Shruti Jolly

Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer

PURPOSE Cardiac toxicity is an important sequela of breast radiotherapy. However, the relationship between dose to cardiac structures and subsequent toxicity has not been well defined, partially due to variations in substructure delineation, which can lead to inconsistent dose reporting and the failure to detect potential correlations. Here we have developed a heart atlas and evaluated its effect on contour accuracy and concordance. METHODS AND MATERIALS A detailed cardiac computed tomography scan atlas was developed jointly by cardiology, cardiac radiology, and radiation oncology. Seven radiation oncologists were recruited to delineate the whole heart, left main and left anterior descending interventricular branches, and right coronary arteries on four cases before and after studying the atlas. Contour accuracy was assessed by percent overlap with gold standard atlas volumes. The concordance index was also calculated. Standard radiation fields were applied. Doses to observer-contoured cardiac structures were calculated and compared with gold standard contour doses. Pre- and post-atlas values were analyzed using a paired t test. RESULTS The cardiac atlas significantly improved contour accuracy and concordance. Percent overlap and concordance index of observer-contoured cardiac and gold standard volumes were 2.3-fold improved for all structures (p < 0.002). After application of the atlas, reported mean doses to the whole heart, left main artery, left anterior descending interventricular branch, and right coronary artery were within 0.1, 0.9, 2.6, and 0.6 Gy, respectively, of gold standard doses. CONCLUSIONS This validated University of Michigan cardiac atlas may serve as a useful tool in future studies assessing cardiac toxicity and in clinical trials which include dose volume constraints to the heart.

Gender differences in time spent on parenting and domestic responsibilities by high-achieving young physician-researchers

The traditional family unit, headed by a breadwinning husband and stay-at-home wife, now characterizes a minority of American households (1). Women have entered the workforce in large numbers over the past few decades, and family structures are considerably more varied than in the past. In families headed by a married couple, responsibility for parenting and domestic activities has been more evenly divided (2). Nevertheless, women in the general population still spend more time on parenting and housework than men (3). Scholars have noted that this may reflect rational economic calculations in the face of a market that still pays men more than women (4), or it may be driven by deeper sociocultural barriers to changes in traditional gender roles (5). In elite professions, such as medicine, where earning potential and professional demands are high and members have self-selected for career commitment by pursuing lengthy training, one may expect to observe less, if any, gender difference in time spent on domestic responsibilities. A recent study of surgeons suggested that although burnout rates were similar among men and women, women were more likely to experience workhome conflicts (6). However, little research to date has considered how highly career-driven contemporary male and female physician-researchers allocate time to professional and domestic responsibilities. Examining gender differences in the nonprofessional responsibilities of physicians is particularly important because of growing evidence that female academic physicians are still not achieving career success at the same rate as their male colleagues (710). Understanding gender differences in nonprofessional responsibilities may help to explain this gap. We investigated these issues in a survey study. To minimize variability in commitment to career and nature of work, we focused on physician-researchers who had received career development awards from the National Institutes of Health (NIH). We selected both K08 and K23 awards, which are highly selective grants made to early-career researchers who hold clinical doctorate degrees to support their career development. We focused on persons who recently received these awards to capture the experiences of Generation X because most recent K award recipients would have been raised when it was common for mothers to work outside the home. Their attitudes have been documented to be relatively egalitarian, both in general (11, 12) and specifically within the medical profession (1316). In so doing, we investigated whether gender differences exist in time allocation within a population in which differences may not be expected and, if present, would lend insights about the causes of gender differences in domestic labor more generally and relevant information for policy development specifically within the medical profession. Methods Data Collection We identified 1719 recipients of new K08 and K23 awards from 2006 to 2009 using the NIH RePORTER (Research Portfolio Online Reporting Tools Expenditures and Results) database. After approval from the institutional review board, we conducted Internet searches and telephone calls that identified valid U.S. mailing addresses for 1708 persons, to whom we mailed a questionnaire and

Adjuvant Therapies and Patient and Tumor Characteristics Associated With Survival of Adult Patients With Adrenocortical Carcinoma

50 incentive. Nonrespondents received follow-up mailings (17). We merged survey responses to data previously collected from RePORTER. Measures We designed the questionnaires after review of the relevant literature; consideration of other instruments used to determine time allocation, responsibilities, and the outcomes of academic careers (18, 19); and cognitive pretesting (20). The final questionnaire included 173 items that assessed demographics, education, time allocation, mentoring experiences, family responsibilities, career satisfaction, and work environment (Appendix Tables 1, 2, 3, and 4). Appendix Table 1. Multivariable Linear Regression Model to Explain Time Spent on Research Appendix Table 2. Multivariable Logistic Regression Model to Explain Time Spent on Teaching Greater Than the Median for Married or Partnered Respondents With Children Appendix Table 3. Frequency and Percentage of Respondents Reporting Teaching Time Greater Than 1 Hour per Week Appendix Table 4. Multivariable Linear Regression Model to Explain Time Spent on Clinical Duties for Married or Partnered Respondents With Children Time Allocation To evaluate time spent on domestic labor, we asked how many hours were spent on parenting and domestic tasks on a typical workday (including the evening) and on a typical weekend (including both days). Definitions were provided: Parenting includes meeting physical needs (such as feeding or bathing), as well as meeting psychosocial needs (such as talking or playing with children, driving them to activities and attending their recitals or sporting events). Domestic Tasks include cooking, cleaning, laundry, home maintenance, yard work, shopping for necessities, errands, finances and other such activities. A continuous variable reflecting weekly total time spent on parenting or domestic tasks was created. We also asked respondents to describe the percentage of all time spent on parenting or domestic tasks by the respondent, their spouse or domestic partner, employed help, relatives, and others. To evaluate time spent on paid labor, we asked respondents to think about their most frequent weekly working pattern and to estimate the total number of hours worked. We then asked how many of those hours were spent on patient care (including time spent rounding with trainees when a primary purpose is patient care), research, and teaching (defined as formal didactic teaching unrelated to patient care or research). Family Responsibilities We inquired whether respondents had children and, if so, asked for their childrens ages. We asked, Do your children require adult supervision or care? and gathered information on who provided that care during work hours (school, day care, family member, nanny or babysitter, spouse or domestic partner, or other). Satisfaction with child care arrangements was ascertained using a 5-point response scale. We also asked: When your children are ill, when school or institutional care is closed (such as during holidays or vacations), or when other disruptions in your usual child care arrangements occur, who usually stays with your children? Respondents selected 1 option: I usually do, My spouse or partner usually does, My spouse or partner and I usually alternate, A friend or neighbor usually does, I usually bring my children to work, A family member usually does, or Other. Additional items, using 5-point response scales, inquired, When you have after hours work (e.g., manuscript writing or grant writing, dinner meetings) to attend to, how easy is it for you to get such work done? (for which responses were dichotomized as difficult vs. so-so or easy) and, How often does child rearing and/or family responsibility currently interfere with your ability to get work-related things done? (for which responses were dichotomized as always, frequently, or sometimes vs. infrequently or never). Individual Characteristics We determined the respondents age (continuous), gender, specialty (grouped by nature into 5 categories as detailed elsewhere [9, 21]: medical [internal medicine and related subspecialties]; surgical [general surgery and surgical subspecialties]; hospital-based [for example, radiology, pathology, and anesthesiology fields]; relating to care of women, children, and families [family medicine, obstetrics and gynecology, pediatrics, and related subspecialties]; or basic sciences), PhD degree (yes or no), and spousal employment (full-time, part-time, or not employed) through self-report. Statistical Analysis We conducted statistical analyses using SAS, version 9.2 (SAS Institute, Cary, North Carolina). We compared respondents with the remainder of the initial target population for gender, K award type and year, and institution (ranked by total NIH funding) using chi-square or Fisher exact tests for categorical data and 2-sample t tests or the Wilcoxon rank-sum test for continuous data. The analytic sample was limited to persons who held MD degrees and were still affiliated with U.S. academic institutions. We described the characteristics of this sample by gender and constructed a multivariate linear regression model to explain the time spent on domestic labor. Time spent on domestic labor was assessed graphically and using other diagnostics and was found to be normally distributed. The model was restricted to the married or partnered population with children using the following theoretically selected respondent characteristics: gender, age, age of the youngest child, number of children, weekly work hours, race, spousal employment, K award type, specialty nature, and MD or MD/PhD status. Most characteristics were categorical and modeled as indicator variables with a reference category. Continuous variables were centered at their medians. We also constructed linear regression models to test for the independent associations of gender with time spent on clinical and research activities. For time spent on teaching, we constructed a logistic regression model for the odds of spending more than the median time of 1 hour on teaching, given the lack of a sufficiently normal distribution for a linear model. We constructed CIs for proportions from categorical data using the exact binomial distribution or the multinomial distribution (22). For statistical inference, we conducted 2-tailed tests and considered P values of 0.05 or less to be significant. Role of the Funding Source This work was supported by the NIH. The funding source had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Results Of the 1719 K awardees identified, 1708 were surveyed, with 1435 of those surve

Cardiac Events After Radiation Therapy: Combined Analysis of Prospective Multicenter Trials for Locally Advanced Non-Small-Cell Lung Cancer.

CONTEXT Adrenocortical carcinoma is a rare malignant endocrine neoplasia. Studies regarding outcome and prognostic factors rely on fairly small studies. Here we summarize the experience with patients with a diagnosis of adrenocortical carcinoma from a large tertiary referral center. OBJECTIVE The objective of the study was to identify prognostic factors in patients with adrenocortical carcinoma and evaluate adjuvant treatment strategies. DESIGN Patient data were collected in a retrospective single-center study. Epidemiological, patient, and tumor characteristics were analyzed for prognostic factors regarding overall and recurrence-free survival in Cox regression models (multivariable and univariable). RESULTS Three hundred ninety-one adult patients with the diagnosis of adrenocortical carcinoma were identified. Median overall survival was 35.2 months. Cortisol production [hazard ratio (HR) 1.4, HR 1.5], tumor stage (HR stage 3 of 2.1 and 2.1, HR stage 4 of 4.8), and tumor grade (HR 2.4 and 2.0) were identified as negative prognostic factors (HR for death, HR for recurrence). Mitotane therapy increases recurrence-free survival, an effect that was significantly further improved by adjuvant radiation therapy but did not impact overall survival. Patients with open adrenalectomy had improved overall survival. CONCLUSIONS This study increases the evidence for adverse risk factors (cortisol production, high tumor stage, and high tumor grade) and suggests the following therapy approach: adrenocortical carcinoma patients should be treated with open adrenalectomy. Adjuvant therapy, particularly mitotane therapy in conjunction with radiation, should be considered to delay tumor recurrence.

Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma

Purpose Radiation therapy is a critical component in the care of patients with non-small-cell lung cancer (NSCLC), yet cardiac injury after treatment is a significant concern. Therefore, we wished to elucidate the incidence of cardiac events and their relationship to radiation dose to the heart. Patients and Materials Study eligibility criteria included patients with stage II to III NSCLC treated on one of four prospective radiation therapy trials at two centers from 2004 to 2013. All cardiac events were reviewed and graded per Common Terminology Criteria for Adverse Events (v4.03). The primary end point was the development of a grade ≥ 3 cardiac event. Results In all, 125 patients met eligibility criteria; median follow-up was 51 months for surviving patients. Median prescription dose was 70 Gy, 84% received concurrent chemotherapy, and 27% had pre-existing cardiac disease. Nineteen patients had a grade ≥ 3 cardiac event at a median of 11 months (interquartile range, 6 to 24 months), and 24-month cumulative incidence was 11% (95% CI, 5% to 16%). On multivariable analysis (MVA), pre-existing cardiac disease (hazard ratio [HR], 2.96; 95% CI, 1.07 to 8.21; P = .04) and mean heart dose (HR, 1.07/Gy; 95% CI, 1.02 to 1.13/Gy; P = .01) were significantly associated with grade ≥ 3 cardiac events. Analyzed as time-dependent variables on MVA analysis, both disease progression (HR, 2.15; 95% CI, 1.54 to 3.00) and grade ≥ 3 cardiac events (HR, 1.76; 95% CI, 1.04 to 2.99) were associated with decreased overall survival. However, disease progression (n = 71) was more common than grade ≥ 3 cardiac events (n = 19). Conclusion The 24-month cumulative incidence of grade ≥ 3 cardiac events exceeded 10% among patients with locally advanced NSCLC treated with definitive radiation. Pre-existing cardiac disease and higher mean heart dose were significantly associated with higher cardiac event rates. Caution should be used with cardiac dose to minimize risk of radiation-associated injury. However, cardiac risks should be balanced against tumor control, given the unfavorable prognosis associated with disease progression.

Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: a molecular based clonality evaluation.

PURPOSE Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been established. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. METHODS AND MATERIALS We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RT at our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. RESULTS From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant differences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P=.0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However, recurrence-free survival was no different between the groups (P=.17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P=.13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group. CONCLUSIONS Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed.

Obstructive sleep apnea and fatigue in head and neck cancer patients.

Background:The clonality of ipsilateral breast tumor recurrences (IBTR) after breast-conserving therapy (BCT) was established using a polymerase chain reaction-based allelic imbalance assay of microsatellite loci to compare tumor suppressor gene alteration patterns. Methods:The clonality of IBTRs relative to the initial invasive carcinomas were analyzed using a polymerase chain reaction-based allelic imbalance assay in 57 patients treated with BCT, including both whole breast irradiation and accelerated partial breast irradiation. Results:Thirty-four IBTRs (60%) were clonally related to the initial carcinoma and 23 (40%) were clonally different. Clonally related IBTRs were more frequently higher grade (70% vs. 32%, P = 0.019) and developed sooner after initial treatment (mean time interval to IBTR was 5.1 years in clonally related versus 9.3 years in clonally different cases [P = 0.002]). Twelve patients subsequently developed distant metastases, of which 9 (75%) had clonally related IBTRs. Clinical IBTR classification and molecular clonality assay results differed in 44% of all cases. The proportion of IBTRs that were clonally related at 5, 10, and 15 years after BCT were 82%, 48%, and 33%, respectively. Conclusions:This analysis demonstrates the inaccuracy of clinically establishing the clonality of most IBTRs. Clonally related IBTRs occurred sooner than clonally different IBTRs, were more frequently associated with the development of distant metastases and had a worse prognosis. Molecular clonality assays provide a reliable means of identifying patients who may benefit from aggressive systemic therapy at the time of IBTR and provide an accurate assessment of the efficacy of various forms of local therapy.

A female pelvic bone shape model for air/bone separation in support of synthetic CT generation for radiation therapy.

There is a systematic relationship between fatigue, sleep, and decreased quality of life in cancer patients, with notably poor sleep quality among many head and neck cancer patients during and after treatment. An often overlooked cause of sleep disturbance in this patient population is obstructive sleep apnea (OSA). This review explores the current literature on the prevalence and clinical correlates of OSA, management outcomes, and data on cytokine-mediated fatigue in OSA. OSA appears to be prevalent in head and neck cancer patients, both at baseline and after treatment, especially with multimodality therapy including radiation therapy. Predictors of developing OSA include larger tumor size and hypopharynx or larynx primary site. There is evidence that the level of fatigue seen in these patients is not necessarily correlated with the severity of their OSA. Current research highlights the role of proinflammatory cytokines, which can also be synergistically activated by radiation therapy, as mediators of fatigue. Primary management of OSA consists of continuous positive airway pressure. Although continuous positive airway pressure has been shown to improve clinical symptoms, compliance with its use remains a problem and will be an area of future research.

Characterization of changes in total body composition for patients with head and neck cancer undergoing chemoradiotherapy using dual-energy x-ray absorptiometry.

Separating bone from air in MR data is one of the major challenges in using MR images to derive synthetic CT. The problem is further complicated when the anatomic regions filled with air are altered across scans due to air mobility, for instance, in pelvic regions, thereby the air regions estimated using an ultrashort echo time (UTE) sequence are invalid in other image series acquired for multispectral classification. This study aims to develop and investigate a female pelvic bone shape model to identify low intensity regions in MRI where air is unlikely to be present in support of synthetic CT generation without UTE imaging. CT scans of 30 patients were collected for the study, 17 of them also have corresponding MR scans. The shape model was built from the CT dataset, where the reference image was aligned to each of the training images using B-spline deformable registration. Principal component analysis was performed on B-spline coefficients for a compact model where shape variance was described by linear combination of principal modes. The model was applied to identify pelvic bone in MR images by deforming the corresponding MR data of the reference image to target MR images, where the search space of the deformation process was constrained within the subspace spanned by principal modes. The local minima in the search space were removed effectively by the shape model, thus supporting an efficient binary search for the optimal solution. We evaluated the model by its efficacy in identifying bone voxels and excluding air regions. The model was tested across the 17 patients that have corresponding MR scans using a leave-one-out cross validation. A simple model using the first leading principal mode only was found to achieve reasonable accuracy, where an averaged 87% of bone voxels were correctly identified. Finally dilation of the optimally fit bone mask by 5 mm was found to cover 96% of bone voxels while minimally impacting the overlap with air (below 0.4%).

Clinical review of physical activity and functional considerations in head and neck cancer patients

Patients with head and neck cancer experience significant weight loss secondary to concurrent chemoradiotherapy (CCRT). Using dual‐energy X‐ray absorptiometry (DEXA) scans, we characterize total body composition changes during and after CCRT in order to develop novel clinical care models that will improve the patients quality of life (QOL).