Community policing in Providence: combating crime and fear

Now in his second year, the new Chief of Police in Providence, Rhode Island, discusses his community policing philosophy and how it is helping to reduce crime in the city.Crime prevention - Rhode Island

The WISDOM Study: breaking the deadlock in the breast cancer screening debate.

There are few medical issues that have generated as much controversy as screening for breast cancer. In science, controversy often stimulates innovation; however, the intensely divisive debate over mammographic screening has had the opposite effect and has stifled progress. The same two questions-whether it is better to screen annually or bi-annually, and whether women are best served by beginning screening at 40 or some later age-have been debated for 20 years, based on data generated three to four decades ago. The controversy has continued largely because our current approach to screening assumes all women have the same risk for the same type of breast cancer. In fact, we now know that cancers vary tremendously in terms of timing of onset, rate of growth, and probability of metastasis. In an era of personalized medicine, we have the opportunity to investigate tailored screening based on a woman's specific risk for a specific tumor type, generating new data that can inform best practices rather than to continue the rancorous debate. It is time to move from debate to wisdom by asking new questions and generating new knowledge. The WISDOM Study (Women Informed to Screen Depending On Measures of risk) is a pragmatic, adaptive, randomized clinical trial comparing a comprehensive risk-based, or personalized approach to traditional annual breast cancer screening. The multicenter trial will enroll 100,000 women, powered for a primary endpoint of non-inferiority with respect to the number of late stage cancers detected. The trial will determine whether screening based on personalized risk is as safe, less morbid, preferred by women, will facilitate prevention for those most likely to benefit, and adapt as we learn who is at risk for what kind of cancer. Funded by the Patient Centered Outcomes Research Institute, WISDOM is the product of a multi-year stakeholder engagement process that has brought together consumers, advocates, primary care physicians, specialists, policy makers, technology companies and payers to help break the deadlock in this debate and advance towards a new, dynamic approach to breast cancer screening

A case report of vanishing bile duct syndrome after exposure to pexidartinib (PLX3397) and paclitaxel.

Pexidartinib (PLX3397) is a small molecule tyrosine kinase and colony-stimulating factor-1 inhibitor with FDA breakthrough therapy designation for tenosynovial giant-cell tumor, and currently under study in several other tumor types, including breast cancer, non-Hodgkin's lymphoma, and glioblastoma. Here, we report a case of severe drug-induced liver injury requiring liver transplantation due to vanishing bile duct syndrome (VBDS) after exposure to pexidartinib in the I-SPY 2 Trial, a phase 2 multicenter randomized neoadjuvant chemotherapy trial in patients with Stage II-III breast cancer. We also review the current literature on this rare, idiosyncratic, and potentially life-threatening entity

Toma de decisión en la prevención del cáncer de mama

Breast cancer is one of the most common cancers among women and the leading cause of death in women between the ages of 45-60 in most developed countries. The efficacy of prevention options has been established and includes lifestyle modifications, chemoprevention, and prophylactic surgery. Despite the efficacy of these options, breast cancer prevention remains underused, resulting in avoidable morbidity and mortality. Here, the main barriers to effective use of breast cancer prevention are outlined and a framework to facilitate patient-centered and evidence-based breast cancer prevention decision making is presented. The framework is intended to encourage a shared decision making approach to prevention decisions, within the context of a woman’s overall health. The inclusion of effective lifestyle interventions makes this framework relevant to most women, and is not exclusive to women at increased risk of developing breast cancer.El cáncer de mama es uno de los canceres más comunes y la causa principal de muerte entre las mujeres de las edades de 45 a 60 en la mayoría de los países desarrollados. La eficacia de las opciones preventivas están bien determinadas e incluyen modificaciones en el estilo de vida, quimioprevención y cirugía profiláctica. A pesar de la eficacia de estas opciones, los medios preventivos están infrautilizados, con resultados de morbilidad y mortalidad que podrían evitarse. En el presente trabajo, se exponen las barreras principales del uso efectivo de los medios de prevención del cáncer de mama y se presenta un encuadre para tomar decisiones en la prevención del cáncer de mama centradas en el paciente y basado en datos acerca de su eficacia. Este encuadre se propone para estimular una aproximación a la toma de decisiones compartida en el contexto de la salud global de la mujer. La inclusión de intervenciones efectivas sobre el estilo de vida hace que este encuadre sea relevante para la mayor parte de las mujeres y no sea exclusivo de las que tengan alto riesgo de cáncer de mama

Estimation of ascertainment bias and its effect on power in clinical trials with time-to-event outcomes

While the gold standard for clinical trials is to blind all parties -- participants, researchers, and evaluators -- to treatment assignment, this is not always a possibility. When some or all of the above individuals know the treatment assignment, this leaves the study open to the introduction of post-randomization biases. In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial, we were presented with the potential for the unblinded clinicians administering the treatment, as well as the individuals enrolled in the study, to introduce ascertainment bias into some but not all events comprising the primary outcome. In this manuscript, we present ways to estimate the ascertainment bias for a time-to-event outcome, and discuss its impact on the overall power of a trial versus changing of the outcome definition to a more stringent unbiased definition that restricts attention to measurements less subject to potentially differential assessment. We found that for the majority of situations, it is better to revise the definition to a more stringent definition, as was done in STRIDE, even though fewer events may be observed.Comment: 31 pages, 11 figures; submitted to Statistics in Medicin

Success rates of re-excision after positive margins for invasive lobular carcinoma of the breast.

Rates of positive margins after surgical resection of invasive lobular carcinoma (ILC) are high (ranging from 18 to 60%), yet the efficacy of re-excision lumpReceptor subtypeectomy for clearing positive margins is unknown. Concerns about the diffuse nature of ILC may drive increased rates of completion mastectomy to treat positive margins, thus lowering breast conservation rates. We therefore determined the success rate of re-excision lumpectomy in women with ILC and positive margins after surgical resection. We identified 314 cases of stage I-III ILC treated with breast conserving surgery (BCS) at the University of California, San Francisco. Surgical procedures, pathology reports, and outcomes were analyzed using univariate and multivariate statistics and Cox-proportional hazards models. We evaluated outcomes before and after the year 2014, when new margin management consensus guidelines were published. Positive initial margins occurred in 118 (37.6%) cases. Of these, 62 (52.5%) underwent re-excision lumpectomy, which cleared the margin in 74.2%. On multivariate analysis, node negativity was significantly associated with successful re-excision (odds ratio [OR] 3.99, 95% CI 1.15-13.81, p = 0.029). After 2014, we saw fewer initial positive margins (42.7% versus 25.5%, p = 0.009), second surgeries (54.6% versus 20.2%, p < 0.001), and completion mastectomies (27.7% versus 4.5%, p < 0.001). In this large cohort of women with ILC, re-excision lumpectomy was highly successful at clearing positive margins. Additionally, positive margins and completion mastectomy rates significantly decreased over time. These findings highlight improvements in management of ILC, and suggest that completion mastectomy may not be required for those with positive margins after initial BCS

The use of multiple imputation in molecular epidemiologic studies assessing interaction effects

Background: In molecular epidemiologic studies biospecimen data are collected on only a proportion of subjects eligible for study. This leads to a missing data problem. Missing data methods, however, are not typically incorporated into analyses. Instead, complete-case (CC) analyses are performed, which result in biased and inefficient estimates. Methods: Through simulations, we characterized the bias that results from CC methods when interaction effects are estimated, as this is a major aim of many molecular epidemiologic studies. We also investigated whether standard multiple imputation (MI) could improve estimation over CC methods when the data are not missing at random (NMAR) and auxiliary information may or may not exist. Results: CC analyses were shown to result in considerable bias while MI reduced bias and increased efficiency over CC methods under specific conditions. It improved estimation even with minimal auxiliary information, except when extreme values of the covariate were more likely to be missing. In a real study, MI estimates of interaction effects were attenuated relative to those from a CC approach. Conclusions: Our findings suggest the importance of incorporating missing data methods into the analysis. If the data are MAR, standard MI is a reasonable method. Under NMAR we recommend MI as a tool to improve performance over CC when strong auxiliary data are available. MI, with the missing data mechanism specified, is another alternative when the data are NMAR. In all cases, it is recommended to take advantage of MI’s ability to account for the uncertainty of these assumptions

Tamoxifen may prevent both ER+ and ER- breast cancers and select for ER- carcinogenesis: an alternative hypothesis

Introduction: Breast Cancer Prevention Trial (BCPT) and Multiple Outcomes of Raloxifene (MORE) data have been interpreted to indicate that tamoxifen reduces the risk of ER+ but not ER- breast carcinogenesis. We explored whether these data also support an alternative hypothesis, that tamoxifen influences the natural history of both ER+ and ER- cancers, that it may be equally effective in abrogating or delaying ER- and ER+ carcinogenesis, and place selection pressure, in some cases, for the outgrowth of ER- cancers. Methods: BCPT and MORE data were used to investigate whether: first, tamoxifen could reduce equally the emergence of ER- and ER+ tumors; and second, tamoxifen could select a fraction of emerging ER+ cancers and promote their transformation to ER- cancers. Assuming that some proportion, Z, of ER+ tumors becomes ER- after tamoxifen exposure and that the risk reduction for both ER- and ER+ tumors is equal, we solved for both the transformation rate and the risk reduction rate. Results: If tamoxifen equally reduces the incidence of ER+ and ER- tumors by 60%, the BCPT results are achieved with a transformation of approximately Z = 20% of ER+ to ER- tumors. Validation with MORE data using an equal risk reduction of 60% associated with tamoxifen produces an almost identical transformation rate Z of 23%. Conclusion: Data support an alternative hypothesis that tamoxifen may promote ER- carcinogenesis from a precursor lesion that would otherwise have developed as ER+ without tamoxifen selection

Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol.

Dedicated breast positron emission tomography (dbPET) is an emerging technology with high sensitivity and spatial resolution that enables detection of sub-centimeter lesions and depiction of intratumoral heterogeneity. In this study, we report our initial experience with dbPET using [F-18]fluoroestradiol (FES) in assessing ER+ primary breast cancers. Six patients with >90% ER+ and HER2- breast cancers were imaged with dbPET and breast MRI. Two patients had ILC, three had IDC, and one had an unknown primary tumor. One ILC patient was treated with letrozole, and another patient with IDC was treated with neoadjuvant chemotherapy without endocrine treatment. In this small cohort, we observed FES uptake in ER+ primary breast tumors with specificity to ER demonstrated in a case with tamoxifen blockade. FES uptake in ILC had a diffused pattern compared to the distinct circumscribed pattern in IDC. In evaluating treatment response, the reduction of SUVmax was observed with residual disease in an ILC patient treated with letrozole, and an IDC patient treated with chemotherapy. Future study is critical to understand the change in FES SUVmax after endocrine therapy and to consider other tracer uptake metrics with SUVmax to describe ER-rich breast cancer. Limitations include variations of FES uptake in different ER+ breast cancer diseases and exclusion of posterior tissues and axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. Further development to improve the field of view and studies with a larger cohort of ER+ breast cancer patients are warranted

The handling of missing data in molecular epidemiologic studies

Background: Molecular epidemiologic studies face a missing data problem as biospecimen data are often collected on only a proportion of subjects eligible for study. Methods: We investigated all molecular epidemiologic studies published in CEBP in 2009 to characterize the prevalence of missing data and to elucidate how the issue was addressed. We considered multiple imputation (MI), a missing data technique that is readily available and easy to implement, as a possible solution. Results: While the majority of studies had missing data, only 16% compared subjects with and without missing data. Furthermore, 95% of the studies with missing data performed a complete-case (CC) analysis, a method known to yield biased and inefficient estimates. Conclusions: Missing data methods are not customarily being incorporated into the analyses of molecular epidemiologic studies. Barriers may include a lack of awareness that missing data exists, particularly when availability of data is part of the inclusion criteria; the need for specialized software; and a perception that the CC approach is the gold standard. Standard MI is a reasonable solution that is valid when the data are missing at random (MAR). If the data are not missing at random (NMAR) we recommend MI over CC when strong auxiliary data are available. MI, with the missing data mechanism specified, is another alternative when the data are NMAR. In all cases, it is recommended to take advantage of MI’s ability to account for the uncertainty of these assumptions. Impact: Missing data methods are underutilized, which can deleteriously affect the interpretation of results