Laura E.G. Warren

The Impact of Radiation Therapy on the Risk of Lymphedema After Treatment for Breast Cancer: A Prospective Cohort Study

PURPOSE/OBJECTIVE Lymphedema after breast cancer treatment can be an irreversible condition with a negative impact on quality of life. The goal of this study was to identify radiation therapy-related risk factors for lymphedema. METHODS AND MATERIALS From 2005 to 2012, we prospectively performed arm volume measurements on 1476 breast cancer patients at our institution using a Perometer. Treating each breast individually, 1099 of 1501 patients (73%) received radiation therapy. Arm measurements were performed preoperatively and postoperatively. Lymphedema was defined as ≥10% arm volume increase occurring >3 months postoperatively. Univariate and multivariate Cox proportional hazard models were used to evaluate risk factors for lymphedema. RESULTS At a median follow-up time of 25.4 months (range, 3.4-82.6 months), the 2-year cumulative incidence of lymphedema was 6.8%. Cumulative incidence by radiation therapy type was as follows: 3.0% no radiation therapy, 3.1% breast or chest wall alone, 21.9% supraclavicular (SC), and 21.1% SC and posterior axillary boost (PAB). On multivariate analysis, the hazard ratio for regional lymph node radiation (RLNR) (SC ± PAB) was 1.7 (P=.025) compared with breast/chest wall radiation alone. There was no difference in lymphedema risk between SC and SC + PAB (P=.96). Other independent risk factors included early postoperative swelling (P<.0001), higher body mass index (P<.0001), greater number of lymph nodes dissected (P=.018), and axillary lymph node dissection (P=.0001). CONCLUSIONS In a large cohort of breast cancer patients prospectively screened for lymphedema, RLNR significantly increased the risk of lymphedema compared with breast/chest wall radiation alone. When considering use of RLNR, clinicians should weigh the potential benefit of RLNR for control of disease against the increased risk of lymphedema.

Brain Metastases in Newly Diagnosed Breast Cancer: A Population-Based Study.

Importance Population-based estimates of the incidence and prognosis of brain metastases at diagnosis of breast cancer are lacking. Objective To characterize the incidence proportions and median survivals of patients with breast cancer and brain metastases at the time of cancer diagnosis. Design, Setting, and Participants Patients with breast cancer and brain metastases at the time of diagnosis were identified using the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. Data were stratified by subtype, age, sex, and race. Multivariable logistic and Cox regression were performed to identify predictors of the presence of brain metastases at diagnosis and factors associated with all-cause mortality, respectively. For incidence, we identified a population-based sample of 238 726 adult patients diagnosed as having invasive breast cancer between 2010 and 2013 for whom the presence or absence of brain metastases at diagnosis was known. Patients diagnosed at autopsy or with an unknown follow-up were excluded from the survival analysis, leaving 231 684 patients in this cohort. Main Outcomes and Measures Incidence proportion and median survival of patients with brain metastases and newly diagnosed breast cancer. Results We identified 968 patients with brain metastases at the time of diagnosis of breast cancer, representing 0.41% of the entire cohort and 7.56% of the subset with metastatic disease to any site. A total of 57 were 18 to 40 years old, 423 were 41 to 60 years old, 425 were 61-80 years old, and 63 were older than 80 years. Ten were male and 958 were female. Incidence proportions were highest among patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive (1.1% among entire cohort, 11.5% among patients with metastatic disease to any distant site) and triple-negative (0.7% among entire cohort, 11.4% among patients with metastatic disease to any distant site) subtypes. Median survival among the entire cohort with brain metastases was 10.0 months. Patients with HR-positive HER2-positive subtype displayed the longest median survival (21.0 months); patients with triple-negative subtype had the shortest median survival (6.0 months). Conclusions and Relevance The findings of this study provides population-based estimates of the incidence and prognosis for patients with brain metastases at time of diagnosis of breast cancer. The findings lend support to consideration of screening imaging of the brain for patients with HER2-positive or triple-negative subtypes and extracranial metastases.

Genetic Insulin Resistance is a Potent Regulator of Gene Expression and Proliferation in Human iPS Cells

Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations.

Insulin Resistance in Human iPS Cells Reduces Mitochondrial Size and Function

Insulin resistance, a critical component of type 2 diabetes (T2D), precedes and predicts T2D onset. T2D is also associated with mitochondrial dysfunction. To define the cause-effect relationship between insulin resistance and mitochondrial dysfunction, we compared mitochondrial metabolism in induced pluripotent stem cells (iPSC) from 5 healthy individuals and 4 patients with genetic insulin resistance due to insulin receptor mutations. Insulin-resistant iPSC had increased mitochondrial number and decreased mitochondrial size. Mitochondrial oxidative function was impaired, with decreased citrate synthase activity and spare respiratory capacity. Simultaneously, expression of multiple glycolytic enzymes was decreased, while lactate production increased 80%. These perturbations were accompanied by an increase in ADP/ATP ratio and 3-fold increase in AMPK activity, indicating energetic stress. Insulin-resistant iPSC also showed reduced catalase activity and increased susceptibility to oxidative stress. Thus, insulin resistance can lead to mitochondrial dysfunction with reduced mitochondrial size, oxidative activity, and energy production.

Mini-clinical evaluation exercise as a student assessment tool in a surgery clerkship: Lessons learned from a 5-year experience

BACKGROUND The mini-clinical evaluation exercise (mini-CEX) used for clinical skill assessment in internal medicine provides in-depth assessment of single clinical encounters. The goals of this study were to determine the feasibility and value of implementation of the mini-CEX in a surgery clerkship. METHODS Retrospective review of mini-CEX evaluations collected for surgery clerkship students at our institution between 2005 and 2010. Returned assessment forms were tallied. Qualitative feedback comments were analyzed using grounded theory. Principal components analysis identified thematic clusters. Thematic comment counts were compared to those provided via global assessments. RESULTS For 124 of 137 (90.5%) students, mini-CEX score sheets were available. Thematic clusters identified comments on 8 distinct clinical skill domains. On the mini-CEX, each student received an average of 6.5 ± 2.2 qualitative feedback comments covering 4.5 ± 1.2 separate skills. Of these, 42.7% were critical. Comments provided in global evaluations were fewer (2.9 ± 0.6; P < .001), constrained in scope (0.8 ± 0.2 skills; P < .001), and rarely critical (9.1%). CONCLUSION A mini-CEX can be incorporated into a surgery clerkship. The number and breadth of feedback comments make the mini-CEX a rich assessment tool. Critical and supportive feedback comments, both highly valuable, are provided nearly equally frequently when the mini-CEX is used as an assessment tool.

Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline

INTRODUCTION The purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery. METHODS AND MATERIALS The American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. RESULTS For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized. CONCLUSIONS WBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.

Myotubes derived from human-induced pluripotent stem cells mirror in vivo insulin resistance

Significance In this manuscript, we have exploited induced pluripotent stem cells (iPS cells) to generate an in vitro model of human skeletal muscle insulin resistance using cells from patients affected by a monogenic form of insulin resistance (Donohue syndrome/leprechaunism). Following differentiation into skeletal muscle cells, these cells show dramatic defects in insulin signaling, glucose uptake, and glycogen accumulation, as well as insulin-regulated gene expression. To our knowledge, this represents the first use of human iPS cells differentiated into muscle to study diabetes and demonstrates that these cells can robustly reproduce insulin resistance in vitro. Induced pluripotent stem cells (iPS cells) represent a unique tool for the study of the pathophysiology of human disease, because these cells can be differentiated into multiple cell types in vitro and used to generate patient- and tissue-specific disease models. Given the critical role for skeletal muscle insulin resistance in whole-body glucose metabolism and type 2 diabetes, we have created a novel cellular model of human muscle insulin resistance by differentiating iPS cells from individuals with mutations in the insulin receptor (IR-Mut) into functional myotubes and characterizing their response to insulin in comparison with controls. Morphologically, IR-Mut cells differentiated normally, but had delayed expression of some muscle differentiation-related genes. Most importantly, whereas control iPS-derived myotubes exhibited in vitro responses similar to primary differentiated human myoblasts, IR-Mut myotubes demonstrated severe impairment in insulin signaling and insulin-stimulated 2-deoxyglucose uptake and glycogen synthesis. Transcriptional regulation was also perturbed in IR-Mut myotubes with reduced insulin-stimulated expression of metabolic and early growth response genes. Thus, iPS-derived myotubes from individuals with genetically determined insulin resistance demonstrate many of the defects observed in vivo in insulin-resistant skeletal muscle and provide a new model to analyze the molecular impact of muscle insulin resistance.

Management of the regional lymph nodes following breast-conservation therapy for early-stage breast cancer: an evolving paradigm.

Radiation therapy to the breast following breast conservation surgery has been the standard of care since randomized trials demonstrated equivalent survival compared to mastectomy and improved local control and survival compared to breast conservation surgery alone. Recent controversies regarding adjuvant radiation therapy have included the potential role of additional radiation to the regional lymph nodes. This review summarizes the evolution of regional nodal management focusing on 2 topics: first, the changing paradigm with regard to surgical evaluation of the axilla; second, the role for regional lymph node irradiation and optimal design of treatment fields. Contemporary data reaffirm prior studies showing that complete axillary dissection may not provide additional benefit relative to sentinel lymph node biopsy in select patient populations. Preliminary data also suggest that directed nodal radiation therapy to the supraclavicular and internal mammary lymph nodes may prove beneficial; publication of several studies are awaited to confirm these results and to help define subgroups with the greatest likelihood of benefit.

A Model of Knowledge Acquisition in Early Stage Breast Cancer Patients

Abstract:  To meaningfully participate in the decision‐making regarding a newly diagnosed breast cancer, a patient must acquire new knowledge. We describe a model of knowledge acquisition that can provide a framework for exploring the process and types of knowledge that breast cancer patients gain following their diagnosis. The four types of knowledge presented in this model—authoritative, technical, embodied, and traditional—are described and potential sources discussed. An understanding of knowledge acquisition in early stage breast cancer patients can provide healthcare practitioners with an important framework for optimizing decision‐making in this population.

Management of the Regional Lymph Nodes in Early-Stage Breast Cancer.

The management of regional nodes in early-stage invasive breast cancer continues to evolve. Improved systemic therapy has contributed to better local regional control, and at the same time it has drawn more attention to its importance. Axillary dissections have decreased, in part because of the increased efficacy of systemic therapy, and also because adjuvant therapy decisions are increasingly driven by biologic characterization of the tumor rather than pathologic nodal information. The trend toward less axillary surgery and a shift toward increased reliance on systemic and radiation therapy to address nodal disease has created interesting questions that were subsequently addressed in recent trials. We review the controversies in regional nodal management, the benefits of current treatment paradigms, the balance between less surgery and more radiation, and the potential tradeoffs vs toxicity.