Citations

BACKGROUNDPrevious research has demonstrated that cancer survivors often fail to receive recommended care and also undergo unnecessary care; this reduces care quality and increases costs.METHODSThis phase 2 trial randomized 100 stage 0 to IIIa breast cancer patients who had primary care providers within a large Massachusetts‐based hospital network (with accessible online records) to either coordinated follow‐up care (CC), which entailed a tailored survivorship care plan (SCP) and patient navigator calls every 3 months, or standard care (SC), which did not include an SCP or patient navigation, for 1 year after the completion of their last chemotherapy, surgery, or radiation treatment. The primary endpoint was the frequency of redundant examinations (>1 breast/chest wall examination per patient within any 30‐day period in the absence of a new breast or chest wall complaint) over the year of follow‐up. The total number of non–plastic surgery visits in the year of follow‐up was a secondary endpoint.RESULTSTwo patients (both on CC) were ineligible, and 2 patients (1 per arm) had a recurrence or died during follow‐up; this left 96 for analysis (47 in the CC arm and 49 in the SC arm). Twenty‐two of the 47 CC patients (47%; 95% confidence interval, 32%‐62%) and 19 of the 49 SC patients (39%; 95% confidence interval, 25%‐54%) had 1 or more redundant breast/chest wall examinations during the year. The median number of non–plastic surgery visits was 12 for CC patients and 8 for SC patients.CONCLUSIONSEarly‐stage breast cancer patients visit health care providers very frequently during their first year of follow‐up and often receive unnecessary breast/chest wall examinations. An SCP and patient navigator calls did not reduce this surrogate for redundant care. Cancer 2016;122:3546–3554. © 2016 American Cancer Society

Galectin-9, a β-galactoside-binding protein, is defined as a negative regulator of T helper 1 (Th1) immune responses, favoring Th2 bias. Systemic immunity in patients with metastatic melanoma is predominantly Th2 biased. We hypothesized that galectin-9 can modulate systemic immunity toward Th2 polarization in patients with advanced melanoma. The presence or concentration of galectin-9 was assessed in tumors and plasma, in patients with metastatic melanoma. The immunomodulatory function of galectin-9 was determined by exposing human peripheral blood mononuclear cells to galectin-9 in vitro. Galectin-9 was expressed in 57% of tumors and was significantly (3.6-fold) increased in the plasma of patients with advanced melanoma compared with healthy controls (P<0.001). High plasma galectin-9 concentration was associated with systemic Th2 polarization and reduced 2-year survival compared with low/no galectin-9 expression. In-vitro, galectin-9 reduced proliferation of healthy peripheral blood mononuclear cells, and promoted Th1 cell apoptosis, Th2-biased cell phenotypes, and cytokine secretion. Galectin-9 also stimulated monocyte differentiation toward an M2 macrophage phenotype, as assessed by chemokine/cytokine secretion and CD206 expression, observed both in vitro as well as in patients with metastatic melanoma. Elevated galectin-9 in patient plasma correlated with Th2 systemic bias and less favorable clinical outcomes for patients with metastatic melanoma. This Th2 bias appears to be not only a feature of the known mechanisms of Th1 apoptosis by T-cell immunoglobulin and mucin-domain containing-3 binding, but also mediated by myeloid cell differentiation toward an M2 phenotype, that favors tumor progression. These data support galectin-9 as a novel therapeutic target for patients with metastatic melanoma.

Background. Previous studies have demonstrated that men are more likely than women to slow in the marathon (footrace). This study investigated whether the sex difference in pacing occurs for a shorter race distance. Materials & Methods. Data were acquired from the Bolder Boulder 10 km road race for the years 2008–2013, which encompassed 191,693 performances. There were two pacing measures, percentage change in pace of the first 3 miles relative to the final 3.2 miles and percentage change in pace of the first mile relative to the final 5.2 miles. Pacing was analyzed as a continuous variable and as two categorical variables, as follows: “maintain the pace,” defined as slowing <5% and “marked slowing,” defined as slowing ≥10%. Results. Among the fastest ( men < 48:40; women < 55:27) and second fastest ( men < 53:54; women < 60:28) sex-specific finishing time sextiles, men slowed significantly more than women with both pacing measures, but there were no consistently significant sex differences in pacing among the slower four sextiles. For the fastest sextile, the odds for women were 1.96 (first pacing measure) and 1.36 (second measure) times greater than men to maintain the pace. For the fastest sextile, the odds for women were 0.46 (first measure) and 0.65 (second measure) times that of men to exhibit marked slowing. Multiple regression indicated that being older was associated with lesser slowing, but the sex difference among faster runners persisted when age was controlled. Conclusions. There was a sex difference in pacing during a 10 km race where glycogen depletion is not typically relevant. These results support the hypothesis that the sex difference in pacing partly reflects a sex difference in decision making.

Fracture risk is significantly increased in both type 1 and type 2 diabetes, and individuals with diabetes experience worse fracture outcomes than normoglycemic individuals. Factors that increase fracture risk include lower bone mass in type 1 diabetes and compromised skeletal quality and strength despite preserved bone density in type 2 diabetes, as well as the effects of comorbidities such as diabetic macro- and microvascular complications. In this Perspective, we assess the developing scientific knowledge regarding the epidemiology and pathophysiology of skeletal fragility in patients with diabetes and the emerging data on the prediction, treatment, and outcomes of fractures in individuals with type 1 and type 2 diabetes.

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 Objective: Onset and symptoms of menopause, and response to hormone therapy (HT) show large interindividual variability. SULT1A1 encodes for a highly expressed enzyme that metabolizes estrogens. We evaluated the relationship between genetic variation in SULT1A1, menopause age, symptoms, and response to HT. Methods: Women enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic were randomized to 48 months of treatment with oral conjugated equine estrogen (n = 34), transdermal 17β-estradiol (E2) (n = 33), or placebo (n = 35). Linear regression models and ANOVA were used to test for association of SULT1A1 copy number, rs3760091, rs750155, and rs9282861 (SULT1A1 ∗ 2), with age at menopause and symptoms, levels of estrogens (estrone [E1], estrone sulfate [E1S], E2, and estradiol sulfate [E2S]), before and after HT. Results: SULT1A1 gene copy number affected the minor allele frequency for each single nucleotide polymorphisms tested. Before administration of exogenous hormones, increasing number of G alleles at rs9282861 was associated with earlier age at menopause (P = 0.014), lower frequency of night sweats (P = 0.009), and less severe insomnia (P = 0.046). After 48 months of treatment, SULT1A1 genotype was not associated with the presence of menopausal symptoms. In women randomized to oral conjugated equine estrogen, increasing number of the A allele at rs750155 was associated with lower E1S and E2S (P = 0.004 and 0.017), whereas increasing number of the C allele at rs3760091 was associated with lower E2S/E2 (P = 0.044). Conclusions: Interindividual variability in onset of menopause and symptoms before initiation of HT is explained in part by genetic variation in SULT1A1 and may represent a step toward individualizing HT treatment decisions.

Purpose Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Abstract Background: Defects in homologous recombination (HR) DNA repair are common in high grade serous ovarian, peritoneal and fallopian tube carcinoma (HGSOC). Other than mutations in BRCA1 and BRCA2 (BRCA1/2), the molecular causes of HR deficiency have not been well delineated. The frequency of HR deficiency in non-serous ovarian carcinoma is not known. We previously identified that germline and somatic HR mutations in 13 genes in OC was associated with improved survival. We sought to replicate these data in an independent tumor set, while sequencing a larger number of DNA repair genes. Methods: We used BROCA-HR to sequence 65 DNA repair genes in germline (blood) and tumor DNA from 363 women with ovarian (262), peritoneal (91), or fallopian tube (10) carcinoma from an institutional tissue bank. Cox proportional hazards models, adjusted for stage and residual tumor after cytoreduction, were used to assess associations between mutations in DNA repair genes in HR or related pathways and overall survival from diagnosis. Results: In total, 96/363 (25%) patients had 59 germline and 45 somatic deleterious mutations in HR genes, including 34 germline and 22 somatic BRCA1/2 mutations. Damaging mutations found in other HR genes included 25 germline and 23 somatic in the following genes: 5 ATM, 6 ATR, 1 BAP1, 2 BARD1, 6 BLM, 2 BRIP1, 2 BRE, 1 BRCC3, 2 CHEK2, 1 ERCC1, 1 FANCG, 1 FANCI, 2 FANCL, 8 FANCM, 1 NBN, 2 PALB2, 1 RAD51D, 1 RBBP8, 1 SLX4, 1 UIMC1 and 1 XRCC2. Of 322 HGSOC, HR mutations occurred in 86 patients (26.7%) including 54 (16.8%) germline and 32 somatic (9.9%). HR mutation rates were similar across the different non-serous histologies. Of 13 clear cell OC, 2 (15.3%) had germline mutations in non-BRCA1/2 HR genes and 3 (23.1%) had PTEN/PIK3CA mutations. Of 27 endometrioid OC, 3 (11.1%) had HR mutations (1 germline BRCA1, and 2 non-BRCA1/2 somatic HR mutations). PTEN/PIK3CA mutations were identified in 9 (2.8%) HGSOC, 3 (23.1%) clear cell and 2 (7.5%) endometrioid. HR mutations demonstrated a trend towards improved long-term overall survival (hazard ratio = 0.78, 96% CI 0.57-1.05) after accounting for stage and debulking status. Conclusions: These data not only indicate that damaging HR mutations, both germline and somatic, are found in endometrioid and clear cell as well as HGSOC, but also confirm our previous results showing an association between HR mutations and improved overall survival in OC. We are now sequencing 163 additional non-serous OC to augment the current analysis and these data will be available at presentation. Citation Format: Maria I. Harrell, Matthew J. Maurer, Ethan P. Heinzen, Ming K. Lee, Kimberly R. Kalli, Kathy J. Agnew, Ann L. Oberg, Tom Walsh, Barbara M. Norquist, Lynn C. Hartmann, Scott H. Kaufmann, Elizabeth M. Swisher. Homologous recombination mutations and overall survival in high-grade serous, endometrioid, and clear cell ovarian carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A07.

Abstract Purpose: American Indian (AI) women have lower rates of cancer, but later stages of diagnosis and higher mortality than the US general population. We hypothesized that mediators found within different theoretical models of health behavior differentiate women who adhere to mammographic screening guidelines from those who do not. Such mediators may be useful in the design of interventions to increase adherence. Experimental Procedures: As a community-based participatory research project, tribal health, Indian Health Service representatives, and community representatives worked with the Mayo Clinic team to design a survey derived from 53 interviews with documented adherent and non-adherent women from one Bemidji Area tribe. The survey explored demographic characteristics and six theoretical mediators: Health Literacy, Social Networks, Planned Behavior, Social Norms, Social Support, and Health Beliefs. The survey was mailed to 1200 women with the goal of obtaining 600 responses. Women completing the survey were provided a modest gift card through an impartial third party who not know their names or responses. Responses were analyzed using Fisher's Exact Test or the Chi-square test where appropriate. Summary of Data: To date, we have achieved a 30% response rate (91 self-described non-adherent and 91 self-described adherent breast cancer screening (mammography) respondents). Mediators from the six theoretical models and demographic features do differentiate AI adherent and non-adherent screeners and may be useful for developing interventions to expand screening adherence. Among significant differences were the following with which adherence associates: (1) Demographic (≤0.01): being married, full-time employed, living at greater distances from health care facility, surgical menopause, and having had a breast biopsy. (2) Health Literacy (≤ 0.001): accurate conceptual understanding of annual mammogram, ultrasound, and family history as a risk factor. (To accommodate the survey format, we replaced the usual measures of health literacy (Short Test of Functional Health Literacy and Rapid Estimate of Adult Literacy in Medicine) for understanding of basic breast screening and breast cancer concepts.) (3) Social Networks (≤ 0.03): having mothers who have encouraged good health. (4) Planned Behavior (≤ 0.001): behavioral beliefs, and intentions. a.) Behavioral Beliefs : looking forward to getting my mammogram; getting my scheduled mammogram rather than accepting an invitation to be with friends; viewing my mammogram as very important. b) Intentions: expecting to screen in each of the next five years, and getting my next mammogram when it is scheduled. (5) Social Norms (≤ 0.001): role of family as a positive influence on my life. (6) Social Support (≤ 0.001): availability of family to comfort one in times of worry. (7) Health Beliefs (≤ 0.001): discounting physical limitations and exam discomfort as justifications for avoiding screening and believing there are no justifications for avoiding mammogram; knowing: how to prepare for a mammogram, what happens during the mammogram process, knowing a mammograms importance, knowing what to do if one feels something unusual in the breast, and knowing someone who has been diagnosed with breast cancer. Conclusions: No single theoretical model appears to differentiate adherent from non-adherent screeners, but mediators associated with each of the various models do differentiate these screeners. These differentiating mediators should be considered for how they might guide development of interventions to improve screening behavior. The self-report nature of the survey demands that results be considered as tentative and limited, in any case, to the respondents of this tribe. Citation Format: Wesley O. Petersen, Ann M. Nicometo, Corinna Sabaque. Do demographic characteristics and theoretical mediators of health behavior differentiate American Indian adherent mammographic screeners from non-adherent screeners? [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 B98.