Citations

Abstract Background: Several randomized trials had shown the benefits of palliative care interventions in patients with metastatic cancer. However, there is a paucity of data evaluating the benefit of palliative care in racially diverse patient populations, and no systematic analysis of the effect of race/ethnicity on these interventions have been done. Recently, our group completed a randomized clinical trial showing that an Advanced Registered Nurse Practitioner (ARNP)-directed palliative care intervention for patients with metastatic cancer leads to improvement in the patients' emotional quality of life (EQoL) as determined by a validated quality of life tool, the FACT-G (PAL-1 study, Dyar et al: J Palliative Medicine 15: 890, 2012). The PAL-2 pilot study reported herein evaluated the feasibility of this program in underserved racially diverse patient populations. PAL-2 incorporated PAL-1 interventions of advanced directives discussions, hospice services education and assessment of QoL using the FACT-G tool. In addition, the PAL-2 program incorporated home visits and implementation of FACT-G driven palliative interventions. Aims: The primary endpoint was to assess the feasibility of an ARNP-directed palliative care intervention trial for racially diverse cancer patients. The ultimate goal was to use the data from this pilot study to plan for a subsequent larger randomized trial. Secondary end points included evaluation of the effects of the intervention on the patient's QoL and emotional well-being as determined by a change in FACT-G , EQoL scores, as well as measurement of knowledge about hospice as determined by changes in a hospice knowledge questionnaire (HKQ) scores. Methods: 25 adult patients with metastatic cancer were recruited. All patients completed a FACT-G and a HKQ at baseline, had an ARNP consultation, and a home visit whenever feasible, with a second ARNP consultation visit 4 weeks later. Results: Of 25 patients who participated (16 males, 9 females, mean age 57, age range 33-89, 16 Caucasians (C), 8 African Americans (AA), 1 Asian), 15 patients (8C, 7AA) completed their first and second ARNP consultation visits and 12 (5C, 7AA) completed all questionnaires and were available for secondary endpoint analysis. The main reason for failure to complete the study was disease progression. The most common interventions implemented were advanced directives discussions, assessment of family support, stress management education, assessment of psychological status, spirituality assessment, financial assistance programs, and pain and symptom management. Interventions offered but not selected by most patients included: use of computer based social networking tools, psychological interventions, occupational training and cancer support group participation. Home visits were completed in 11 patients and provided significant insight into the patients' needs and their available support. The palliative care intervention and the FACT-G tool were well accepted by patients. There was no significant change in the EQoL as a result of the intervention ( EQoL change, mean (SD)= -1.2 (13.52), median 3.7, p=0.6719). A trend was observed towards improvement in HKQ results (n=8, change from baseline score mean (SD)= 21.2 (29.58), median 15.4, p= 0.0938). Conclusions: The FACT-G tool was well received by the patients and providers, and its use can be incorporated into clinical care to direct palliative care interventions and assess their impact on patients' QoL. A nurse practitioner-directed palliative care intervention is well accepted by patients of diverse race. Significant attrition of participants due to disease progression (40%) will need to be considered in planning larger randomized trials. Randomized clinical trials evaluating the impact of race, ethnicity and socio-economic status on the benefits of different palliative care interventions in patients with metastatic cancer are feasible and needed. Citation Format: Gerardo Colon-Otero, Mary Lesperance, Fauzia Rana, Robert Shannon, Jeffrey Sloan. A nurse practitioner-directed palliative care intervention trial in racially diverse patients with metastatic cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A42.

Abstract Purpose: The study purpose is to learn whether theoretical mediators (Planned Behavior/Reasoned Action, Social Norms, Social Support, Social Networks, Health Beliefs, Health Literacy) can be used to distinguished American Indian women who are adherent with Indian Health Service (IHS) mammographic screening guidelines from those who are not adherent with these guidelines. Women in the Bemidji Area of the Indian Health Service have mammographic screening rates much lower than the IHS average for all IHS areas. Bemidji Area women are diagnosed at later stage and have higher mortality than is seen in the overall IHS. Our ultimate goal is to develop interventions to increase adherence among non-adherent screeners. Experimental procedures: In phase one, we have identified 64 women for interviews. Based on women's risk factors and screening histories, women were assigned to one of four groups: high risk/adherent, low risk/adherent, high risk/non-adherent, and low risk/non-adherent. Our goal is to have 16 women in each group. Currently, we have interviewed and conducted preliminary analysis of 19 women (4 higher risk/ adherent; 7 lower risk/non-adherent, 4 higher risk, non-adherent, 4 lower risk/adherent). Interview responses have been coded for themes, then categorized and descriptively quantified. Preliminary results: Adherent and non-adherent mammographic screeners can be differentiated by: 1) Theory of Planned Behavior (personal attitudes toward screening; perceived attitudes of family/friends and tribe toward annual screening; and past screening behavior). 2) Social Norms (perceptions of general health of respondents, family/friends, and tribe; health behaviors; barriers to screening; influences on attitudes and behaviors; healthy behaviors; health values; perceptions of common cancers among tribal members and women; the mammography experience; and influential members within social networks). 3) Social Support (emotional support for worry and fear and companionship. 4) Health Beliefs (susceptibility and severity of cancer). In other regards, these mediators and Health Literacy do not distinguish between adherent and non-adherent screeners. Conclusions: Theoretical mediators may be a useful way to distinguish between adherent and non-adherent screeners and point to potential avenues to intervene in the non-adherent population of American Indian women. Citation Format: Wesley Petersen, Ann M. Nicometo. Do theoretical mediators differentiate adherent and nonadherent American Indian mammographic screeners? Preliminary results from one tribe. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A32.

Abstract Background: In 2000, cyclophosphamide(C), epirubicin(E) and fluorouracil (F) (CEF) and doxorubicin (A) and C followed by paclitaxel (T) (AC/T) given every three weeks were commonly used regimens in Canada and the USA to treat women with node positive or high risk node negative operable breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of dose-dense EC was equivalent to six months of CEF. We hypothesized that the addition of 3 months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. In a randomized trial in women with early breast cancer we compared CEF, dose dense EC/T and AC/T. An interim analysis (JCO, 2010) conducted when 50% of the events for the relapse-free-survival (RFS) analysis were observed, demonstrated that AC/T administered every 3 weeks was significantly inferior to CEF or EC/T. The results of the final RFS including CEF versus EC/T will be presented. Methods: Women, 60 years or younger, with operable axillary node positive or high risk node negative breast cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was given for 6 cycles and consisted of: C 75 mg/m2 orally on Days 1–14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF patients received concurrent antibiotic prophylaxis. EC/T consisted of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2, both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from Days 2–13 and epoetin alpha 40,000 units subcutaneous once weekly. After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with filgrastim and epoetin alpha were given. The AC/T regimen consisted of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles. This was followed by T 175 mg/m2 every 21 days for 4 cycles. The final analysis for RFS was planned when 453 events were observed permitting the detection of a hazard ratio (HR) of 1.43 between CEF and AC/T and a HR of 1.43 between EC/T and the best of the other two arms. Quality of Life data using the EORTC C-30 and the Breast Cancer Chemotherapy questionnaires were collected throughout the study. The results will be available at the time of the presentation. Results: A total of 2104 women were enrolled between December 2000 and April 2005. The required 453 events for the RFS analysis were observed by the clinical cut-off date of March 30, 2012. At this point 369 deaths had been observed. The median follow-up is 87.5 months. Outstanding data and queries are currently being collected and reviewed with an expected database lock and final analysis mid August, 2012. Febrile neutropenia remains higher on the CEF and EC/T arms while more neuropathy was seen in the taxane containing regimens. Conclusions: Although the two regimens considered a standard of care at the time the study was initiated are no longer widely used, the trial results will enhance our understanding of the magnitude of benefit of taxane following an anthracycline, the significance of cumulative anthracycline dose, and the role of dose density/ intensity as backbone of conventional chemo regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-01.

Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell‐derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.Diagnosis: Diagnosis is based on bone marrow morphology. The presence ofJAK2,CALR, orMPLmutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are “triple‐negative.” None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). Prefibrotic PMF mimics ET in its presentation and the distinction, enabled by careful bone marrow morphological examination, is prognostically relevant. Differential diagnosis also includes chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.Risk Stratification: The Dynamic International Prognostic Scoring System‐plus (DIPSS‐plus) uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109/L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, −7/7q−, i(17q), inv(3), −5/5q−, 12p−, or 11q23 rearrangement). The presence of 0, 1, “2 or 3,” and ≥4 adverse factors defines low, intermediate‐1, intermediate‐2, and high‐risk disease with median survivals of approximately 15.4, 6.5, 2.9, and 1.3 years, respectively. High risk disease is also defined byCALR−/ASXL1+mutational status.Risk‐Adapted Therapy: Observation alone is adequate for asymptomatic low/intermediate‐1 risk disease, especially withCALR+/ASXL1−mutational status. Stem cell transplant is considered for DIPSS‐plus high risk disease or any risk disease withCALR−/ASXL1+mutational status. Investigational drug therapy is reasonable for symptomatic intermediate‐1 or intermediate‐2 risk disease. Splenectomy is considered for drug‐refractory splenomegaly. Involved field radiotherapy is most useful for post‐splenectomy hepatomegaly, non‐hepatosplenic EMH, PMF‐associated pulmonary hypertension, and extremity bone pain. Am. J. Hematol. 89:916–925, 2014. © 2014 Wiley Periodicals, Inc.

AimsThe pathogenesis of intraosseous mucoepidermoid carcinoma (IMEC) remains unknown. Coexistence with odontogenic cysts (ODC) has been reported in 32–48% of IMEC. Furthermore, prosoplastic mucous cells are often seen in the epithelial lining of ODCs. MECT1–MAML2 fusion transcripts have been identified in >66% of salivary gland MEC cases. The aim of this study was to investigate the presence of MAML2 rearrangement in ODCs featuring mucous prosoplasia.Methods and resultsTen cases of ODC with a mucous cell component and three cases of IMEC were evaluated using fluorescence in‐situ hybridization. All cases occurred in the mandible. The ODCs exhibited a M:F ratio of 4:1 (mean age 49.2 years), while all IMECs occurred in women (mean age 68.3 years). All three IMECs demonstrated MAML2 rearrangement, in 26–61% of tumour cells. Successful hybridization was observed in nine of 10 cases of ODC. In two of these nine, there was MAML2 rearrangement in 12% and 24% of the lining epithelial cells, while three of the nine showed rearrangement in 7–8% of cells; the remaining four cases were negative.ConclusionsWe identified MAML2 rearrangements in five of nine ODCs lined by mucus‐secreting cells. This suggests that at least a subset of ODCs with mucous prosoplasia are characterized by molecular events considered diagnostic for intraosseous and extraosseous MEC.

Abstract Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210–7. ©2014 AACR.

ABSTRACTMutations in sarcomere genes have been found in many inheritable human diseases, including hypertrophic cardiomyopathy. Elucidating the molecular mechanisms of sarcomere assembly shall facilitate understanding of the pathogenesis of sarcomere‐based cardiac disease. Recently, biochemical and genomic studies have identified many new genes encoding proteins that localize to the sarcomere. However, their precise functions in sarcomere assembly and sarcomere‐based cardiac disease are unknown. Here, we review zebrafish as an emerging vertebrate model for these studies. We summarize the techniques offered by this animal model to manipulate genes of interest, annotate gene expression, and describe the resulting phenotypes. We survey the sarcomere genes that have been investigated in zebrafish and discuss the potential of applying this in vivo model for larger‐scale genetic studies. Anat Rec, 297:1681–1693, 2014. © 2014 Wiley Periodicals, Inc.