Risk Factors for Double Primary Breast and Ovarian Cancer in Women Across the Risk Spectrum

Advancements in medicine and technology have led to an increasing number of cancer survivors. The development of a second primary cancer is one of the most severe sequelae of a cancer diagnosis, particularly for cancers that lack an effective screening tool as with ovarian cancer. Breast and ovarian cancer are major causes of morbidity and mortality in women; in the U.S., breast cancer has the highest incidence in women and ovarian cancer is the most fatal of gynecological cancers. Further, these two cancers have been found to co-occur. Along with possible treatment effects of the first cancer, shared risk factors, shared genetics, and interactions between these two have been hypothesized to contribute to their co-occurrence. Research on shared risk factors for second cancers is lacking and being able to identify potentially modifiable factors associated with second primary cancer could improve clinical recommendations for cancer survivors. Therefore, this dissertation examined risk factors for the development of double primary breast and ovarian cancer (DPBOC) in three parts 1) a comprehensive review of the literature to identify studies assessing risk factors for DPBOC, 2) a case-control study assessing the association between three potentially-modifiable risk factors (oral contraceptive (OC) use, parity, and breastfeeding), and risk of second primary ovarian cancer following breast cancer (BR-OV), second primary breast cancer following ovarian cancer (OV-BR), single primary ovarian cancer (OV), and single primary breast cancer (BR), and 3) a cohort study assessing OC use, parity, and breastfeeding and risk of BR-OV, OV, and BR. The comprehensive review identified few studies assessing epidemiologic risk factors for the development of DPBOC and most of the findings were not statistically significant. The majority of studies focused on treatment of breast cancer and risk of second primary ovarian cancer. While most of the findings on chemotherapy, radiotherapy, and Tamoxifen were heterogeneous and lacked statistical significance, hormone therapy for breast cancer may be associated with an increased risk of second primary ovarian cancer. The majority of studies on genetic risk factors for DPBOC looked at BRCA1/2 mutations or a crude measure of family history. Both BRCA1/2 and family history were consistently associated with risk of DPBOC, but studies varied on the extent of this risk due to differences in study design, exposure and outcome definition, and statistical power. No studies were identified examining DNA methylation and risk of DPBOC. The case-control study used data from the three clinic-based sites of the Breast Cancer Family Registry (BCFR) which consisted of women from breast and ovarian cancer families. We observed an inverse association with both OC use (OR=0.38, 95% CI: 0.22, 0.60) and breastfeeding (OR=0.52, 95% CI: 0.31, 0.87) and risk of DPBOC, but a positive association with parity (≥2 full-term pregnancies: OR=5.78, 95% CI: 2.82, 14.58), regardless of diagnosis order (BR-OV or OV-BR). We found similar associations for our OV and BR outcomes as well. When we examined differences between high and average risk women (using BRCA1/2 mutation status and predicted lifetime risk of breast or ovarian cancer), the inverse association with OC use only remained in women at average risk while the inverse association with breastfeeding only remained in women at high risk. As the positive association with parity and all of our outcomes disagreed with our hypothesis we conducted several sensitivity analyses to explore this finding. Survivor bias may have influenced our results as we observed differences in our findings between cases diagnosed ≤2 or ≤5 years before the baseline interview (pseudo-incident) and cases diagnosed >2 or >5 years before the baseline interview (prevalent). Specifically, the inverse association with OC use and all of our outcomes, and the positive association with parity and all of our outcomes were attenuated in the pseudo-incident group. To address concerns of selection and information bias in our case-control study, we conducted a cohort study using data from The Breast Cancer Prospective Family Study Cohort (ProF-SC). In contrast to our case-control findings, we observed a suggestive positive association between OC use and risk of BR-OV (HR=1.62, 95% CI: 0.91, 2.90) which became stronger in women at high risk, and an inverse association between having two or more full-term pregnancies compared to nulliparous and risk of BR-OV (HR=0.47, 95% CI: 0.22, 0.97) which did not vary by underlying risk of breast and ovarian cancer. However, our BR-OV results may have similarly been influenced by survivor bias as we observed differences in our results between our pseudo-incident and prevalent BR-OV cases; the association between OC use and BR-OV only remained in the prevalent cases. In summary, the results of this dissertation highlight the methodological challenges in the study of second primary cancers and the importance of considering survivor bias in a cohort of cancer survivors being followed for second cancers. Further, our results are suggestive of a discordant effect of OC use on first primary versus second primary ovarian cancer which should be explored in future studies

“Even the Little Things Matter:” a Phenomenological Study On Factors Impacting Student Motivation During and After COVID-Related Disruptions in Education

The COVID-19 pandemic brought about unprecedented disruptions in education, as schools were forced to make a rapid transition to virtual learning in March 2020. Students’ motivation seemed to decline significantly during and after this virtual learning period, which ranged from months to over a year in various areas of the United States. This study seeks to understand the factors impacting student motivation during and after this virtual learning period. This action research study was conducted using a qualitative, phenomenological approach. Data was collected from open-ended surveys and semi-structured interviews during Spring 2021 and Spring 2022. Data was analyzed through the lenses of self-determination theory (SDT), sociocultural theory (SCT), and social contagion theory. This study found that major factors impacting student motivation stayed relatively consistent between the 2020-21 and 2021-22 school years. The most critical factors impacting student motivation were relationships, a sense of helplessness resulting from pandemic-related educational disruptions, and a desire for structure and consistency. Implications of this study suggest that many factors impacting student motivation are in the scope of teachers’ control. This study also has implications for the emerging body of scholarship on change and continuity in student motivation during and after pandemic-related educational disruptions

Using experience-based design to understand the patient and caregiver experience with delirium

Hospital-acquired delirium negatively affects clinical outcomes and the care experience for patients and family caregivers. Following the qualitative methods of experience-based design, we completed observations of hospital units and interviews of patients, caregivers (including family members and other companions), and hospital nurses and other staff regarding their experiences with delirium. In addition, we administered an experience-based design questionnaire to another 130 subjects from the same groups. Key findings included: there is a need for preparation of the patients and family caregivers for the possibility of delirium (particularly before surgery), and patients and caregivers lack understanding of delirium and its potential prolonged aftereffects. We identified that caregivers may both contribute and detract from delirium care as they: (1) often identify delirium early; (2) are invaluable for supporting patients during re-orientation after delirium episodes; (3) frequently lack the preparation and skills for adequate delirium detection and response; (4) may not be present at critical times; (5) can be challenging for the delirium management team, and (6) are frequently discussed as the person who best understands the patients’ baseline cognitive state and behavior. Experience-based design is an innovative framework to increase our qualitative understanding of the patient and caregiver experience during and following episodes of hospital acquired delirium

A Review of Transcranial Magnetic Stimulation and Multimodal Neuroimaging to Characterize Post-Stroke Neuroplasticity

Following stroke, the brain undergoes various stages of recovery where the central nervous system can reorganize neural circuitry (neuroplasticity) both spontaneously and with the aid of behavioral rehabilitation and non-invasive brain stimulation. Multiple neuroimaging techniques can characterize common structural and functional stroke-related deficits, and importantly, help predict recovery of function. Diffusion tensor imaging (DTI) typically reveals increased overall diffusivity throughout the brain following stroke, and is capable of indexing the extent of white matter damage. Magnetic resonance spectroscopy (MRS) provides an index of metabolic changes in surviving neural tissue after stroke, serving as a marker of brain function. The neural correlates of altered brain activity after stroke have been demonstrated by abnormal activation of sensorimotor cortices during task performance, and at rest, using functional magnetic resonance imaging (fMRI). Electroencephalography (EEG) has been used to characterize motor dysfunction in terms of increased cortical amplitude in the sensorimotor regions when performing upper limb movement, indicating abnormally increased cognitive effort and planning in individuals with stroke. Transcranial magnetic stimulation (TMS) work reveals changes in ipsilesional and contralesional cortical excitability in the sensorimotor cortices. The severity of motor deficits indexed using TMS has been linked to the magnitude of activity imbalance between the sensorimotor cortices. In this paper, we will provide a narrative review of data from studies utilizing DTI, MRS, fMRI, EEG, and brain stimulation techniques focusing on TMS and its combination with uni- and multimodal neuroimaging methods to assess recovery after stroke. Approaches that delineate the best measures with which to predict or positively alter outcomes will be highlighted

Coastal Ice-Core Record of Recent Northwest Greenland Temperature and Sea-Ice Concentration

Coastal ice cores provide an opportunity to investigate regional climate and sea-ice variability in the past to complement hemispheric-scale climate reconstructions from ice-sheet-interior ice cores. Here we describe robust proxies of Baffin Bay temperature and sea-ice concentration from the coastal 2Barrel ice core collected in the Thule region of northwest Greenland. Over the 1990–2010 record, 2Barrel annually averaged methanesulfonic acid (MSA) concentrations are significantly correlated with May–June Baffin Bay sea-ice concentrations and summer temperatures. Higher MSA is observed during warmer years with less sea ice, indicative of enhanced primary productivity in Baffin Bay. Similarly, 2Barrel annually averaged deuterium excess (d-excess) values are significantly correlated with annual Baffin Bay sea-ice concentrations and summer and annual temperatures. Warm (cool) years with anomalously low (high) sea-ice concentration are associated with proportionally more (less) low-d-excess Baffin Bay moisture at the ice-core site. Multilinear regression models incorporating 2Barrel MSA, d-excess and snow accumulation account for 38–51% of the Baffin Bay sea-ice and temperature variance. The annual temperature model is significantly correlated with temperatures throughout most of Greenland and eastern Arctic Canada due to the strong influence of the North Atlantic Oscillation and Atlantic Multidecadal Oscillation

Analysis of the Brinkman-Forchheimer equations with slip boundary conditions

In this work, we study the Brinkman-Forchheimer equations driven under slip boundary conditions of friction type. We prove the existence and uniqueness of weak solutions by means of regularization combined with the Faedo-Galerkin approach. Next we discuss the continuity of the solution with respect to Brinkman's and Forchheimer's coefficients. Finally, we show that the weak solution of the corresponding stationary problem is stable

Women’s responses to changes in U.S. preventive task force’s mammography screening guidelines: results of focus groups with ethnically diverse women

Background: The 2009 U.S. Preventive Services Task Force (USPSTF) changed mammography guidelines to recommend routine biennial screening starting at age 50. This study describes women’s awareness of, attitudes toward, and intention to comply with these new guidelines. Methods: Women ages 40–50 years old were recruited from the Boston area to participate in focus groups (k = 8; n = 77). Groups were segmented by race/ethnicity (Caucasian = 39%; African American = 35%; Latina = 26%), audio-taped, and transcribed. Thematic content analysis was used. Results: Participants were largely unaware of the revised guidelines and suspicious that it was a cost-savings measure by insurers and/or providers. Most did not intend to comply with the change, viewing screening as obligatory. Few felt prepared to participate in shared decision-making or advocate for their preferences with respect to screening. Conclusions: Communication about the rationale for mammography guideline changes has left many women unconvinced about potential disadvantages or limitations of screening. Since further guideline changes are likely to occur with advances in technology and science, it is important to help women become informed consumers of health information and active participants in shared decision-making with providers. Additional research is needed to determine the impact of the USPSTF change on women’s screening behaviors and on breast cancer outcomes

Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions

Purpose: Intratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor. Experimental Design: Cal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of 18F-fluorodeoxyglucose (18F-FDG) uptake in clinical PET scans. Results: IR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous 18F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors. Conclusion: Hypoxia is associated with increased intratumoral metabolic heterogeneity. 18F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis. © 2014 Nakajima et al

Obesity Is A Modifier of Autonomic Cardiac Responses to Fine Metal Particulates

Background: Increasing evidence suggests that obesity may impart greater susceptibility to adverse effects of air pollution. Particulate matter, especially PM$_{2.5}$ (particulate matter with aero-dynamic diameter ≤2.5 μm), is associated with increased cardiac events and reduction of heart rate variability (HRV).Objectives Our goal was to investigate whether particle-mediated autonomic modulation is aggravated in obese individuals.Methods We examined PM$_{2.5}$-mediated acute effects on HRV and heart rate (HR) using 10 24-hr and 13 48-hr ambulatory electrocardiogram recordings collected from 18 boilermakers (39.5 ± 9.1 years of age) exposed to high levels of metal particulates. Average HR and 5-min HRV [SDNN: standard deviation of normal-to-normal intervals (NN); rMSSD: square-root of mean squared-differences of successive NN intervals; HF: high-frequency power 0.15–0.4 Hz] and personal PM$_{2.5}$ exposures were continuously monitored. Subjects with body mass index ≥ 30 kg/m$^2$ were classified as obese. Mixed-effect models were used for statistical analyses. Results: Half (50%) of the study subjects were obese. After adjustment for confounders, each 1-mg/m$^3$ increase in 4-hr moving average PM$_{2.5}$ was associated with HR increase of 5.9 bpm [95% confidence interval (CI), 4.2 to 7.7] and with 5-min HRV reduction by 6.5% (95% CI, 1.9 to 11.3%) for SDNN, 1.7% (95% CI, –4.9 to 8.4%) for rMSSD, and 8.8% (95% CI, –3.8 to 21.3%) for HF. Obese individuals had greater PM$_{2.5}$-mediated HRV reductions (2- to 3-fold differences) than nonobese individuals, and had more PM$_{2.5}$-mediated HR increases (9-bpm vs. 4-bpm increase in HR for each 1-mg/m$^3$ increase in PM$_{2.5}$; p < 0.001). Conclusions: Our study revealed greater autonomic cardiac responses to metal particulates in obese workers, supporting the hypothesis that obesity may impart greater susceptibility to acute cardiovascular effects of fine particles