Understanding Treatment Decision-Making in Older Women With Breast Cancer: A Survey-Based Study.

INTRODUCTION: For women ≥70 y old with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, the national guidelines recommend the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy. However, national-level data suggest these treatments remain common. We utilized a survey-based approach to explore patient-level factors driving overutilization. METHODS: We recruited women ≥70 y old with early-stage hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer within 6 mo of surgery. An exploratory cross-sectional survey captured information on offered and pursued treatments, the importance of patient-centered outcomes, and the influence of each outcome on treatment decision-making. Descriptive statistics were used for analysis. RESULTS: 31/51 patients completed the survey with a response rate of 61%. Most patients (86%) received a lumpectomy. Twenty-eight percent of patients received SLNB, and 56% of lumpectomy patients underwent adjuvant radiotherapy. When considering treatment options, the patient-centered outcomes, most important for decision-making, were overall survival, breast-specific survival, and preventing local recurrence, while breast appearance, financial costs, and avoiding the need for pills (endocrine therapy) were the least important. CONCLUSIONS: Patients' treatment decisions align with their values. The correlation between patient-stated values and treatment decisions suggests a perceived mortality benefit of low-value SLNB and radiotherapy. These findings can inform targeted efforts to deimplement low-value care in breast cancer through patient-focused tools and education.

De-Implementation of Low-Value Care for Women 70 Years of Age or Older with Low-Risk Breast Cancer During the COVID-19 Pandemic.

BACKGROUND: Older women with early-stage estrogen receptor-positive (ER+) invasive breast cancer (IBC) are at risk for overtreatment. Guidelines allow for sentinel lymph node biopsy (SLNB) and radiotherapy omission after breast-conserving surgery (BCS) for women 70 years of age or older with T1, clinical node negativity (cN0), and ER+ IBC. The study objective was to evaluate radiotherapy and SLNB de-implementation in older women with low-risk IBC after the resource limitations of the COVID-19 pandemic. METHODS: An institutional database was analyzed to identify women 70 years of age or older who received BCS for IBC from 2012 to 2022. The patients were divided into two cohorts: (1) patients with low-risk IBC (pT1, cN0, and ER+/HER2-) who were eligible for radiotherapy and SLNB omission and (2) patients with high-risk IBC (pT2-T4, cN+, ER-, or HER2+) who were ineligible for therapy omission. Clinicopathologic variables in both cohorts were analyzed. RESULTS: The study enrolled 881 patients. For the patients with low-risk IBC, the annual rates of radiotherapy were stable from 2012 to 2019. However, radiotherapy utilization decreased significantly from 2020 to 2022 (58% in 2012 vs 36% in 2022; p = 0.04). In contrast, radiotherapy usage among the patients with high-risk IBC was stable from 2012 to 2022 (79% in 2012 vs 79% in 2022; p = 0.95). Among the patients with low-risk IBC, SLNB rates decreased from 86% in 2012 to 56% in 2022, but this trend predated those in 2020. The factors significantly associated with SLNB and receipt of radiotherapy among the patients with low-risk IBC were younger age, larger tumors, grade 3 disease, and involved nodal status (p < 0.01). CONCLUSION: This study demonstrated appropriate and sustained de-escalation of radiotherapy in older women with low-risk IBC after the COVID-19 pandemic.

Avoiding Overtreatment of Women ≥70 With Early-Stage Breast Cancer: A Provider-Level Deimplementation Strategy.

INTRODUCTION: National guidelines recommend against routine axillary staging with sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy (RT) in women ≥70 y with early-stage, hormone receptor-positive, HER2-negative breast cancer and clinically negative axilla; however, these practices remain common. METHODS: We conducted a prospective pilot study from August 2021 to 2022 using an intervention targeting breast surgeons and radiation oncologists in Michigan that aimed to reduce SLNB and RT in eligible patients. The intervention consisted of (1) a geriatric assessment, (2) an assessment of the patient's medical maximizing-minimizing preferences, and (3) a tailored script with counterpoints to reasons patients commonly seek SLNB or RT. At the end of the study period, participants completed a survey providing feedback with the primary outcomes being: acceptability, appropriateness, feasibility, and intention and motivation to use the materials based on validated measures. RESULTS: Participants (n = 23) included 15 breast surgeons and 8 radiation oncologists. Collectively, the materials were used with 115 patients. Considering all materials holistically, acceptability, appropriateness, and feasibility of the intervention were high; participants also intended and were motivated to use the intervention. Scores across all measures were highest for the geriatric assessment and lowest for the tailored script. The major barriers to using the intervention were limited time and instances of disagreement on treatment recommendations among surgeons and radiation oncologists. CONCLUSIONS: The omission of SLNB and adjuvant RT should be discussed in appropriately selected patients. A multifaceted provider-level deimplementation strategy may be an effective means for achieving this goal.

Facility-Level Variation of Low-Value Breast Cancer Treatments in Older Women with Early-Stage Breast Cancer: Analysis of a Statewide Claims Registry.

BACKGROUND: Since 2004, national guidelines have supported the omission of sentinel lymph node biopsy (SLNB) and radiotherapy for women ≥ 70 years of age with early-stage, hormone receptor-positive (HR+) breast cancer, but many women continue to receive at least one of these services. Provider- and patient-level factors may contribute to persistent utilization, but the role of facility-level factors is unknown. We aimed to determine facility-level variation of SLNB and adjuvant radiotherapy utilization in older women with early-stage, HR+ breast cancer undergoing breast-conserving surgery (BCS). Additionally, we aimed to explore factors associated with SLNB and radiotherapy utilization and the intra-facility correlation in their utilization. METHODS: We conducted a retrospective cohort study using a statewide registry of claims data. We included women ≥70 years of age diagnosed with breast cancer who underwent BCS from 2012 to 2019 at 80 hospitals in the Michigan Value Collaborative. The main outcome was inter-facility rates and variation of SLNB and radiotherapy, as well as intra-facility correlation in their utilization. RESULTS: The cohort included 7253 women (median age 77 years). Only 20% (n = 1440) underwent BCS alone, whereas 71% (n = 5122) underwent SLNB and 52% (n = 3793) received radiotherapy. Inter-facility rates of SLNB ranged from 35 to 82% (median 70%), and radiotherapy ranged from 19 to 72% (median 49%). SLNB and radiotherapy were positively correlated (r = 0.27, p = 0.016). CONCLUSIONS: SLNB and radiotherapy rates remain high with significant variation in utilization at the facility level. High utilizers of SLNB are likely to be high utilizers of radiotherapy, suggesting the opportunity for strategic targeting of these facilities and their clinicians.

Incremental Spending Associated with Low-Value Treatments in Older Women with Breast Cancer.

BACKGROUND: In most women ≥ 70 years old with hormone-receptor-positive breast cancer, axillary staging and adjuvant radiotherapy provide no survival advantage over surgery and hormone therapy alone. Despite recommendations for their omission, sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy rates remain high. While treatment side effects are well documented, less is known about the incremental spending associated with SLNB and adjuvant radiotherapy. METHODS: Using a statewide multipayer claims registry, we examined spending associated with breast cancer treatment in a retrospective cohort of women ≥ 70 years old undergoing surgery. RESULTS: 9074 women ≥70 years old underwent breast cancer resection between 2012 and 2019, with 78% (n = 7122) receiving SLNB and/or adjuvant radiotherapy within 90 days of surgery. Women undergoing SLNB were more likely to receive radiation (51% vs. 28%; p < 0.001 and OR = 2.68). Average 90-day spending varied substantially based upon treatment received, ranging from US$10,367 (breast-conserving surgery alone) to US$27,370 (mastectomy with SLNB and adjuvant radiotherapy). The relative increases in 90-day treatment spending in the breast-conserving surgery cohort was 65% for SLNB, 82% for adjuvant radiotherapy, and 120% for both treatments. CONCLUSIONS: SLNB and adjuvant radiotherapy have significant spending implications in older women with breast cancer, even though they are unlikely to improve survival.

Using Tailored Messages to Target Overuse of Low-Value Breast Cancer Care in Older Women.

BACKGROUND: National recommendations allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 y/o with early-stage, hormone-receptor positive invasive breast cancer, but these therapies remain common. Previous work demonstrates an individual's maximizing-minimizing trait-an inherent preference for more or less medical care-may influence the preference for low-value care. MATERIALS AND METHODS: We recruited an equal number of women ≥ 70 yrs who were maximizers, minimizers, or neutral based on a validated measure between September 2020 and November 2020. Participants were presented a hypothetical breast cancer diagnosis before randomization to one of three follow-up messages: maximizer-tailored, minimizer-tailored, or neutral. Tailored messaging aimed to redirect maximizers and minimizers toward declining SLNB and radiotherapy. The main outcome measure was predicted probability of choosing SLNB or radiotherapy. RESULTS: The final analytical sample (n = 1600) was 515 maximizers (32%), 535 neutral (33%) and 550 (34%) minimizers. Higher maximizing tendency positively correlated with electing both SLNB and radiotherapy on logistic regression (P < 0.01). Any tailoring (maximizer- or minimizer-tailored) reduced preference for SLNB in maximizing and neutral women but had no effect in minimizing women. Tailoring had no impact on radiotherapy decision, except for an increased probability of minimizers electing radiotherapy when presented with maximizer-tailored messaging. CONCLUSIONS: Maximizing-minimizing tendencies are associated with treatment preferences among women facing a hypothetical breast cancer diagnosis. Targeted messaging may facilitate avoidance of low-value breast cancer care, particularly for SLNB.

Gaps in Online Breast Cancer Treatment Information for Older Women.

BACKGROUND: For women older than 70 years with early-stage breast cancer, the routine use of sentinel lymph node biopsy (SLNB) and adjuvant radiotherapy offers no overall survival benefit and may be perceived as undesirable by many women. National guidelines allow possible omission of these practices for older women. This study aimed to assess the availability of web-based educational materials targeting older women and their age-specific treatment recommendations. METHODS: The study systematically assessed the websites of the top 25 "Best Hospitals for Cancer" ranked by the U.S. News & World Report, as well as the websites of four prominent national cancer organizations. RESULTS: Websites for the leading cancer hospitals and national cancer organizations contain extremely limited information directed toward older patients with breast cancer. Both SLNB and adjuvant radiotherapy are described as treatments "typically," "most often," or "usually" used in combination with breast-conserving surgery without circumstances noted for possible omission. Specifically, no hospital website and only one national organization in this study included information on the recommendation to avoid routine SLNB. Only two hospitals and two national organizations included information suggesting possible omission of adjuvant radiotherapy for patients older than 70 years. CONCLUSION: The absence of online material for older patients with breast cancer represents a gap potentially contributing to overtreatment by framing SLNB and adjuvant radiotherapy as necessary. Informational resources available to women aged 70 years or older may aid in informed physician-patient communication and decision-making, which may reduce SLNB and adjuvant radiotherapy for patients who might opt out of these procedures if fully informed about them.

Medical Maximizing-Minimizing Preferences in Relation to Low-Value Services for Older Women with Hormone Receptor-Positive Breast Cancer: A Qualitative Study.

BACKGROUND: Multiple studies have demonstrated the safety of omitting therapies in older women with breast cancer. Despite de-implementation guidelines, up to 65% of older women continue to receive one or more of these low-value services. Previous work has investigated the role of both provider and patient attitudes as barriers to de-implementation; however, the importance of the patient's maximizing-minimizing preferences within this context remains unclear. METHODS: In this qualitative study, we conducted 30 semi-structured interviews with women ≥ 70 years of age without a previous diagnosis of breast cancer to elicit perspectives on breast cancer treatment in relation to their medical maximizing-minimizing preferences, as determined by the single-item maximizer-minimizer elicitation question (MM1). We used an interpretive description approach in analysis to produce a thematic survey. RESULTS: Participants were relatively evenly distributed across the MM1 (minimizer, n = 8; neutral, n = 13; maximizer, n = 9). Despite being told of recommendations allowing for the safe omission of sentinel lymph node biopsy and post-lumpectomy radiotherapy, maximizers consistently stated preferences for more medical intervention and aggressive therapies over minimizers and neutral individuals. CONCLUSION: Medical maximizing-minimizing preferences in older women correspond with preferences for breast cancer treatment options that guidelines identify as potentially unnecessary. Increased awareness of patient-level variability in maximizing-minimizing preferences may be valuable in developing optimal intervention strategies to reduce utilization of low-value care.

Trends in Breast Cancer Treatment De-Implementation in Older Patients with Hormone Receptor-Positive Breast Cancer: A Mixed Methods Study.

INTRODUCTION: Guidelines allow for the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy in women ≥ 70 years of age with hormone receptor-positive (HR +) breast cancer. Despite this, national data suggest these procedures have not been widely de-implemented. OBJECTIVES: Our objectives were to evaluate trends in SLNB and post-lumpectomy radiotherapy utilization in patients who are eligible for omission, and evaluate patient preferences as a target for de-implementation of low-value care. METHODS: We performed a sequential explanatory mixed-methods study by first analyzing an institutional database of patients ≥ 70 years of age with HR + breast cancer who received surgical treatment from 2014 to 2018. Based on the quantitative data, we conducted semi-structured interviews with women identified as high or low utilizers of breast cancer treatments to elicit patient perspectives on de-implementation. RESULTS: SLNB and post-lumpectomy radiotherapy were performed in 68% and 43% of patients, respectively, who met the criteria for omission. There was a significant decrease in SLNB rates from 2014 to 2018. Forty-nine percent of patients were classified as high utilizers and 26% were classified as low utilizers. Qualitative analysis found that the most important factors influencing decision making regarding SLNB and post-lumpectomy radiotherapy omission for both high and low utilizers were trust in their provider and a desire for peace of mind. CONCLUSIONS: Despite efforts to de-implement low-value care, older women with HR + breast cancer remain at risk of overtreatment. Patient perspectives suggest that multi-level de-implementation strategies will need to target provider practice patterns and patient-provider communication to promote high-quality decision making and reduction in breast cancer overtreatment.

A Health Systems Ethical Framework for De-implementation in Health Care.

INTRODUCTION: Unnecessary health care not only drive up costs, but also contribute to avoidable patient harms, underscoring an ethical obligation to eliminate practices which are harmful, lack evidence, and prevent spending on more beneficial services. To date, de-implementation ethics discussions have been limited and focused on clinical ethics principles. An analysis of de-implementation ethics in the broader context of the health care system is lacking. METHODS: To better understand the ethical considerations of de-implementation, recognizing it as a health care systems issue, we applied Krubiner and Hyder's bioethical framework for health systems activity. We examine ethics principles relevant to de-implementation, which either call for or facilitate the reduction of low value surgery. RESULTS AND DISCUSSION: From 11 health systems principles proposed by Krubiner and Hyder, we identified the 5 principles most pertinent to the topic of de-implementation: evidence and effectiveness, transparency and public engagement, efficiency, responsiveness, and collaboration. An analysis of de-implementation through the lens of these principles not only supports de-implementation but proves an obligation at the health system level to eliminate low value care. Recognizing the challenge of defining "value," the proposed framework may increase the legitimacy and objectivity of de-implementation. CONCLUSIONS: While there is no single ideal ethical framework from which to approach de-implementation, a health systems framework allows for consideration of the systems-level factors impacting de-implementation. Framing de-implementation as a health systems issue with systems-wide ethical implications empowers providers to think about new ways to approach potential roadblocks to reducing low-value care.

Trends in Contralateral Prophylactic Mastectomy Utilization for Small Unilateral Breast Cancer.

BACKGROUND: For average-risk women with unilateral breast cancer, contralateral prophylactic mastectomy (CPM) offers no survival benefit and contributes to increased costs and patient harm. Despite recommendations from professional societies against CPM, utilization of this service is increasing, partly due to patients' desire for breast symmetry when undergoing mastectomy. Most women with small tumors are candidates for breast-conserving surgery (BCS) and could avoid CPM. We describe CPM utilization in women with small, unilateral tumors, and identify determinants of possible overuse. METHODS: Using the National Cancer Database, we identified women with unilateral, T1 breast cancer. We evaluated utilization of BCS, unilateral mastectomy, and CPM and assessed patient, tumor, and facility factors associated with CPM. RESULTS: Of 765,487 women with small, unilateral breast cancer, 69% underwent BCS and 31% chose mastectomy. Of 176,673 women ≥70 y, 75% underwent BCS and 25% chose mastectomy. CPM rates in both cohorts have increased since 2006. Decreased adjuvant radiotherapy in older women was associated with increased BCS rates. Patient factors (younger age, white race, private insurance, and breast reconstruction), tumor factors (lobular histology, higher grade, and human epidermal growth factor receptor 2 positive/estrogen receptor negative status), and facility factors (type and geographic location) were associated with increased CPM rates compared with unilateral mastectomy in multivariable models. CONCLUSIONS: Most women with small unilateral breast cancer are candidates for BCS, yet one-third elects to undergo a mastectomy, of which a rising percentage opts for CPM. Tailoring deimplementation strategies to factors influencing treatment may help reduce CPM utilization and associated financial toxicity, pain, and disability.

Comparison of Clinical Breast Exam to Breast MRI Surveillance in Patients Following Nipple-Sparing Mastectomy.

BACKGROUND: Nipple sparing mastectomy (NSM) is increasingly being performed for patients with breast cancer. However, optimal postoperative surveillance has not been defined. METHODS: A prospectively maintained database identified patients with in-situ and invasive cancer who underwent NSM between 2007-2021. Clinical data on postoperative breast surveillance and interventions were collected. Patients who had MRI surveillance versus clinical breast exam (CBE) alone were compared with respect to tumor characteristics, recurrence, and survival. RESULTS: A total of 483 NSMs were performed on 399 patients. 255 (63.9%) patients had invasive ductal carcinoma, 31 (7.8%) invasive lobular carcinoma, 92 (23.1%) DCIS, 6 (1.5%) mixed ductal and lobular carcinoma, 9 (2.3%) others, and 6 (1.5%) unknown. Postoperatively, 265 (66.4%) patients were followed with CBE alone and 134 (33.6%) had surveillance MRIs. At a median follow-up of 33 months, 20 patients (5.0%) developed in-breast recurrence, 6 patients had (1.5%) an axillary recurrence, and 28 with (7.0%) distant recurrence. 14 (53.8%) LRR were detected in the CBE group and 12 (46.2%) were detected in the MRI group (P = .16). Overall survival (OS) was 99%, with no difference in OS between patients who had CBE alone versus MRI (P = .46). MRI was associated with higher biopsy rates compared to CBE alone (15.8% vs. 7.8%, P = .01). CONCLUSIONS: Compared to CBE alone, the use of screening MRI following NSM results in higher rate of biopsy and no difference in overall survival.

Pilot testing a patient decision aid as a strategy to reduce overtreatment for older women with early-stage breast cancer.

BACKGROUND: Despite national guidelines recommending omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy (RT) in older women with early-stage, hormone receptor-positive (HR+) breast cancer, these practices persist. This pilot study assesses whether a decision aid can target patient-level determinants of low-value treatments. METHODS: We adapted and pilot-tested a decision aid in women ≥70 years old with early-stage HR â€‹+ â€‹breast cancer. Primary outcomes included acceptability and appropriateness of the decision aid. Secondary outcomes included treatment choice and satisfaction with decision. RESULTS: Twenty-three patients enrolled in the trial. 19 completed survey one; 16 completed survey two. Primary outcomes demonstrated that 84% of patients agreed or strongly agreed the aid was acceptable and appropriate. Secondary outcomes demonstrated that 19% of patients underwent SLNB (below pre-intervention baseline), and 85% received adjuvant RT (change not statistically significant). CONCLUSIONS: We demonstrate that a decision aid may effectively target patient-level factors contributing to overuse of low-value therapies.

OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma.

Sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), but the underlying molecular mechanisms remain controversial and why some patients do not respond to this therapy is poorly understood. In this study, we show that sorafenib triggers cell growth inhibition and apoptosis in HCC cells by directly targeting the mitochondria. Treatment with sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria fusion-related protein optic atrophy 1 (OPA1). Exposure of cells or isolated mitochondria to sorafenib substantially induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to sorafenib-induced apoptosis. Furthermore, sorafenib has no apparent apoptotic toxicity to normal human primary hepatocytes. Sorafenib inhibits HCC xenograft tumor growth in vivo and murine xenograft tumor tissue analysis reveals mitochondria fusion protein. OPA1 expression levels are strongly downregulated by sorafenib treatment. Western blotting evaluation of patient HCC with matched non-tumor tissue samples demonstrates that OPA1 expression is decreased in up to 40% of HCC patients. Taken together, we have shown that sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC.

Incorporating Value-Based Decisions in Breast Cancer Treatment Algorithms.

Given the excellent prognosis and availability of evidence-based treatment, patients with early-stage breast cancer are at risk of overtreatment. In this review, we summarize key opportunities to incorporate value-based decisions to optimize the delivery of high-value treatment across the breast cancer care continuum.

Cyclooxygenase-2 and Akt mediate multiple growth-factor-induced epithelial-mesenchymal transition in human hepatocellular carcinoma.

BACKGROUND AND AIM: Cancer invasion and metastasis are characterized by epithelial-mesenchymal transition (EMT). Hepatocellular carcinoma (HCC) causes metastasis and significant mortality. Elucidating factors promoting EMT in HCC are necessary to develop effective therapeutic strategies. METHODS: The LH86 cell line was developed in our laboratory from well-differentiated HCC without associated hepatitis or cirrhosis and used as a model to study EMT in HCC. Effects of transforming growth factor ß-1, epidermal growth factor, hepatocyte growth factor and basic fibroblast growth factor (bFGF) were examined using morphology, molecular markers, effects on migration and tumorigenicity. The involvement of cyclooxygenase-2 (COX-2) and Akt were examined. RESULTS: LH86 cells display epithelial morphology. Transforming-growth-factor-ß-1-, epidermal-growth-factor-, hepatocyte-growth-factor- and basic-fibroblast-growth-factor-induced mesenchymal changes in them were associated with loss of E-cadherin, albumin, α-1 anti-trypsin expression and increased expression of vimentin, collagen I and fibronectin. There was associated increased migration, tumorigenicity and increased expression of COX-2, prostaglandin E2 (PGE2), Akt and phosphorylated Akt. Inhibition of COX-2 and Akt pathways led to inhibition of characteristics of EMT. CONCLUSIONS: Multiple growth factors induce EMT in HCC. COX-2 and Akt may mediate EMT-associated development and progression of HCC and molecular targeting of COX-2 and Akt may be an effective therapeutic or chemopreventive strategy in advanced and metastatic HCC.

Statewide Episode Spending Variation of Mastectomy for Breast Cancer.

BACKGROUND: Centralizing complex cancer operations, such as pancreatectomy and esophagectomy, has been shown to increase value, largely due to reduction in complications. For high-volume operations with low complication rates, it is unknown to what degree value varies between facilities, or by what mechanism value may be improved. To identify possible opportunities for value enhancement for such operations, we sought to describe variations in episode spending for mastectomy with a secondary aim of identifying patient- and facility-level determinants of variation. STUDY DESIGN: Using the Michigan Value Collaborative risk-adjusted, price-standardized claims data, we evaluated mean spending for patients undergoing mastectomy at 74 facilities (n = 7,342 patients) across the state of Michigan. Primary outcomes were 30- and 90-day episode spending. Using linear mixed models, facility- and patient-level factors were explored for association with spending variability. RESULTS: Among 7,342 women treated across 74 facilities, mean 30-day spending by facility ranged from $11,129 to $20,830 (median $14,935). Ninety-day spending ranged from $17,303 to $31,060 (median $23,744). Patient-level factors associated with greater spending included simultaneous breast reconstruction, bilateral surgery, length of stay, and readmission. Among women not undergoing reconstruction, variation persisted, and length of stay, bilateral surgery, and readmission were all associated with increased spending. CONCLUSION: Michigan hospitals have significant variation in spending for mastectomy. Reducing length of stay through wider adoption of same-day discharge for mastectomy and reducing the frequency of bilateral surgery may represent opportunities to increase value, without compromising patient safety or oncologic outcomes.

Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells.

BACKGROUND: Glycochenodeoxycholate (GCDA) is one of the major human bile salts. Bile salts stimulate cell survival and proliferation through the mitogen-activated protein kinase, but the downstream signaling mechanism(s) remains enigmatic. Mcl-1 is an antiapoptotic molecule of the Bcl2 family that is extensively overexpressed in tumor tissues of patients with hepatocellular carcinoma (HCC). RESULTS: Here we found that exposure of HepG2 cells to GCDA results in activation of ERK1 and ERK2 and phosphorylation of Mcl-1 in a PD98059 (MEK inhibitor)-sensitive manner. GCDA stimulates Mcl-1 phosphorylation in cells expressing WT but not T163A Mcl-1 mutant, indicating that GCDA-induced Mcl-1 phosphorylation occurs exclusively at the T163 site in its PEST region. GCDA-induced Mcl-1 phosphorylation at T163 enhances the half-life of Mcl-1. Treatment of HepG2 cells with GCDA facilitates Mcl-1 dissociation from Mule (a physiological Mcl-1 ubiquitin E3 ligase). Specific depletion of Mcl-1 from HepG2 cells by RNA interference increases sensitivity of HepG2 cells to chemotherapeutic drugs (i.e. cisplatin and irinotecan). In addition to activation of the ERK/Mcl-1 survival pathway, GCDA can also induce dose-dependent apurinic/apyrimidinic (AP) sites of DNA lesions, which may partially neutralize its survival activity. CONCLUSION: Our findings suggest that bile salt may function as a survival agonist and/or potential carcinogen in the development of HCC. Molecular approaches that inactivate Mcl-1 by blocking its T163 phosphorylation may represent new strategies for treatment of HCC.