Patient Preferences and Satisfaction With Decisions in Stage-III Melanoma: A Mixed Methods Study.

INTRODUCTION: Rapid accumulation of data in surgical and medical oncology has changed the treatment landscape for patients with stage-III melanoma, introducing options for active surveillance and adjuvant systemic therapy; however, these options have increased the complexity of decision making. METHODS: We conducted an explanatory sequential mixed-methods study consisting of surveys and semistructured interviews among patients diagnosed with stage-III melanoma at a single institution from August 2019 to December 2021. The survey included the validated 30-point satisfaction with decision scale (SWD). The interview guide was developed using a shared decision-making framework. RESULTS: Twenty-six participants completed the survey (response rate 40%) and 17 were interviewed. In the survey, 69% of participants reported receiving a recommendation for active surveillance and 23% received a recommendation for adjuvant systemic therapy. Overall SWD for treatment of the lymph node basin and adjuvant systemic therapy was high at 27.94 and 26.21 out of 30, respectively. In the interviews, participants stressed the importance of the physician's recommendation as well as the desire to minimize intervention and avoid potential side effects in their decisions. However, they demonstrated persistent knowledge gaps in their understanding of the treatment options. CONCLUSIONS: Like other cancer types where the option for active surveillance exists, the physician's recommendation is influential in shaping decisions for patients with stage-III melanoma. Physicians can improve shared decision making in this complex treatment landscape through improved multidisciplinary collaboration and mechanisms for ensuring patients' understanding of the treatment options.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Implementation of melanoma guidelines in the multidisciplinary setting: A qualitative analysis.

BACKGROUND: Data suggest variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy (AT) for sentinel lymph node-positive melanoma. We aimed to explore how clinicians consider multidisciplinary treatment options. METHODS: We conducted semi-structured interviews of surgical oncologists, medical oncologists, and otolaryngologists to produce a thematic analysis. RESULTS: Participants (n = 26) described melanoma care as inherently "multidisciplinary," noting the importance of conversations facilitated by shared clinic days or space. Despite believing that their practice mirrored other clinicians, participants revealed diverging perspectives on CLND and AT. Multidisciplinary care presented challenges for surveillance as surgeons expressed desire to retain ownership of patients but did not feel comfortable overseeing AT needs. Participants questioned the fidelity of nodal ultrasounds, noted redundancy in their roles, and described a "surveillance burden" for patients. CONCLUSION: Opportunities exist to improve multidisciplinary melanoma care through broader consensus of how to translate emerging data into patient care and delineating surveillance roles.

Demographic Factors Associated With Research and Career Interests in Aspiring Academic Surgeons: What are the Implications for Tomorrow's Workforce?

OBJECTIVE: To evaluate the research and career interests of aspiring academic surgeons and determine the influence of demographic factors. DESIGN: Cross-sectional survey SETTING: Single institution, academic general surgery residency program PARTICIPANTS: Medical students invited to interview during 2019-2020 and 2020-2021 residency cycle RESULTS: One hundred fifty-four of 160 (96%) potential respondents representing 63 medical schools completed the survey, American Association for Public Opinion Research Response Rate 6. Fifty-three percent of the study population was female. Seventeen percent identified as Black, 14% Asian, 13% Latinx, 50% white, and 6% other. Respondents were most interested in education, professional development, and surgical culture (32%) followed by basic and translational science (23%), global and community health (20%), and health services (18%). On multiple logistic regression, interest in global/community health was associated with identifying as Black (OR 5.9 [2.0, 17.8] p = 0.001) and female (OR 2.7 [1.0, 7.0] p = 0.044). A plurality of participants were undecided on future specialty (n = 63, 41%). The most common specialty interests were surgical oncology (n = 28, 18%); trauma, acute care, or surgical critical care (n = 21, 14%); pediatric and cardiothoracic surgery (n = 20 for each, 13%); and abdominal transplant (n = 15, 10%). CONCLUSIONS: In this cross-sectional survey of highly competitive academic general surgery applicants, respondents who were underrepresented in medicine (URiM) and women were more interested in research fields with a history of lower relative NIH funding. In light of these findings, academic programs seeking a more diverse residency workforce should consider strategies beyond recruitment to promote the scholarly achievement of women and URiM residents.

How We Do It: An Innovative General Surgery Mentoring Program.

OBJECTIVE: The taxing nature of surgery residency is well-documented in the literature, with residents demonstrating high rates of burnout, depression, suicidal thoughts, sexual harassment, and racial discrimination. Mentoring has been shown to improve camaraderie, address challenges of underrepresentation in medicine, and be associated with lower burnout. However, existing formal mentoring programs tend to be career-focused and hierarchal without opportunity to discuss important sociocultural issues. An innovative approach is needed to address these cultural and anthropological issues in surgery residencies while creating camaraderie and learning alternative perspectives across different levels of training. We sought to describe the framework we used to fill these needs by creating and implementing a novel mentoring program. DESIGN: A vertical, near-peer mentoring system of 7 groups was created consisting of the following members: 1 to 2 medical students, a PGY-1 general surgery resident, a PGY-4 research resident, and a faculty member. Meetings occur every 3 to 4 months in a casual setting with the first half of the meeting dedicated to intentional reflection and the second half focused on an evidence-based discussion regarding a specific topic in the context of surgery (i.e., burnout, discrimination, allyship, and finding purpose). SETTING: Program implementation took place at the University of Michigan in Ann Arbor, MI. PARTICIPANTS: Medical students, general surgery residents, and general surgery faculty were recruited. CONCLUSIONS: We have successfully launched the pilot year of a cross-spectrum formal mentoring program in general surgery. This program emphasizes camaraderie throughout training while providing opportunities for evidence-based discussion regarding sociocultural topics. We have included increased opportunities for community inclusivity and mentoring while allowing trainees and faculty members to discuss sensitive topics in a supportive environment. We plan to continue developing the program with robust evaluation and to expand the program to other surgical specialties and to other institutions.

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.

Factors associated with disease-free and abdominal recurrence-free survival in abdominopelvic and retroperitoneal sarcomas.

BACKGROUND AND OBJECTIVES: Retroperitoneal and abdominopelvic sarcomas are rare heterogeneous malignancies. The only therapy proven to improve disease-free survival (DFS) is R0/R1 surgical resection. We sought to analyze whether additional factors such as radiation and systemic therapy were associated with DFS and abdominal recurrence-free survival (RFS). METHODS: Retrospective review of adults (≥18) with resectable abdominopelvic and retroperitoneal sarcomas who underwent intent-to-cure surgery at a high-volume tertiary referral center between 1998 and 2015. The main outcome measures were DFS and abdominal RFS. RESULTS: Overall, 159 patients met the criteria for inclusion. Median follow-up was 4.8 years (range 0.1-18.9 years). The most common histology was liposarcoma (49%). Systemic therapy was administered to 48% of patients and was not associated with improved outcomes. The neoadjuvant radiotherapy group (11%) had improved adjusted DFS (5.46 years, 95% CI [3.68, 7.24] vs. 3.1 years, 95% CI [2.48, 3.73]) and abdominal RFS (6.14 years, 95% CI [4.38, 7.89] vs. 3.22 years, 95% CI [2.61, 3.84]). The adjuvant radiotherapy group (19%) had no improvement. CONCLUSIONS: In a cohort of patients undergoing resection for retroperitoneal or abdominopelvic sarcoma, neoadjuvant radiation improved DFS and abdominal RFS. A follow-up of over three years was needed to appreciate a difference in outcomes.

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.

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.

Variations in Persistent Use of Low-Value Breast Cancer Surgery.

Importance: Through the Choosing Wisely campaign, surgical specialties identified 4 low-value breast cancer operations. Preliminary data suggest varying rates of deimplementation and have identified patient-level and clinician-level determinants of continued overuse. However, little information exists about facility-level variation or determinants of differential deimplementation. Objective: To identify variation and determinants of persistent use of low-value breast cancer surgical care. Design, Setting, and Participants: Retrospective cohort study in which reliability-adjusted facility rates of each procedure were calculated using random-intercept hierarchical logistic regression before and after evidence demonstrated that each procedure was unnecessary. The National Cancer Database is a prospective cancer registry of patients encompassing approximately 70% of all new cancer diagnoses from more than 1500 facilities in the United States. Data were analyzed from November 2019 to August 2020. The registry included women 18 years and older diagnosed as having breast cancer between 2004 and 2016 and meeting inclusion criteria for each Choosing Wisely recommendation. Main Outcomes and Measures: Rate of each low-value breast cancer procedure based on facility type and breast cancer volume categories before and after the release of data supporting each procedure's omission. Results: The total cohort included 920 256 women with a median age of 63 years. Overall, 86% self-identified as White, 10% as Black, 3% as Asian, and 4.5% as Hispanic. Most women in this cohort were insured (51% private and 47% public), were living in a metropolitan or urban area (88% and 11%, respectively), and originated from the top half of income-earning households (65.5%). While there was significant deimplementation of axillary lymph node dissection and lumpectomy reoperation in response to guidelines supporting omission of these procedures, rates of contralateral prophylactic mastectomy and sentinel lymph node biopsy in older women increased during the study period. Academic research programs and high-volume facilities overall demonstrated the greatest reduction in use of these low-value procedures. There was significant interfacility variation for each low-value procedure. Facility-level axillary lymph node dissection rates ranged from 7% to 47%, lumpectomy reoperation rates ranged from 3% to 62%, contralateral prophylactic mastectomy rates ranged from 9% to 67%, and sentinel lymph node biopsy rates ranged from 25% to 97%. Pearson correlation coefficient for each combination of 2 of the 4 procedures was less than 0.11, suggesting that hospitals were not consistent in their deimplementation performance across all 4 procedures. Many were high outliers in one procedure but low outliers in another. Conclusions and Relevance: Interfacility variation demonstrates a performance gap and an opportunity for formal deimplementation efforts targeting each procedure. Several facility-level characteristics were associated with differential deimplementation and performance.

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.

Teamwork at the Bench: Strategies for Collaborative Surgical Science in a Pandemic.

The Center for Basic and Translational Science was formed to address the unique challenges faced by surgeon-scientists. Shortly after its inception, COVID-19 upended research workflows at our institution. We discuss how the collaborative Center for Basic and Translational Science framework was adapted to support laboratories during the pandemic by assisting with ramp-down, promoting mentorship and community building, and maintaining research productivity.

Management of the positive sentinel lymph node in the post-MSLT-II era.

BACKGROUND AND OBJECTIVES: The publication of MSLT-II shifted recommendations for management of sentinel lymph node biopsy positive (SLNB+) melanoma to favor active surveillance. We examined trends in immediate completion lymph node dissection (CLND) following publication of MSLT-II. METHODS: Using a prospective melanoma database at a high-volume center, we identified a cohort of consecutive SLNB+ patients from July 2016 to April 2019. Patient and disease characteristics were analyzed with multivariate logistic regression to examine factors associated with CLND. RESULTS: Two hundred and thirty-five patients were included for analysis. CLND rates were 67%, 33%, and 26% for the year before, year after, and second-year following MSLT-II. Factors associated with undergoing CLND included primary located in the head and neck (59% vs 33%, P = .003 and odds ratio [OR], 5.22, P = .002) and higher sentinel node tumor burden (43% vs 10% for tumor burden ≥0.1 mm, P < .001 and OR, 8.64, P = .002). CONCLUSIONS: Rates of CLND in SLNB+ melanoma decreased dramatically, albeit not uniformly, following MSLT-II. Factors that increased the likelihood of immediate CLND were primary tumor located in the head and neck and high sentinel node tumor burden. These groups were underrepresented in MSLT-II, suggesting that clinicians are wary of implementing active surveillance recommendations for patients perceived as higher risk.

Shock index, pediatric age-adjusted (SIPA) is more accurate than age-adjusted hypotension for trauma team activation.

BACKGROUND: We demonstrated previously that shock index, pediatric age-adjusted identifies severely injured children accurately after blunt trauma. We hypothesized that an increased shock index, pediatric age-adjusted would identify more accurately injured children requiring the highest trauma team activation than age-adjusted hypotension. METHODS: We reviewed all children age 4-16 admitted after blunt trauma with an injury severity score ≥15 from January 2007-June 2013. Criteria used as indicators of need for activation of the trauma team included blood transfusion, emergency operation, or endotracheal intubation within 24 hours of admission. Shock index, pediatric age-adjusted represents maximum normal shock index based on age. Cutoffs included shock index >1.22 (ages 4-6), >1.0 (7-12), and >0.9 (13-16). Age-adjusted cutoffs for hypotension were as follows: systolic blood pressure <90 (ages 4-6), systolic blood pressure <100 (7-16). RESULTS: A total of 559 children were included; 21% underwent operation, 37% endotracheal intubation, and 14% transfusion. Hypotension alone predicted poorly the need for operation (13%), endotracheal intubation (17%), or transfusion (22%). Operation (30%), endotracheal intubation (40%), and blood transfusion (53%) were more likely in children with an increased shock index, pediatric age-adjusted; 25 children required all three interventions, 3 (12%) were hypotensive at presentation, 15 (60%) had an increased shock index, pediatric age-adjusted (P < .001). CONCLUSION: An increased shock index, pediatric age-adjusted is superior to age-adjusted hypotension to identify injured children likely to require emergency operation, endotracheal intubation, or early blood transfusion.

Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects.

CONTEXT: A substantial number of obese individuals are relatively insulin sensitive and the etiology for this variation remains unknown. OBJECTIVE: The primary objective was to detect factors in adipose tissue differentiating obese insulin-sensitive (OBIS) from obese insulin-resistant (OBIR) individuals and investigate whether adipose tissue hypoxia is a contributing factor in the pathogenesis of insulin resistance. DESIGN AND SETTING: This was a cross-sectional study in the general community. PARTICIPANTS: Subjects consisted of nondiabetic OBIS and OBIR subjects with similar body mass index, age, and total body fat but different insulin sensitivity index as well as lean insulin-sensitive subjects. INTERVENTIONS(S): There were no interventions. MAIN OUTCOME MEASURE(S): We examined adipocytokines and the expression of candidate genes regulating hypoxia, inflammation, and lipogenesis in adipose tissue and adipose tissue oxygenation. RESULTS: OBIS subjects had increased plasma adiponectin but similar plasma TNFα and leptin levels as compared with OBIR subjects. Genes regulating inflammation (CD68, MCP1, scavenger receptor A, and oxidized LDL receptor 1) were increased by 40%­60% (P < .05) in OBIR vs OBIS cohorts. In addition, genes involved in extracellular matrix formation such as collagen VI and MMP7 were up-regulated by 43% and 78% (P < .05), respectively, in OBIR vs OBIS. The expression of HIF1α and VEGF gene expression was increased by 37% and 52%, respectively, in OBIR vs OBIS (P < .01). Despite the differential expression in hypoxia-related genes, adipose tissue oxygenation measured by a Licox oxygen probe was not different between OBIS and OBIR subjects, but it was higher in lean subjects as compared with obese subjects. CONCLUSIONS: We confirmed that adipose tissue inflammation and fibrosis play an important role in the pathogenesis of insulin resistance independent of obesity in humans. Whether hypoxia is simply a consequence of adipose tissue expansion or is related to the pathogenesis of obesity-induced insulin resistance is yet to be understood.

Pharmacodynamic Effects of Low-Dose Pioglitazone in Patients with the Metabolic Syndrome without Diabetes Mellitus.

STUDY OBJECTIVE: To determine the effects of low-dose pioglitazone on plasma adipocyte-derived cytokines, high-sensitivity C-reactive protein (hs-CRP), and components of the metabolic syndrome in adults with the metabolic syndrome without diabetes mellitus. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University of Colorado Clinical and Translational Research Center. PATIENTS: Thirty-two men and women, aged 30-60 years, without diabetes who had a clinical diagnosis of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute criteria. INTERVENTION: Patients were randomly assigned to receive oral pioglitazone 7.5 mg daily or matching placebo for 8 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was the change in plasma high-molecular-weight (HMW) adiponectin level from baseline to week 8. Other end points were changes in plasma total adiponectin, omentin, and hs-CRP levels, and changes in components of the metabolic syndrome (e.g., insulin sensitivity) from baseline to week 8. Pioglitazone was associated with a significant increase in plasma HMW adiponectin from baseline to week 8 compared with placebo (+47% vs -10%, p<0.001). Insulin sensitivity increased significantly from baseline to week 8 in the pioglitazone group (+88%, p=0.02) but not in the placebo group (+15%, p=0.14). Change in HMW adiponectin was significantly correlated with the change in insulin sensitivity in the pioglitazone group (r = 0.784, p=0.003). No significant differences in mean percentage changes in plasma total adiponectin, omentin, and hs-CRP levels were observed between the pioglitazone and placebo groups. Likewise, changes in body weight, insulin sensitivity, glucose, lipids, and blood pressure did not differ significantly between the groups. CONCLUSION: Low-dose pioglitazone favorably modulates plasma HMW adiponectin, which was associated with an improvement in insulin sensitivity, in patients with the metabolic syndrome without diabetes.