Citations

BACKGROUNDPatients with FMS like tyrosine kinase 3 (FLT3)‐mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT).METHODSData from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes.RESULTSIn total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild‐type (WT) group (38% [95% confidence interval (CI), 30%‐45%] vs 28% [95% CI, 24%‐33%]; P = .04; relative risk, 1.60 [95% CI, 1.15‐2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia‐free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3‐year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%‐57%; WT group: 55%, 95% CI, 50%‐60%; P = .20).CONCLUSIONSThe current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long‐term survivors. Cancer 2016;122:3005‐3014. © 2016 American Cancer Society.

Abstract Background/Purpose: Cancer registry data suggests that Duval County (greater Jacksonville, FL) has the highest breast cancer mortality rate for African American (AA) women in the southeastern US. Recent research revealed that race, residence, and insurance were associated with significantly poorer breast cancer outcomes in this area. Therefore we conducted a series of focus groups with AA breast cancer survivors from the urban core of Jacksonville, FL to directly address the disparities observed in our quantitative data. Methods: A series of focus groups were conducted to obtain qualitative data topics that included: breast cancer beliefs; delays to diagnosis and treatment; disparities; and health behaviors. Results: A total of 56 AA breast cancer survivors living in the urban core, with either Medicaid or who were uninsured, participated in the focus groups. Mean age was 62 years, with an average of 3.4 years since diagnosis. Only 21% of women were employed. Participants reported their mean time to see a doctor initially for their breast cancer was 39 days, and mean time to first treatment was 178 days. Participants responded that fear, financial limitations, and personal beliefs played the biggest roles in delays to diagnosis and treatment. Participants responded that poor health behaviors, genetics, lack of education, and personal beliefs accounted for both causing breast cancer, and the disparities observed in breast cancer mortality, and felt that environmental factors from living in the urban core also contribute. Conclusions: Our findings highlight several areas for potential intervention to reduce disparities in breast cancer. Citation Format: Sarah Osian, Monica Albertie, David Monticalvo, Steven Ames, Laila Samiian, Gerardo Colon-Otero. Examining reasons for breast cancer disparities in African American women in Duval County, FL. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C06.

Abstract Background: Human papillomavirus (HPV) is a causative agent in cervical cancer as well as anal, oropharyngeal, penile, and vaginal/vulvar cancers. Licensed, effective HPV vaccines have been available in the U.S. since mid-2006 for females and late 2011 for males and are recommended up to age 26. Despite this, in 2014, only 39.7% of U.S. girls and 21.6% of boys 13 to 17 years of age completed the three-dose vaccine series. ‘Lack of knowledge’ was a primary reason cited among parents for not vaccinating their children. HPV vaccination rates are lower still among 19-26 year olds, particularly among the uninsured. We assessed awareness and knowledge of HPV disease, HPV-related cancers, and HPV vaccines among working, uninsured adults and used 2014 data from the Health Information National Trends Survey (HINTS cycle 4) as a national benchmark against which to compare our data. Methods: Self-administered surveys were offered to patients attending appointments at the Volunteers in Medicine (VIM) clinic in Jacksonville, FL between September 10, 2014 and October 24, 2014. VIM provides free primary care for working individuals without insurance living and/or working in Duval County. Patients were eligible to participate if they were at least 18 years of age, not in acute distress, and had not completed a survey during pilot-testing. Surveys were available in English and Spanish and contained a validated HPV knowledge measure assessing disease knowledge and vaccine knowledge. Additionally, HPV-related cancer knowledge was assessed: 5 HPV-related (cervical, anal, throat, penile, vaginal/vulvar) and 4 not currently known to be HPV-related (lung, breast, prostate, skin). High knowledge was defined as having a knowledge score in the upper quartile of positive values. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression to assess the association of demographic characteristics with having high knowledge of HPV, HPV vaccines, and HPV-related cancer. Additional models assessed individual cancers. During the study period 356 patients were eligible to participate; of these, 55 declined (84% participation rate). Of the 301 surveys, 5 surveys were excluded from analysis due to excessive missing data; a total of 296 surveys were analyzed. Results: 50.3% of participants (n=149) had heard of HPV, 37.2% (n=110) correctly indicated that HPV is sexually transmitted, and 32.1% (n=95) had heard of the HPV vaccine. In HINTS 4, these estimates were 63.6%, 44.0%, and 62.7%, respectively. In adjusted models, high HPV disease knowledge was associated with race (OR non-white = 0.39 (0.19, 0.78)) and education (OR >high school = 2.34 (1.14, 4.84)) while high HPV vaccine knowledge was associated with race (OR non-white = 0.42 (0.21, 0.82)), education (OR >high school = 5.04 (2.30, 11.06)), and sex (OR male = 0.34 (0.12, 0.94)). Of the HPV-related cancers, 43.9% answered correctly for cervical, 9.1% for anal, 11.1% for mouth/throat, 11.5% for penile, and 30.7% for vaginal/vulvar cancer. Males were less likely than females to know that HPV is a causative agent for cervical (OR=0.41 (0.22, 0.75)) and vaginal/vulvar cancers (OR=0.43 (0.22, 0.86)). Conclusion: Using estimates obtained in HINTS 4 as a benchmark, awareness and knowledge of HPV, HPV-related cancers, and HPV vaccines were low among working, uninsured adult patients. In addition to improving access to HPV vaccination (e.g. volunteer clinics), the findings demonstrate a need for strategies to educate medically underserved adults about HPV. Maximizing access to HPV vaccination, including catch-up vaccination for adults up to age 26 are consistent with the recommendations of the President's Cancer Panel, the American College of Obstetricians and Gynecologists, the American College of Physicians, and the Advisory Committee on Immunization Practices. Citation Format: Carmen Radecki Breitkopf, Lila Finney Rutten, Debra Jacobson, Patrick Wilson, Monica Albertie, Robert M. Jacobson, Gerardo Colon-Otero. Awareness and knowledge of HPV, HPV-related cancers, and HPV vaccines in a working, uninsured clinic population. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B91.

Abstract Background: It has been shown that t(14;18), a translocation involving IgH and BCL-2 genes that is present in over 80% of all cases of follicular lymphomas, is detectable in the peripheral blood of up to 52% of normal Caucasian patients from Germany and up to 16% of normal individuals from Japan (Yasukawa et al, Blood 2001). The fact that follicular lymphoma is one of the two most common lymphomas in the USA and Germany and much less common in Japan, demonstrates that this molecular alteration is perhaps an early event in the development of this malignancy which is not sufficient for its causation. There have not been any studies evaluating the prevalence of this translocation in healthy African American (AA) subjects. We speculated that the prevalence of this translocation will be lower in healthy AA subjects given the findings of lower prevalence of IgH translocations in AA patients with multiple myeloma compared with Caucasian patients, which may explain the better outcome of myeloma in AA subjects (Baker et al, Blood 2013). This effort to evaluate the prevalence of t (14; 18) in AA subjects, was part of a pilot study in which we brought an educational program on the importance of cancer research together with concomitant access to a translational research project to AA churches utilizing a mobile research unit in an attempt to overcome some of the known barriers to AA subject participation in clinical research (Colon-Otero et al, Cancer2008; Colon-Otero et al, J Cancer Educ 2012). Methods: IRB approval of the project was obtained and peripheral blood samples collected from consented subjects during educational sessions in Northeast Florida AA Churches. Caucasian subjects were identified from the Mayo Clinic Bio-bank. DNA was isolated from the buffy coat fractions and a PCR quality control assay targeting a 293bp fragment of an HLA class II gene was used to determine acceptable DNA quality and quantity. Next, a two-step semi-nested PCR was performed on the t (14;18) major and minor breakpoint cluster regions using ~500ng of DNA for each assay. A consensus JH primer was used in combination with primers complementary to BCL-2 sequences for both, the major and minor breakpoint cluster regions. PCR products were run on a 1% agarose gel. In order to confirm the positive results, positive PCR products were analyzed by direct sequence by Sanger method and subsequently assembled to the human genome using BLAST tool. Results: A total of 110 blood samples from AA subjects were analyzed for the presence of t (14;18). A total of 13 of the samples were positive for the major breakpoint site (12%) and 4 were positive for the minor breakpoint site (4%), for a total of 17 positive samples (15%). In 167 Caucasian patients samples, a total of 22 (13%) were positive for the major breakpoint site and 5 (3%) were positive for the minor breakpoint site for a total of 27 positive samples (16%). All cases were confirmed by Sanger sequencing. Conclusions: The prevalence of t(14;18) is not significantly different among African American and Caucasian subjects from the USA based on our findings. This represents the first report of the prevalence of t(14;18) in an African American population. The prevalence found in our Caucasian subjects is significantly lower than what had been described in previous population series. A plausible explanation is the high heterogeneity of approaches used across studies, significantly affecting the assay sensitivity. Additional studies with larger series may reveal minor differences in the prevalence of t(14;18) among these populations. Citation Format: Scott Van Wier, Gerardo Colon-Otero, Gregory Ahmann, Esteban Braggio, Monica Albertie, Sikander Ailawadhi, Rafael Fonseca. Similar prevalence of t(14,18) in African American and Caucasian subjects. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B48.

Abstract There is a paucity of data on African Americans in community-based research secondary to difficulties in recruitment. These challenges include transportation, outreach barriers, fear and mistrust of researchers, lack of knowledge about disorder/issue under study, and lack of incentives. We hypothesized that we could improve recruitment in rural African American women by engaging community centers such as churches, community health centers, and doctor's offices. Over a 1 month period, we sought to recruit 40 women for a community based research project with a primary outcome of increasing activity in rural African American women (45-70 years old) with knee pain. The outlets used to recruit these women included: five churches with a community liaison, many primary care physicians' offices, and a newspaper ad. In 1 month, 67 women expressed interest in our program by initiating contact. Of those 67 women, 42 were eligible and 37 were enrolled. Of the 42 eligible women, 24 were recruited from churches, 11 through word of mouth, 3 from physicians' offices, and 3 from the newspaper ad. Lack of literature on how to recruit in rural African American communities is a significant barrier to research participation among African Americans. In this project, we provide a reproducible recruitment process for engaging rural African American women in community based research. While our primary focus was knee pain, this recruitment process can easily be translated into other areas of community based research including cancer and cardiovascular disease among others. Citation Format: Michelle Scott, Tamara Huff, Monica Albertie, Gerardo Colon-Otero. Recruitment methods for engaging rural African American populations in community-based research. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr A27.

Abstract Background LIV-1, a multispan transmembrane protein and downstream target of STAT3, is highly expressed in breast cancer cells (Sussman 2014). It has been associated with lymph node involvement and linked with malignant progression to metastasis (Manning 1994). SGN-LIV1A is an anti-LIV-1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE). Upon binding to cell-surface LIV-1, SGN-LIV1A is internalized and releases MMAE, which binds to tubulin and induces G2/M arrest and apoptosis. Methods A phase 1, open-label, dose-escalation study is ongoing to evaluate the safety, tolerability, antitumor activity, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of SGN-LIV1A monotherapy (q3 wks IV) in women with LIV-1-positive, metastatic breast cancer (MBC) (NCT01969643). Patients (pts) with either hormone receptor-positive/HER2-negative (HR+/HER2–) or triple-negative (TN) disease were eligible if they had measurable disease and received ≥2 prior cytotoxic regimens in the metastatic setting. Pts with ≥ Grade 2 neuropathy were excluded. Response was assessed per RECIST v1.1, and pts with stable disease (SD) or better were eligible to continue treatment until disease progression or intolerable toxicity. Fresh tumor biopsies were obtained pre- and post-treatment to evaluate the LIV-1 expression-response relationship, mechanism of action, and tumor sensitivity to SGN-LIV1A. Results To date, 21 pts (17 HR+/HER2–, 4 TN) have received a median of 3 cycles (range, 1–7) of SGN-LIV1A at doses of 0.5–2.8 mg/kg. Median age was 58 yrs (range, 34–73), and pts had a median of 8 prior systemic metastatic therapies (range, 2–15). At baseline, 19 pts had visceral disease and 15 had bone involvement. No dose-limiting toxicities (DLTs) in Cycle 1 were observed in the 18 DLT-evaluable pts; MTD has not yet been identified. Treatment-emergent adverse events (AEs) reported in ≥30% of pts were primarily Grade 1/2 in severity and were: nausea (57%), fatigue and peripheral neuropathy (43% each), alopecia (38%), and vomiting (33%). Two pts discontinued treatment due to AEs (1 nausea, 1 tachycardia). Preliminary PK data suggest a linear increase in antibody-drug conjugate (ADC) exposure with increasing dose. In the 19 efficacy-evaluable pts, the overall response rate (ORR) was 11% (2 partial responses [PRs]) with clinical benefit of SD or better achieved in 63% (2 PR, 10 SD) of pts. Of note, all 4 pts with TN MBC achieved clinical benefit: 2 PR and 2 SD. Currently, the median duration of clinical benefit is 12.7 wks (range, 6.1–26.3). Four pts remain on treatment. To date, of the 179 MBC tumor specimens evaluated for LIV-1, 156 (87%) were LIV-1-positive; moderate-to-high LIV-1 expression (H-score ≥100) was present in 91% (94 of 103) of HR+/HER2– and 81% (47 of 58) of TN samples. Conclusions LIV-1 is expressed in the majority of metastatic breast cancer tissue samples, with moderate-to-high expression in both HR+/HER2- and TN disease. To date, SGN-LIV1A monotherapy has been generally well tolerated and resulted in a clinical benefit of SD or better in 63% of these heavily pre-treated pts, including 2 PRs in the 4 TN MBC pts. Response duration data continue to evolve. Clinical subtype-specific expansion cohorts are planned. Citation Format: Forero A, Burris III H, Mita M, Specht J, Weise A, Liu MC, Modi S, Pusztai L, Kostic A, Yang J, Li M, Hengel S, Miller K. Interim analysis of a phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-14-05.

Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes.

Currently, no standard defines the clinical skills that medical students must demonstrate upon graduation. The Liaison Committee on Medical Education bases its standards on required subject matter and student experiences rather than on observable educational outcomes. The absence of such established outcomes for MD graduates contributes to the gap between program directors’ expectations and new residents’ performance. In response, in 2013, the Association of American Medical Colleges convened a panel of experts from undergraduate and graduate medical education to define the professional activities that every resident should be able to do without direct supervision on day one of residency, regardless of specialty. Using a conceptual framework of entrustable professional activities (EPAs), this Drafting Panel reviewed the literature and sought input from the health professions education community. The result of this process was the publication of 13 core EPAs for entering residency in 2014. Each EPA includes a description, a list of key functions, links to critical competencies and milestones, and narrative descriptions of expected behaviors and clinical vignettes for both novice learners and learners ready for entrustment. The medical education community has already begun to develop the curricula, assessment tools, faculty development resources, and pathways to entrustment for each of the 13 EPAs. Adoption of these core EPAs could significantly narrow the gap between program directors’ expectations and new residents’ performance, enhancing patient safety and increasing residents’, educators’, and patients’ confidence in the care these learners provide in the first months of their residency training.