Promoting Women and Historically Excluded Minorities in Medicine as Essential Leaders of Research.

Women and historically excluded minorities are underrepresented in clinical research. At the ASTRO 2021 annual meeting, the authors reviewed several strategies to improve on this issue. Implementation of such strategies should not only improve their visibility but also provide increased opportunities for their advancement and work in clinical research.

Pathologic Complete Response and Clinical Outcomes in Patients With Localized Soft Tissue Sarcoma Treated With Neoadjuvant Chemoradiotherapy or Radiotherapy: The NRG/RTOG 9514 and 0630 Nonrandomized Clinical Trials.

Importance: Pathologic complete response (pCR) may be associated with prognosis in patients with soft tissue sarcoma (STS). Objective: We sought to determine the prognostic significance of pCR on survival outcomes in STS for patients receiving neoadjuvant chemoradiotherapy (CT-RT) (Radiation Therapy Oncology Group [RTOG] 9514) or preoperative image-guided radiotherapy alone (RT, RTOG 0630) and provide a long-term update of RTOG 0630. Design, Setting, and Participants: RTOG has completed 2 multi-institutional, nonrandomized phase 2 clinical trials for patients with localized STS. One hundred forty-three eligible patients from RTOG 0630 (n = 79) and RTOG 9514 (n = 64) were included in this ancillary analysis of pCR and 79 patients from RTOG 0630 were evaluated for long-term outcomes. Intervention: Patients in trial 9514 received CT interdigitated with RT, whereas those in trial 0630 received preoperative RT alone. Main Outcomes and Measures: Overall and disease-free survival (OS and DFS) rates were estimated by the Kaplan-Meier method. Hazard ratios (HRs) and P values were estimated by multivariable Cox model stratified by study, where possible; otherwise, P values were calculated by stratified log-rank test. Analysis took place between December 14, 2016, to April 13, 2017. Results: Overall there were 42 (53.2%) men; 68 (86.1%) were white; with a mean (SD) age of 59.6 (14.5) years. For RTOG 0630, at median follow-up of 6.0 years, there was 1 new in-field recurrence and 1 new distant failure since the initial report. From both studies, 123 patients were evaluable for pCR: 14 of 51 (27.5%) in trial 9514 and 14 of 72 (19.4%) in trial 0630 had pCR. Five-year OS was 100% for patients with pCR vs 76.5% (95% CI, 62.3%-90.8%) and 56.4% (95% CI, 43.3%-69.5%) for patients with less than pCR in trials 9514 and 0630, respectively. Overall, pCR was associated with improved OS (P = .01) and DFS (HR, 4.91; 95% CI, 1.51-15.93; P = .008) relative to less than pCR. Five-year local failure rate was 0% in patients with pCR vs 11.7% (95% CI, 3.6%-25.1%) and 9.1% (95% CI, 3.3%-18.5%) for patients with less than pCR in 9514 and 0630, respectively. Histologic types other than leiomyosarcoma, liposarcoma, and myxofibrosarcoma were associated with worse OS (HR, 2.24; 95% CI, 1.12-4.45). Conclusions and Relevance: This ancillary analysis of 2 nonrandomized clinical trials found that pCR was associated with improved survival in patients with STS and should be considered as a prognostic factor of clinical outcomes for future studies. Trial Registration: ClinicalTrials.gov Identifiers: RTOG 0630 (NCT00589121); RTOG 9514 (NCT00002791).

WeWhoCurie: An Initiative to Advocate for Those Underrepresented in Radiation Oncology.

Purpose: An initiative to advocate for those underrepresented in radiation oncology. Methods and Materials: Inspired by the success of the #ILookLikeAnEngineer and #ILookLikeASurgeon campaigns, this initiative aimed to break down stereotypes in traditionally male-dominated fields. In honor of Marie Curie's birthday, on November 7, 2018, the Society for Women in Radiation Oncology launched a social media campaign called #WomenWhoCurie day. However, as the popularity of the social media campaign increased, it become evident that members of the wider radiation community, in particular women of color, nonbinary and transgender people did not feel supported by the #WomenWhoCurie movement. In November 2021, after consultation with diversity and inclusion leaders and members of other national radiation oncology organizations, Society for Women in Radiation Oncology launched #WeWhoCurie alongside the #WomenWhoCurie campaign for women and gender minorities in radiation oncology. Radiation oncologists, physicists, dosimetrist, therapists, nurses, and other professionals from around the world gathered and shared photos and social media posts throughout the day on multiple platforms including Facebook, Instagram, and Twitter. Results: In the year #WeWhoCurie, #WomenWhoCurie, #_______ WhoCurie campaign launched, we saw an increase in participation across the globe from 9 countries: the United States, Canada, Mexico, Brazil, Italy, Spain, China, New Zealand, and Australia. There were over 720 tweets contributing to the campaign with over 2000 messages, representing 3,365,444 "potential impacts", or the number of times someone saw the hashtag. Conclusions: Through this campaign we aim to celebrate the incredible women, gender minorities, and allies who are "Curie-ing" patients with cancer and conducting cutting edge research to improve cancer care across the globe. As an organization we believe adding our voices to the masses will foster a culture of inclusion for everyone. Afterall, what good is the practice of radiation oncology if all are not equally welcome?

Personalising therapy for early-stage oestrogen receptor-positive breast cancer in older women.

Age is one of the most important risk factors for the development of breast cancer. Nearly a third of all breast cancer cases occur in older women (aged ≥70 years), with most cases being oestrogen receptor-positive (ER+). Such tumours are often indolent and unlikely to be the ultimate cause of death for older women, particularly when considering other comorbidities. This Review focuses on unique clinical considerations for screening, detection, and treatment regimens for older women who develop ER+ breast cancers-specifically, we focus on recent trends for de-implementation of screening, staging, surgery, and adjuvant therapies along the continuum of care. Additionally, we also review emerging basic and translational research that will further uncover the unique underlying biology of these tumours, which develop in the context of systemic age-related inflammation and changing hormone profiles. With prevailing trends of clinical de-implementation, new insights into mechanistic biology might provide an opportunity for precision medicine approaches to treat patients with well tolerated, low-toxicity agents to extend patients' lives with a higher quality of life, prevent tumour recurrences, and reduce cancer-related burdens.

Pre-operative partial breast irradiation: revolutionizing radiation treatment for women with early stage breast cancer.

Partial breast irradiation (PBI) has been increasingly accepted as a suitable component of breast conservation in the management of patients with early stage breast cancer, however the majority of existing studies have focused on the use of adjuvant or intra-operative techniques. Several early stage studies have more recently shown that PBI can be safely used in the pre-operative setting. Early data show similar local control without evidence of increased toxicity or worsening cosmesis, as compared to postoperative PBI or standard whole breast irradiation. While long term data are still maturing, pre-operative accelerated PBI (PAPBI) offers a number of possible clinical advantages including reducing the treatment field and increasing the number of patients eligible for PBI, identifying biomarkers of response to radiation, and improving the rates of breast conservation and treatment compliance. This review discusses key concepts and controversies surrounding PBI as it has increasingly been adopted in the US, Canada, and Europe, and introduces the concepts and early studies of PAPBI. In addition, we summarize ongoing clinical trials investigating PAPBI, review clinical benefits and challenges associated with PAPBI versus postoperative PBI, and discuss ongoing limitations as well as next generation technologies important to the implementation of PAPBI in the management of patients with early-stage localized breast cancer.

Vaginal cuff brachytherapy: do we need to treat to more than a two-centimeter active length?

PURPOSE: American Brachytherapy Society (ABS) guidelines recommend using a 3-5 cm active length (AL) when treating vaginal cuff (VC) in adjuvant setting of endometrial cancer (EC). The purpose of this study was to evaluate local control and toxicity, using an AL of 1 or 2 cm and immobilization with a traditional table-mounted (stand) or patient-mounted (suspenders) device. MATERIAL AND METHODS: Between 2005 and 2019, 247 patients with EC were treated with adjuvant high-dose-rate vaginal cuff (HDR-VC) brachytherapy with or without external beam radiation (EBRT). Treatment was prescribed to a 0.5 cm depth, with an AL of 1 or 2 cm, using stand or suspenders. VC boost after EBRT was typically administered with 2 fractions of 5.5 Gy, while VC brachytherapy alone was typically applied with 3 fractions of 7 Gy or 5 fractions of 5.5 Gy. RESULTS: The combination of suspender immobilization and an AL of 2 cm (n = 126, 51%) resulted in 5-year local control of 100%. An AL of 2 cm compared to 1 cm correlated with better local control (99.1% vs. 88.5%, p = 0.0479). Regarding immobilization, suspenders correlated with improved local control compared to stand (100% vs. 86.7%, p = 0.0038). Immobilization technique was significantly correlated with AL (p < 0.0001). Only 5 (2.0%) patients experienced grade ≥ 3 toxicity, all of whom received EBRT. CONCLUSIONS: In the present series, an AL of 2 cm provided excellent local control, while 1 cm was inadequate. Suspender immobilization was a practical alternative to stand immobilization in HDR brachytherapy of the vaginal cuff.

Safety and Efficacy of Palbociclib and Radiation Therapy in Patients With Metastatic Breast Cancer: Initial Results of a Novel Combination.

PURPOSE: Palbociclib is a selective cyclin-dependent kinase 4/6 inhibitor approved for metastatic ER+/HER2- breast cancer. Preclinical evidence suggests a possible synergistic effect of palbociclib when combined with radiation therapy (RT); however, the toxicity of this pairing is unknown. We report preliminary results on the use of this combination. METHODS AND MATERIALS: Records of patients treated with palbociclib at our institution from 2015 to 2018 were retrospectively reviewed. Patients who received RT for symptomatic metastases concurrently or within 14 days of palbociclib were included. Local treatment effect was assessed by clinical examination and subsequent computed tomography/magnetic resonance imaging. Toxicity was graded based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 16 women received palliative RT in close temporal proximity to palbociclib administration. Four patients received palbociclib before RT (25.0%), 5 concurrently (31.3%), and 7 after RT (43.8%). The median interval from closest palbociclib use to RT was 5 days (range, 0-14). The following sites were irradiated in decreasing order of frequency: bone (11 axial skeleton [9 vertebra and 2 other]; 4 pelvis; 3 extremity), brain (4: 3 whole brain RT and 1 stereotactic radiosurgery), and mediastinum (1). The median and mean follow-up time is 14.7 and 17.6 months (range, 1.7-38.2). Pain relief was achieved in all patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. Leukopenia, neutropenia, and thrombocytopenia were seen in 4 (25.0%), 5 (31.3%), and 1 (6.3%) patient before RT. After RT, 5 (31.3%), 1 (6.3%), and 3 (18.8%) patients were leukopenic, neutropenic, and thrombocytopenic, respectively. All but 2 (grade 2) hematologic toxicities were grade 1. No acute or late grade 2+ cutaneous, neurologic, or gastrointestinal toxicities were noted. Toxicity results did not differ based on disease site, palbociclib-RT temporal association, or irradiated site. CONCLUSIONS: The use of RT in patients receiving palbociclib resulted in minimal grade 2 and no grade 3+ toxicities. This preliminary work suggests that symptomatic patients receiving palbociclib may be safely irradiated.

A Survey Study of Female Radiation Oncology Residents' Experiences to Inform Change.

PURPOSE: Women remain underrepresented at all levels within the field of radiation oncology. We sought to study current female residents' experiences and concerns to inform interventions to promote gender equity. Furthermore, we evaluated interest in a professional society specifically for women radiation oncologists. METHODS AND MATERIALS: An anonymous 76-item survey was designed and distributed to current women residents in radiation oncology in 2017-2018. Analyses describe personal, program, and family characteristics and experiences before and after joining the field. RESULTS: Of 170 female residents surveyed, 125 responded (74% response rate). Over one-quarter were in programs with ≤2 female residents (29%) and ≤2 female attendings (29%). One-third (34%) reported having children. Over half (51%) reported that lack of mentorship affected career ambitions. Over half (52%) agreed that gender-specific bias existed in their programs, and over a quarter (27%) reported they had experienced unwanted sexual comments, attention, or advances by a superior or colleague. Only 5% reported no symptoms of burnout. Almost all (95%) agreed that radiation oncology is perceived as family friendly; however, only 52% agreed that it actually is. An overwhelming majority (90%) expressed interest in joining a professional group for women in radiation oncology. CONCLUSIONS: In the first study to our knowledge to focus specifically on the experiences of women residents in radiation oncology, a number of areas for potential improvement were highlighted, including isolation and underrepresentation, mentorship needs, bias and harassment, and gender-based obstacles such as need for support during pregnancy and motherhood. These findings support the organization of groups such as the Society for Women in Radiation Oncology, which seeks to target these needs to promote gender equity.

The Impact of Graduates' Job Preferences on the Current Radiation Oncology Job Market.

PURPOSE: To examine the role of radiation oncology (RO) graduates' application patterns and personal preferences in current labor concerns. METHODS AND MATERIALS: An anonymous, voluntary survey was distributed to 665 domestic RO graduates from 2013 to 2017. Questions assessed graduates' regional (Northeast [NE]; Midwest [MW]; South [SO]; West [WT]) job type and population size preferences. Top regional choice was compared across other categorical and numerical variables using the χ2 test and analysis of variance, respectively. RESULTS: Complete responses were obtained from 299 (45.0% response rate) participants: 82 (27.4%), 74 (24.7%), 85 (28.4%), and 58 (19.4%) graduated from NE, MW, SO, and WT programs. The most to least commonly applied regions were SO (69.2%), MW (55.9%), and then NE/WT (55.2% each). The first and last regional choices were the WT (29.4%) and MW (15.7%), respectively. The most and least common application and top choice preferences were consistent in terms of city size: >500,000 (86.0% and 64.5%, respectively) and <100,001 (26.1% and 7.0%, respectively). The majority of applicants applied to both academic and nonacademic positions (60.9%), with top job type choice being equally split. The majority of respondents independently received a job offer in their preferred region (75.3%), city population size (72.6%) or job type (81.9%). Additionally, 52.5% received a job offer that included all three preferences. Those who underwent residency training (44.3% vs 62.0%-83.6%, P < .001) or medical schooling (50.7% vs 56.3%-75.6%, P < .001) or grew up in the MW (60.8% vs 70.0%-74.7%, P < .001) were least likely to choose this region as their top regional choice compared with other regions. CONCLUSIONS: The MW and jobs in smaller cities are less appealing to RO graduates, even if they receive training in the MW, which may contribute to current job market concerns. Nonetheless, the majority of respondents received a job offer in the region, population size, and job type of their top choice. Assessing prospective candidates' city size and geographic preferences and prioritizing applicants who are compatible with positions may help address potential job market discrepancies.

Is Proton Therapy a "Pro" for Breast Cancer? A Comparison of Proton vs. Non-proton Radiotherapy Using the National Cancer Database.

Background: Limited data exists demonstrating the clinical benefit of proton radiotherapy (PRT) in breast cancer. Using the National Cancer Database, we evaluated predictors associated with PRT use for patients with breast cancer. An exploratory analysis also investigates the impact of PRT on overall survival (OS). Methods: Patients with non-metastatic breast cancer treated with adjuvant radiotherapy from 2004 to 2014 were identified. Patients were stratified based on receipt of PRT or non-PRT (i.e., photons ± electrons). A logistic regression model was used to determine predictors for PRT utilization. For OS, Multivariable analysis (MVA) was performed using Cox proportional hazard model. Results: A total of 724,492 patients were identified: 871 received PRT and 723,621 received non-PRT. 58.3% of the PRT patients were group stage 0-1. Median follow-up time was 62.2 months. On multivariate logistic analysis, the following factors were found to be significant for receipt of PRT (all p < 0.05): academic facility (odds ratio [OR] = 2.50), South (OR = 2.01) and West location (OR = 12.43), left-sided (OR = 1.21), ER-positive (OR = 1.59), and mastectomy (OR = 1.47); pT2-T4 disease predicted for decrease use (OR = 0.79). PRT was not associated with OS on MVA for all patients: Hazard Ratio: 0.85, p = 0.168. PRT remained not significant on MVA after stratifying for subsets likely associated with higher heart radiation doses, including: left-sided (p = 0.140), inner-quadrant (p = 0.173), mastectomy (p = 0.095), node positivity (p = 0.680), N2-N3 disease (p = 0.880), and lymph node irradiation (LNI) (p = 0.767). Conclusions: Receipt of PRT was associated with left-sided, ER+ tumors, mastectomy, South and West location, and academic facilities, but not higher group stages or LNI. PRT was not associated with OS, including in subsets likely at risk for higher heart doses. Further studies are required to determine non-OS benefits of PRT. In the interim, given the high cost of protons, only well-selected patients should receive PRT unless enrolled on a clinical trial.

Factors Affecting Gender-based Experiences for Residents in Radiation Oncology.

PURPOSE: Although women constitute approximately half of medical school graduates, an uneven gender distribution exists among many specialties, including radiation oncology, where women fill only one third of residency positions. Although multiple social and societal factors have been theorized, a structured review of radiation oncology resident experiences has yet to be performed. METHODS AND MATERIALS: An anonymous and voluntary survey was sent to 611 radiation oncology residents practicing in the United States. Residents were asked about their gender-based experiences in terms of mentorship, their professional and learning environment, and their partnerships and personal life. RESULTS: A total of 203 participants submitted completed survey responses. Fifty-seven percent of respondents were men, and 43% were women, with a mean age of 31 years (standard deviation=3.7 years). Although residents in general value having a mentor, female residents prefer mentors of the same gender (P<.001), and noted having more difficulty finding a mentor (P=.042). Women were more likely to say that they have observed preferential treatment based on gender (P≤.001), and they were more likely to perceive gender-specific biases or obstacles in their professional and learning environment (P<.001). Women selected residency programs based on gender ratios (P<.001), and female residents preferred to see equal numbers of male and female faculty (P<.001). Women were also more likely to perceive work-related strain than their male counterparts (P<.001). CONCLUSIONS: Differences in experiences for male and female radiation oncology residents exist with regard to mentorship and in their professional and learning environment.

Once-weekly hypofractionated breast irradiation: fool's gold or diamond in the rough?

Daily conventionally fractionated breast irradiation over 5-7 weeks is costly and inconvenient. Its use is associated with disparities in both the delivery of quality care and outcomes for vulnerable populations. Alternatively, daily hypofractionated breast irradiation delivered over 3 weeks exhibits equal efficacy and toxicity profiles. Today, a new generation of accelerated radiotherapy for breast cancer has emerged. Once-weekly hypofractionated breast irradiation has been tested in pilot and large randomized studies and the initial data appear promising. As the data mature, this new approach has implications for cost-efficacy and provision of radiotherapy services. The purpose of this review is to explore the evolution of once-weekly hypofractionated breast irradiation including our ongoing institutional clinical trial at the University of Louisville.

Negative effect of seroma on breast balloon brachytherapy dosimetry.

PURPOSE: Balloon brachytherapy is commonly used to deliver Accelerated Partial Breast Irradiation (APBI). Seroma interference is a relatively common phenomenon during APBI. The negative effect of seroma accumulation on the planning target volume evaluation (PTV_Eval) coverage is not well understood. METHODS AND MATERIALS: This is a dosimetric replanning study on 10 patients with evidence of seroma collection at time of initial computed tomographic simulation around the catheter. Total dose was 34 Gy given at 3.4 Gy twice a day over 5 treatment days. A total of 20 plans were generated, 10 plans without accounting for and 10 after subtracting the seroma. We then compared the changes seen in PTV_Eval between plans as a factor of the seroma volume. RESULTS: Median age was 62 years (51-83). Histology was invasive in 7/10 cases and in situ in 3/10. Median balloon to skin distance was 8.5 mm (3-14). Median balloon volume was 39 cc (30-104). Median seroma volume was 3.34 cc (1.13-13.71). For every 1 cc of accumulated seroma the percentage of PTV_Eval coverage by the 90% isodose line (V90) was found to decrease by 2.45% (P < .0001; confidence interval [CI], 1.87-3.03) and coverage by the 100% isodose line (V100) was decreased by 1.11% (P < .0001; CI, 0.81-1.41). Fifty percent (5/10) of previously acceptable plans with seroma not accounted for failed to meet the V90 ≥90% requirement after subtracting the seroma. CONCLUSIONS: Accumulation of seroma was associated with a considerable negative impact on PTV_Eval dosimetry with a greater impact on V90 compared with the V100. Clinicians must be careful in detecting and accounting for such accumulation in treatment plans to prevent underdosing of the at risk target breast tissue.

Delay of adjuvant chemotherapy after elective mastectomy and immediate reconstruction in breast-conservation candidates: a matched-pair analysis.

OBJECTIVES: To analyze factors that influence the timing of adjuvant chemotherapy in patients who are candidates for breast-conservation therapy (BCT) but elect mastectomy with immediate reconstruction (M-IR). METHODS: We identified 35 consecutively treated patients with stage I or II breast cancer between 2004 and 2009 who underwent M-IR and adjuvant chemotherapy from the University of Louisville Cancer Registry. We matched these patients for age and AJCC stage to 35 controls who underwent BCT and adjuvant chemotherapy. We examined the timing and delay of initiation of chemotherapy using univariate logistic regression and McNemar test for matched pairs. RESULTS: For the 70 patients evaluated, the median age was 46 years (range, 30 to 65 y), and the distribution for stage I, IIA, and IIB was 22.9%, 65.7%, and 11.4%, respectively. The 2 groups were well balanced in terms of race, rural/urban status, smoking, diabetes, insurance coverage, and histology. For BCT and M-IR, the median time to chemotherapy initiation was 38 days (range, 25 to 103 d) and 55 days (range, 30 to 165 d), respectively. Patients undergoing M-IR were more likely to experience any delay (>45 d; 54.3% vs. 22.9%; P<0.001) and/or significant delay (>90 d; 20.0% vs. 2.9%; P<0.001). On univariate logistic regression analysis, surgery type had a major impact on delay of chemotherapy (odds ratio=8.35; 95% confidence interval, 2.86-24.4; P<0.001). CONCLUSIONS: The use of M-IR in breast-conservation candidates independently predicts for delay in initiation of adjuvant chemotherapy. Further study is needed to qualify the causes and clinical significance of these delays.

Contralateral prophylactic mastectomy: clinical and pathological features from a prospective database.

INTRODUCTION: In keeping with recently documented national trends, a significant and increasing number of patients will have chosen contralateral prophylactic mastectomy (CPM) based on personal preference, without traditional clinical or pathological indication. METHODS: Women who underwent CPM at the University of Louisville from 2003 to 2009 were selected for this study. Descriptive factors were evaluated such as age, race, family history of breast cancer, laterality, hormone receptor status, stage, grade and histology of the index breast lesion. Statistical analysis was used to compute predictive factors for occult contralateral pathology. RESULTS: A total of 107 patients underwent CPM and had adequate medical information to be included in this study. The median age was 48 years, with 88% being white and 12% being African American. Seventy-six percent of the index breast cancers were infiltrating ductal carcinoma and 12% were infiltrating lobular carcinoma. Five "significant" occult pathologies were found in the prophylactically removed breast. Two of the lesions were ductal carcinoma in situ, 2 were lobular carcinoma in situ and 1 was an invasive mucinous carcinoma. On bivariate analysis, there were no factors identified predictive for occult contralateral pathology. CONCLUSIONS: In line with previously reported data, we noted that fewer than 5% of patients who underwent CPM had pathology in the contralateral breast. We were unable to correlate any clinical or pathological characteristics in women who presented with contralateral breast cancer. This study raises serious questions regarding the clinical utility of CPM in detecting synchronous clinically and radiographically occult contralateral primaries.

Medical student mentorship in a university setting as a strategy for a career in surgery.

Gender balance in surgery is a respectable and necessary goal. At the University of Louisville (UL) School of Medicine, we have compared percentages of UL medical student applicants to general surgery or surgical subspecialty residency programs, surgical residents, and surgical faculty with the rest of the nation. Although UL has at times paralleled or exceeded the nation in many of these categories, there is room for improvement and the comparison data allow for strategic planning initiatives. To promote gender balance among future generations of surgeons at UL, we recently implemented a mentoring program that pairs medical students with residents and faculty in surgery. We plan to track the success over time and correct any shortcomings of this program. Virginia Commonwealth University's commitment to gender balance in surgery is exemplary. As part of a more comprehensive vision to create a mentorship program for female medical students at the UL School of Medicine, we have recently recruited female surgical residents and faculty, whom we hope will provide the type of inspiration and guidance that will increase the number of women from UL who decide to train in general surgery and the surgical specialties. To understand why women across the nation are not generally at numerical parity in these fields, it is important to consider the length and intensity of the surgical residency programs in the context of the other goals and objectives that a woman might have for her future. This article does not address this broad topic but provides a perspective of how a medical school can evaluate and perhaps intervene to mentor medical students more effectively about the satisfaction derived from a career in surgery. As part of this project, we have evaluated each step of the path through medical school and a surgical residency by comparing data for our students, residency programs, and faculty with national data.

Estrogen receptor alpha 46 is reduced in tamoxifen resistant breast cancer cells and re-expression inhibits cell proliferation and estrogen receptor alpha 66-regulated target gene transcription.

Resistance to endocrine therapy is a major clinical problem in breast cancer. The role of ERalpha splice variants in endocrine resistance is largely unknown. We observed reduced protein expression of an N-terminally truncated ERalpha46 in endocrine-resistant LCC2, LCC9, and LY2 compared to MCF-7 breast cancer cells. Transfection of LCC9 and LY2 cells with hERalpha46 partially restored growth inhibition by TAM. Overexpression of hERalpha46 in MCF-7 cells reduced estradiol (E(2))-stimulated endogenous pS2, cyclin D1, nuclear respiratory factor-1 (NRF-1), and progesterone receptor transcription. Expression of oncomiR miR-21 was lower in TAM-resistant LCC9 and LY2 cells compared to MCF-7 cells. Transfection with ERalpha46 altered the pharmacology of E(2) regulation of miR-21 expression from inhibition to stimulation, consistent with the hypothesis that hERalpha46 inhibits ERalpha activity. Established miR-21 targets PTEN and PDCD4 were reduced in ERalpha46-transfected, E(2)-treated MCF-7 cells. In conclusion, ERalpha46 appears to enhance endocrine responses by inhibiting selected ERalpha66 responses.

Mouse Ae1 E699Q mediates SO42-i/anion-o exchange with [SO42-]i-dependent reversal of wild-type pHo sensitivity.

The SLC4A1/AE1 gene encodes the electroneutral Cl(-)/HCO(3)(-) exchanger of erythrocytes and renal type A intercalated cells. AE1 mutations cause familial spherocytic and stomatocytic anemias, ovalocytosis, and distal renal tubular acidosis. The mutant mouse Ae1 polypeptide E699Q expressed in Xenopus oocytes cannot mediate Cl(-)/HCO(3)(-) exchange or (36)Cl(-) efflux but exhibits enhanced dual sulfate efflux mechanisms: electroneutral exchange of intracellular sulfate for extracellular sulfate (SO(4)(2-)(i)/SO(4)(2-)(o) exchange), and electrogenic exchange of intracellular sulfate for extracellular chloride (SO(4)(2-)(i)/Cl(-)(o) exchange). Whereas wild-type AE1 mediates 1:1 H(+)/SO(4)(2-) cotransport in exchange for either Cl(-) or for the H(+)/SO(4)(2-) ion pair, mutant Ae1 E699Q transports sulfate without cotransport of protons, similar to human erythrocyte AE1 in which the corresponding E681 carboxylate has been chemically converted to the alcohol (hAE1 E681OH). We now show that in contrast to the normal cis-stimulation by protons of wild-type AE1-mediated SO(4)(2-) transport, both SO(4)(2-)(i)/Cl(-)(o) exchange and SO(4)(2-)(i)/SO(4)(2-)(o) exchange mediated by mutant Ae1 E699Q are inhibited by acidic pH(o) and activated by alkaline pH(o). hAE1 E681OH displays a similarly altered pH(o) dependence of SO(4)(2-)(i)/Cl(-)(o) exchange. Elevated [SO(4)(2-)](i) increases the K(1/2) of Ae1 E699Q for both extracellular Cl(-) and SO(4)(2-), while reducing inhibition of both exchange mechanisms by acid pH(o). The E699Q mutation also leads to increased potency of self-inhibition by extracellular SO(4)(2-). Study of the Ae1 E699Q mutation has revealed the existence of a novel pH-regulatory site of the Ae1 polypeptide and should continue to provide valuable paths toward understanding substrate selectivity and self-inhibition in SLC4 anion transporters.