CDK4/6 Inhibition With Lerociclib is a Potential Therapeutic Strategy for the Treatment of Pediatric Sarcomas.

BACKGROUND: Sarcomas are a heterogenous collection of bone and soft tissue tumors. The heterogeneity of these tumors makes it difficult to standardize treatment. CDK 4/6 inhibitors are a family of targeted agents which limit cell cycle progression and have been shown to be upregulated in sarcomas. In the current preclinical study, we evaluated the effects of lerociclib, a CDK4/6 inhibitor, on pediatric sarcomas in vitro and in 3D bioprinted tumors. METHODS: The effects of lerociclib on viability, proliferation, cell cycle, motility, and stemness were assessed in established sarcoma cell lines, U-2 OS and MG-63, as well as sarcoma patient-derived xenografts (PDXs). 3D printed biotumors of each of the U-2 OS, MG-63, and COA79 cells were utilized to study the effects of lerociclib on tumor growth ex vivo. RESULTS: CDK 4/6, as well as the intermediaries retinoblastoma protein (Rb) and phosphorylated Rb were identified as targets in the four sarcoma cell lines. Lerociclib treatment induced cell cycle arrest, decreased proliferation, motility, and stemness of sarcoma cells. Treatment with lerociclib decreased sarcoma cell viability in both traditional 2D culture as well as 3D bioprinted microtumors. CONCLUSIONS: Inhibition of CDK 4/6 activity with lerociclib was efficacious in traditional 2D sarcoma cell culture as well as in 3D bioprints. Lerociclib holds promise and warrants further investigation as a novel therapeutic strategy for management of these heterogenous groups of tumors.

The impact of social constraints on insomnia among African-American breast cancer survivors: The mediating role of fear of recurrence.

OBJECTIVE: Insomnia is a significant concern among African-American breast cancer survivors (BCS). Social constraints (SC)-receiving unsupportive or critical responses when expressing trauma-related emotions-and fear of recurrence (FOR) have been associated with insomnia. We examined FOR as a mediator in the relationship between SC and insomnia in African-American BCS. We hypothesized a direct effect of SC on insomnia, and an indirect effect of SC on insomnia through FOR. METHODS: Sixty-four African-American BCS completed a questionnaire assessing demographics, clinical characteristics, SC, FOR, and insomnia. Participants were an average of M = 8.41 (SD = 5.8) year survivors. The mediation was tested using PROCESS for SPSS. RESULTS: The direct effect of SC on insomnia was significant (direct effect = .17, SE = .08, P = .04). Moreover, the indirect effect of SC on insomnia through FOR was significant (indirect effect = .19, SE = .10, 95% CI = .05, .41). CONCLUSIONS: Experiencing SC from family and friends could produce cognitions that impact sleep for BCS, and FOR could be one of those cognitions. Family-based models of care that emphasize the emotional needs of survivors and families could be a relevant strategy to address the SC that impacts sleep.

A Restorative Yoga Intervention for African-American Breast Cancer Survivors: a Pilot Study.

BACKGROUND: Data show that yoga is effective for improving health-related outcomes in breast cancer survivors. While breast cancer is the most commonly diagnosed cancer among African-American women (AAW), AAW are less likely to engage in yoga compared to other ethnic groups. The goals of the current study were to assess the feasibility of an 8-week restorative yoga program among African-American breast cancer survivors (AA BCS). Specifically, study aims were to (1) measure changes in study outcomes in a restorative yoga (RY) group compared to a wait list control group, (2) assess adherence to the RY program, and (3) assess program satisfaction among study participants. METHODS: Thirty-three AA BCS were randomly assigned to either the RY intervention (n = 18) or wait list control group (n = 15). RY classes met once per week for 8 weeks. Pre- and post-testing assessments were measured at 0 and 8 weeks (immediately post-intervention). RESULTS: Depression scores at follow-up were significantly lower in the yoga group (M = 4.78, SD = 3.56) compared to the control group (M = 6.91, SD = 5.86). No significant group differences were observed for sleep quality, fatigue, or perceived stress. Yoga program participants completing baseline assessments demonstrated 61% adherence to the yoga classes. Average rating of the yoga program was "very useful." Recommendations for future yoga programs were provided. CONCLUSIONS: This study suggests that yoga has a beneficial effect on depression in AA BCS. There is, however, a need to further explore the benefits of yoga among minority breast cancer survivors using a study with larger sample sizes.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA Mutation-Associated Advanced Ovarian Cancer.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx BRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44-64], and median duration of response was 9.2 months (95% CI, 6.6-11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165-70. ©2017 AACRSee related commentary by Kohn et al., p. 7155.

Correlates of Triple Negative Breast Cancer and Chemotherapy Patterns in Black and White Women With Breast Cancer.

BACKGROUND: Triple negative breast cancer (TNBC) tumors are estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor-negative. TNBC is responsive to chemotherapy, but chemotherapy might be underused in some patient subgroups. The goal of the present study was to characterize the patterns of chemotherapy use (uptake and completion) in TNBC patients. PATIENTS AND METHODS: Women with primary invasive, nonmetastatic breast cancer were recruited in Washington, DC, and Detroit. Data were collected using a standardized telephone survey that captured sociocultural and health care process factors. Clinical data were abstracted from the medical records. We used χ2 tests to access the association between the receipt of chemotherapy use (initiation and completion) and categorical variables, and t tests were used for continuous variables. Logistic regression models were used to evaluate the factors associated with chemotherapy uptake. RESULTS: Women with TNBC (16% of sample) were more likely to be black than white (68% vs. 32%; P < .05). Among women with TNBC, 60% underwent chemotherapy. Chemotherapy uptake was greater for black than for white women (48.3% vs. 11.7%; P = .01) and in women without (vs. with) healthcare discrimination (35% vs. 25%; P = .04). In multivariable models, only race was associated with the receipt of chemotherapy. Black women were more likely to receive chemotherapy than were white women. The odds ratio of receiving chemotherapy by race was 4.1 (95% confidence interval, 1.3-13.1). Each 1-year increase in age was associated with a lower likelihood of chemotherapy completion (odds ratio, 0.9; 95% confidence interval, 0.826-0.981; P = .02). Women with at least some college were less likely to complete chemotherapy than were those with other education levels (P = .02). CONCLUSION: A substantial number of TNBC patients failed to receive and/or complete chemotherapy. Differences in chemotherapy uptake by race and sociocultural factors diminished in multivariable models but age and stage remained significant. Suboptimal treatment among women with TNBC could contribute to adverse outcomes. Future investigations are necessary to assess whether the noninitiation and/or noncompletion of chemotherapy is clinically warranted.

Predictors of Self-Reported Family Health History of Breast Cancer.

The objective of this study was to identify predictors of self-reported family health history of breast cancer in an ethnically diverse population of women participating in a breast cancer screening program. Participants completed a self-administered questionnaire about their demography, health, breast health and family health history of breast cancer. The association between family health history of breast cancer and categorical variables were analyzed using the T test, chi square, and multi-nominal logistic regression. Those who were least likely to report a family history of cancer were African Americans (p = 0.02), and immigrant women from South America (p < 0.001) and Africa (p = 0.04). However, 34.4 % reported having a second-degree maternal relative with breast cancer compared to 6.9 % who reported having a second degree paternal relative with breast cancer. Therefore, there is a need to increase efforts to educate families about the importance of collecting and sharing one's family health history.

Disparities in breast cancer surgery delay: the lingering effect of race.

BACKGROUND: Delays to surgical breast cancer treatment of 90 days or more may be associated with greater stage migration. We investigated racial disparities in time to receiving first surgical treatment in breast cancer patients. METHODS: Insured black (56 %) and white (44 %) women with primary breast cancer completed telephone interviews regarding psychosocial (e.g., self-efficacy) and health care factors (e.g., communication). Clinical data were extracted from medical charts. Time to surgery was measured as the days between diagnosis and definitive surgical treatment. We also examined delays of more than 90 days. Unadjusted hazard ratios (HRs) examined univariate relationships between delay outcomes and covariates. Cox proportional hazard models were used for multivariate analyses. RESULTS: Mean time to surgery was higher in blacks (mean 47 days) than whites (mean 33 days; p = .001). Black women were less likely to receive therapy before 90 days compared to white women after adjustment for covariates (HR .58; 95 % confidence interval .44, .78). Health care process factors were nonsignificant in multivariate models. Women with shorter delay reported Internet use (vs. not) and underwent breast-conserving surgery (vs. mastectomy) (p < .01). CONCLUSIONS: Prolonged delays to definitive breast cancer surgery persist among black women. Because the 90-day interval has been associated with poorer outcomes, interventions to address delay are needed.

Patterns of 21-gene assay testing and chemotherapy use in black and white breast cancer patients.

BACKGROUND: In women with early stage, hormone receptor (HR)-positive (HR(+)) breast cancer, the 21-gene recurrence score (RS) assay quantifies recurrence risk and predicts chemotherapy responsiveness. Recent data suggest that not all women with early-stage, HR(+) disease receive this testing. We examined sociodemographic, clinical, and attitudinal factors associated with RS testing receipt and the RS testing effect on chemotherapy use in black and white patients. PATIENTS AND METHODS: Women with newly diagnosed invasive, nonmetastatic breast cancer were recruited and interviewed to collect sociocultural and health care process data; clinical data were collected from charts. Of the sample (n = 359), 270 had HR(+) disease. Primary analysis focused on those with HR(+) node-negative disease (n = 143); secondary analyses included node-positive women. Logistic regression models evaluated factors associated with receipt of RS testing and chemotherapy. RESULTS: Among women eligible for the 21-gene assay, 62 patients [43%] received RS testing. In multivariable analysis, older age (odds ratio, 1.04 per 1 year increase; 95% confidence interval, 1.01-1.08) was associated with RS testing after adjustment for covariates. Chemotherapy use was 23%. In multivariable analysis, positive attitudes about chemotherapy and greater risk of recurrence were associated with chemotherapy use (P < .05). CONCLUSION: Patterns of genomic testing might vary according to age. Efforts to understand factors associated with low testing rates will be important.

Computer-based cognitive training for individuals with intellectual and developmental disabilities: pilot study.

BACKGROUND: There is a growing focus in the United States on preserving cognitive functioning. However, individuals with intellectual and developmental disabilities (ID/DD) are not provided with opportunities to prevent cognitive decline. To investigate whether participants with ID/DD would improve in cognitive function after cognitive training, a cognitive training group (N = 11) was compared to 2 control groups, a computer games group (N = 11) and a waitlist group (N = 10) on performance on 15 cognitive functions. FINDINGS: (1) Very high adherence rates (94%) of the sample and 100% of the cognitive training group indicate that when given adequate individual support, adults with ID/DD can successfully use a cognitive stimulation program. (2) No significant between- or within-group effects were observed for cognitive training when a stringent α, corrected for multiple comparisons, was used. (3) Trends of improvement in cognitive function were observed for the cognitive training group.

Effect of lung cancer screening awareness on smoking cessation behavior.

BACKGROUND AND OBJECTIVES: Emphasizing the risk of lung cancer can encourage smoking cessation; however, computerized tomography (CT) scans reduced lung cancer mortality in a recent randomized screening trial. We postulated that awareness of lung cancer screening test will negatively impact smoking cessation behavior. METHODS: We identified 7,141 respondents who answered questions concerning their smoking-related behavior in the 2007 Health Information National Trends Survey (HINTS). We used survey weights in all analyses and used logistic regression models to assess the association of smoking status with awareness of lung cancer screening tests and evaluated smoking cessation behaviors. RESULTS: Overall, 2,183 (27.6%) of respondents had heard of a lung cancer screening test (26.9% among never smokers, 29.6% among former smokers, and 27.1% among current smokers). Smoking status was not associated with awareness of lung cancer screening tests. Among current smokers, awareness of lung cancer screening had no effect on quit attempts in the previous 12 months (OR=1.14, 95% CI=0.68-1.91) and consideration to quit in the next 6 months (OR=1.08; 95% CI=0.69-1.67). CONCLUSIONS: Smoking cessation should be recommended for all current smokers, and those with a history of smoking should be informed about lung cancer screening with CT scan.

Narrowing racial gaps in breast cancer chemotherapy initiation: the role of the patient-provider relationship.

Chemotherapy improves breast cancer survival but is underused more often in black than in white women. We examined associations between patient-physician relationships and chemotherapy initiation and timeliness of initiation among black and white patients. Women with primary invasive, non-metastatic breast cancer were recruited via hospitals (in Washington, DC and Detroit) and community outreach between July 2006 and April 2011. Data were collected via telephone interviews and medical records. Logistic regression models evaluated associations between chemotherapy initiation and independent variables. Since there were race interactions, analyses were race-stratified. Factors associated with time from surgery to chemotherapy initiation and delay of ≥90 days were evaluated with linear and logistic regressions, respectively. Among eligible women, 82.8 % were interviewed and 359 (90.9 %) of those had complete data. The odds of initiating chemotherapy were 3.26 times (95 % CI: 1.51, 7.06) higher among black women reporting greater communication with physicians (vs. lesser), after considering covariates. In contrast, the odds of starting chemotherapy were lower for white women reporting greater communication (vs. lesser) (adjusted OR 0.22, 95 % CI: 0.07, 0.73). The opposing direction of associations was also seen among the sub-set of black and white women with definitive clinical indications for chemotherapy. Among those initiating treatment, black women had longer mean time to the start of chemotherapy than whites (71.8 vs. 55.0 days, p = 0.005), but race was not significant after considering trust in oncologists, where initiation time decreased as trust increased, controlling for covariates. Black women were also more likely to delay ≥90 days than whites (27 vs. 8.3 %; p = 0.024), but this was not significant after considering religiosity. The patient-physician dyad and sociocultural factors may represent leverage points to improve chemotherapy patterns in black women.

Distinct idiotypes of insulin autoantibody in autoimmune polyendocrine syndrome type 2 and childhood onset type 1 diabetes.

Insulin autoantibodies (IAA) are present in type 1 diabetes (T1D) and other autoimmune diseases. The differences in the IAA epitopes in various clinical diseases have not been evaluated. We used phage display to select phagotopes specific to IAA from a newly diagnosed T1D child (designated FPP) and from an adult-onset T1D subject with autoimmune polyendocrine syndrome type 2 (APS-II). The phagotopes randomly selected were tested as antiidiotope reagents to displace human radiolabeled insulin in the microfiltration radiobinding assay using IAA(+) sera from T1D subjects and insulin antibody (IA(+)) sera from insulin-treated type 2 diabetes subjects. The DNA of the phagotopes selected from the FPP and APS sera revealed consensus amino acid sequences of GRG and LGKRS, respectively. Phagotope FPP-10 displaced insulin binding in 90% of IAA(+) subjects but not in the IA(+) or the APS subject. Phagotope APS-4 was able to displace insulin binding from the APS subject but not in the IAA(+) or IA(+) subjects. We have demonstrated antiidiotope reagents able to distinguish childhood-onset T1D-associated IAA(+) from adult-onset T1D (APS-II-associated IAA(+)) that are different from their specificity for human insulin and from its antiidiotope amino acid sequence.