body mass index categories, 14% of normal weight women, 13% of overweight women, and 13.4% of obese women did not use any type of contraception. Neither the bivariate analysis nor the logistic regressions found body mass index categories to be statistically associated with contraceptive use. The relationship between body mass index categories and contraceptive method was found to be statistically significant. The predictive probability graph found that women at all levels of BMI have a lower probability of using barrier contraception methods as compared to procedural and hormonal methods. Hormonal contraception methods have the highest probability of use for women with a BMI of 15 to 25. In contrast, the probability of using procedural contraception methods is relatively flat and less than hormonal methods for BMI between 15 and 25. However, the probability of using procedural contraception increases dramatically with a BMI greater than 25. At a BMI greater than 42, women have a greater than 50% probability of using procedural contraception. Although a relationship between body mass index and contraception use was not found, contraception method was found to be associated with body mass index. The reasons why normal weight women prefer hormonal contraception while overweight/obese women are more likely to use procedural methods needs to be explored. By understanding the relationship between obesity and contraception, we can hopefully decrease unintended pregnancies and overall improve pregnancy related health outcomes. To determine if relationships between contraception use/type and body mass index exist, further research needs to be conducted on a national level. ^

Contraceptive attitudes and knowledge of female adolescents

Despite the recent decline in adolescent pregnancy rates, adolescent pregnancy continues to be a significant public health issue in the United States. The United States consistently reports the highest rate of adolescent pregnancy among developed countries. Adolescent mothers are more likely to have multiple pregnancies, to access welfare and other social services, and to be unmarried. Teen mothers are less likely to complete high school, enter college, and typically command much less earning power throughout their lifetime as compared to women who delay childbirth until later. Moreover, the United States spends approximately $9.1 billion annually on teen pregnancies. ^ Additionally disconcerting is recent data which demonstrates that the decline in teen pregnancy rates is leveling off and that the rate of adolescent pregnancy has increased for the first time since 1993. Contraceptive use is a key component to the prevention of adolescent pregnancy. Contraceptive nonuse and failure result in unintended pregnancies among adolescents. This review sought to assess the levels of knowledge and attitudes toward contraception among adolescent females.^ Levels of knowledge of contraception among adolescents are tolerable; however, there is substantial room for improvement. Misperceptions about the side effects and mechanisms of action of contraception are pervasive among this population. Adolescents who have low levels of knowledge regarding contraception tend to discontinue usage or use inconsistently. Attitudes toward contraception are greatly influenced by levels of knowledge. As a result, adolescents tend to develop more positive attitudes as misperceptions are abated. Moreover, clear disparities persist among adolescents with minority and young adolescents being at increased risk of pregnancy, poor contraceptive use, and insufficient knowledge about contraception.^ Understanding the level of knowledge of and attitudes toward contraceptives among adolescents is essential to the development of effective pregnancy prevention programs. In order to effectively reduce adolescent pregnancy, prevention initiatives must target the vulnerable populations and incorporate the necessary cultural components.^

Deployed military women: A second look at gender-specific infections

This descriptive, cross-sectional study addressed the relationship between variables of deployed military women and prevalence of gender-specific infections. The analysis of secondary data will look at the last deployment experience of 880 randomly selected U.S. military women who completed a mailed questionnaire (Deployed Female Health Practice Questionnaire (FHPQ)) in June 1998. The questionnaire contained 191 items with 80 data elements and one page for the subject's written comments. The broad categories of the questionnaire included: health practices, health promotion, disease prevention and treatment, reproduction, lifestyle management, military characteristics and demographics. The research questions are: (1) What is the prevalence of sexually transmitted diseases (STD), urinary tract infections (UTI) and vaginal infections (VI) related to demographic data, military characteristics, behavioral risk factors and health practices of military women during their last deployment? and (2) What are the differences between STD, UTI and VI related to the demographic data, military characteristics, behavioral risk factors and health practices of military women during their last deployment. The results showed that (1) STDs were found to be significantly associated with age and rank but not location of deployment or military branch; (2) UTI were found to be significantly associated with intrauterine device (IUD) use, prior UTI and type of items used for menses management, but not education or age; and (3) VI were significantly associated with age, rank and deployment location but not ethnicity or education. Although quantitative research exploring hygiene needs of deployed women continues, qualitative studies may uncover further “hidden” issues of importance. It cannot be said that the military has not made proactive changes for women, however, continued efforts to hone these changes are still encouraged. Mandatory debriefings of “seasoned” deployed women soldiers and their experiences would benefit leadership and newly deployed female soldiers with valuable “lessons learned.” Tailored hygiene education material, prevention education classes, easy access website with self-care algorithms, pre-deployment physicals, revision of military protocols for health care providers related to screening, diagnosing and treatment of gender-specific infections and process changes in military supply network of hygiene items for women are offered as recommendations. ^

Effects of congressional modernization laws on public access to innovative medical device technologies

The Federal Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid (CMS) play key roles in making Class III, medical devices available to the public, and they are required by law to meet statutory deadlines for applications under review. Historically, both agencies have failed to meet their respective statutory requirements. Since these failures affect patient access and may adversely impact public health, Congress has enacted several “modernization” laws. However, the effectiveness of these modernization laws has not been adequately studied or established for Class III medical devices. ^ The aim of this research study was, therefore, to analyze how these modernization laws may have affected public access to medical devices. Two questions were addressed: (1) How have the FDA modernization laws affected the time to approval for medical device premarket approval applications (PMAs)? (2) How has the CMS modernization law affected the time to approval for national coverage decisions (NCDs)? The data for this research study were collected from publicly available databases for the period January 1, 1995, through December 31, 2008. These dates were selected to ensure that a sufficient period of time was captured to measure pre- and post-modernization effects on time to approval. All records containing original PMAs were obtained from the FDA database, and all records containing NCDs were obtained from the CMS database. Source documents, including FDA premarket approval letters and CMS national coverage decision memoranda, were reviewed to obtain additional data not found in the search results. Analyses were conducted to determine the effects of the pre- and post-modernization laws on time to approval. Secondary analyses of FDA subcategories were conducted to uncover any causal factors that might explain differences in time to approval and to compare with the primary trends. The primary analysis showed that the FDA modernization laws of 1997 and 2002 initially reduced PMA time to approval; after the 2002 modernization law, the time to approval began increasing and continued to increase through December 2008. The non-combined, subcategory approval trends were similar to the primary analysis trends. The combined, subcategory analysis showed no clear trends with the exception of non-implantable devices, for which time to approval trended down after 1997. The CMS modernization law of 2003 reduced NCD time to approval, a trend that continued through December 2008. This study also showed that approximately 86% of PMA devices do not receive NCDs. ^ As a result of this research study, recommendations are offered to help resolve statutory non-compliance and access issues, as follows: (1) Authorities should examine underlying causal factors for the observed trends; (2) Process improvements should be made to better coordinate FDA and CMS activities to include sharing data, reducing duplication, and establishing clear criteria for “safe and effective” and “reasonable and necessary”; (3) A common identifier should be established to allow tracking and trending of applications between FDA and CMS databases; (4) Statutory requirements may need to be revised; and (5) An investigation should be undertaken to determine why NCDs are not issued for the majority of PMAs. Any process improvements should be made without creating additional safety risks and adversely impacting public health. Finally, additional studies are needed to fully characterize and better understand the trends identified in this research study.^

A CASE-CONTROL STUDY OF RISK FACTORS FOR ECTOPIC PREGNANCY (ROCHESTER, MINNESOTA, OBSTETRICS)

A population-based case-control study of risk factors for ectopic pregnancy has been conducted. The investigation includes 274 cases diagnosed in Rochester, Minnesota residents from 1935 through 1982, and 548 matched controls selected from live birth deliveries. Risk factor information documented prior to the last index menstrual period was obtained via medical record abstract for 22 potential risk factor variables.^ Univariate matched analyses revealed nine variables with significantly elevated odds ratios (ORs). Following conditional logistic regression for matched sets, four variables remained as significant risk factors for ectopic pregnancy. These risk factors with ORs and 95% confidence intervals (Cls) were: current intrauterine device use (OR = 13.7, Cl = 1.6 - 120.6), infertility (OR = 2.6, Cl = 1.6 - 4.2), pelvic inflammatory disease (OR = 3.3, Cl = 1.6 - 6.6), and tubal surgery (OR = 4.5, Cl = 1.5 - 13.9). After adjusting for these four major risk factors, the following variables did not have statistically significant ORs: abdominal/pelvic surgery (OR = 2.0), acute appendicitis (OR = 2.0), anovulation (OR = 1.2), clomiphene citrate use during the index conception (OR = 3.5), induced abortion (OR = 2.1), in utero exposure to diethylstilbestrol (OR = 1.6), myomas (OR = 0.7), ovarian cysts (OR = 1.0), and past intrauterine device use (OR = 1.2). ^