Citations

479 Background: We and others have previously shown that the ccRCC epigenome is characterized by widespread DNA hypermethylation (CCR 2014, Nature 2014). Various important tumor suppressor genes (TSGs), such as SMAD7 (inhibitor of oncogenic TGF-β signaling), are under-expressed due to aberrantly methylated promoters or enhancers. We hypothesized that the hypermethylation in ccRCC could be due to low activity of the TET enzymes, which convert methylcytosine (5-mc) to hydroxymethylcytosine (5-hmc). Loss of function of TET enzymes can occur with an inactivating mutation (TET-2 is mutated in about 6% of ccRCC (Science Signaling 2013) or hypoactivity of normal TET enzymes, through inhibition by metabolic intermediates. AA is an essential co-factor for TET enzymes (JACS 2015). We hypothesized that high dose AA treatment of ccRCC could potentially increase the functional activity of TET enzymes leading to demethylation of the RCC genome, and enhance expression of TSGs. Methods: In vitro TET activity was performed on ccRCC cell line 769P with increasing doses of AA (L-AA). Genome wide quantitative 5-mc and 5-hmc was evaluated using mass spectrometry. SMAD7 expression was determined using qRT-PCR. Proliferation assay (MTT) was performed with AA in combination with pazopanib. Cell cycle and apoptosis assays were performed. Results: AA, at doses achieved only by the intravenous route (1-10mM), increased TET activity in ccRCC cell line 769P. Genome wide 5-mc was significantly reduced and 5-hmc was increased, correlating with increase in TET activity. SMAD7 expression was increased with AA treatment. High dose AA led to proliferation inhibition with a cell cycle arrest in the G1 phase, and had a synergistic effect with pazopanib. Since AA leads to the generation of H2O2 in-vitro, catalase was used as control. This did not reverse the effect of AA on epigenetic changes; and proliferation inhibition was seen despite catalase control. Conclusions: High dose AA causes TET mediated DNA demethylation of the hypermethylated RCC genome, resulting in the re-expression of TSGs, and proliferation inhibition. Sequencing and xenograft studies are underway.

193 Background: National standards recommend distress screening as part of cancer care. While many patients report improved quality of life after cancer treatment concludes there remains a population who experience ongoing anxiety and depressive symptoms. We sought to describe psychosocial distress in lymphoma survivors and frequency of visits to mental health providers (MHP). Methods: Lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource and systematically followed. Brief Profile of Mood States (POMS) and State Trait Anxiety Inventory (STAI) were administered 3 yrs after diagnosis. Lower scores on POMS indicated more distress. A higher score on STAI indicated more anxiety, and a score ≥ 40 was considered clinically significant. Pts were asked if they ever saw a MHP due to their lymphoma. Results: Between 2002-2012, 2465 lymphoma pts age 18-91 (10% 18-40, 54% 41-65, and 36% > 65) were enrolled, met survivor definition, and completed 3-yr POMS and STAI questionnaires. 57% were male. 40% had aggressive and 60% had indolent lymphoma. The median score on STAI 1 (state) was 32 (range 20-76) and on STAI 2 (trait) was 31 (range 20-77). Median POMS total mood disturbance (TMD) score was 88 (range 1-100). 8% of pts reported seeing a MHP. 609 pts (25%) had clinically significant anxiety by STAI 1, 73 (12%) of whom saw a MHP. Those who reported clinically significant anxiety on STAI were more likely to be younger, unemployed, unmarried, and less likely to have seen a MHP. Anxiety levels were similar between those with aggressive lymphoma and indolent lymphoma regardless of treatment. Higher distress levels, measured by TMD, were more often reported by those who were unemployed or over age 65 while there was no association with lymphoma subtype, marital status, or choice of therapy. Conclusions: Clinically significant anxiety was reported in 25% of 3-yr survivors of lymphoma and was associated with younger age, unmarried status, and unemployment. Higher distress levels were associated with older age, and unemployment. However, only 8% of our cohort was seen by a MHP. Identifying distress and appropriately referring to a MHP is important for the optimal care of lymphoma survivors.

64 Background: The goals of our Lymphoma Survivorship Clinic (SC) are to coordinate care, educate patients, and create a survivorship care plan (SCP). The aim of this study was to determine if patient-centered outcomes are improved after a SC visit. Methods: From 11/13-5/15, surveys were mailed to recently-treated lymphoma patients who were within 4 weeks of their last visit and in remission. Quality of life (QOL) was measured with PROMIS and distress was measured with the Impact of Events scale. Responses between those who attended SC and those who were eligible but did not attend were analyzed. Results: There were 96 surveys sent to the SC group; 59 were returned (61% response rate). Of the non-SC group, 140 surveys were sent and 84 were returned (60% response rate). Mean age was 57 years (range 23-77) in the SC group and 59 years (23-88) in the non-SC group. There were more females in the SC group (52% vs 30%) but no differences in race, marital status, education, or health literacy. Those who attended the SC were more likely to recall receiving a summary of cancer treatment and recommendations for follow-up care (90% SC vs. 75% non-SC, p = 0.03). Furthermore, SC attendees were more likely to “definitely” recall discussion on improving health or preventing illness (89% vs. 53%), getting help in making changes in habits/lifestyle (76% vs. 50%), diet (80% vs. 31%), and exercise (82% vs. 51%), all p < 0.001. There were no differences in discussions regarding smoking, follow-up testing, and symptom monitoring. The SC group was less likely to need more information regarding sexuality (6% vs 20%, p = 0.045). There were no differences in need for information regarding anxiety, fitness, familial cancer risk, fertility, complementary therapies, and social issues. The SC group was slightly more confident that they could get information or advice related to cancer (completely confident 76% vs. 61%, p = 0.07). There were no differences in QOL or distress. Conclusions: A Lymphoma SC visit increased receipt of SCP and provided more information on survivorship issues, particularly health behaviors, but did not improve QOL or distress. Further study is needed to determine if this leads to long-term health benefits.

236 Background: Patients (pts) with aggressive lymphoma are generally treated with curative intent and many become long-term survivors. There is little data on health behaviors after lymphoma diagnosis and their effect on QOL and long-term outcomes. Methods: Lymphoma pts were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and systematically followed. We measured QOL (FACT-G) and health behaviors (tobacco/alcohol use; diet/exercise habits) 3 years after diagnosis. For this study, “survivor” was defined as alive at 3 years from diagnosis with no active disease or treatment within the previous year. Results: From 2002-2012, 671 patients with aggressive lymphoma were enrolled, met survivor definition, and completed 3-year QOL and health behavior questionnaires. At 3-years, 31% of female (F) and 48% of male (M) reported a history of tobacco use for 6+ months. Of these, 13% of F and 7% of M were still smoking; 52% reported decreased use from baseline. 66% reported no change in alcohol intake at 3-years while 25% of F and 34% of M reported decreased intake. 60% often chose whole grains and 65% get 2+ servings of vegetables daily. 42% of F and 38% of M “somewhat” believed diet could change the course of their lymphoma. Most pts endorsed no significant change in diet as a result of diagnosis. Those who made changes did so primarily out of concern for “health problems other than cancer”. Overweight/obese responders were 72% pre- and 66% post-treatment. A desire to lose weight was reported by 55% of pts. 14% of F and 23% of M often engaged in regular physical activity (PA). Nearly 50% reported a decrease in PA. Pts with advanced stage (p = 0.006), age > 60 (p = 0.001), ECOG PS > 2 (p = 0.04), and worse prognostic score (p = 0.006) were more likely to report decreased PA since diagnosis. 68% of F and 61% of M intend to become more active in the next months. Regular PA (p = < 0.0001) was associated with higher QOL, while increased alcohol intake was associated with lower QOL (p = 0.009) at 3 years. Conclusions: Many survivors of aggressive NHL strive to adopt healthy behaviors and these behaviors are associated with higher QOL. Interventions aimed at emphasizing these behaviors may have potential to improve long-term outcomes and QOL.

PURPOSE: To study the prognostic value of plasmablastic morphology after autologous stem-cell transplantation for relapsed or primary refractory myeloma. PATIENTS AND METHODS: Seventy-five patients were studied. Investigators blinded to the clinical details of the individual cases reviewed bone marrow aspirate slides to determine plasmablastic classification. Plasmablasts were defined using strict, well-described criteria. Plasmablastic morphology was considered to be present (plasmablastic myeloma) when 2% or more plasmablasts were present in the plasma-cell population. RESULTS: Patients underwent transplantation 5 to 88 months (median, 20 months) after the initial diagnosis of myeloma. Twenty-eight percent of patients had plasmablastic morphology. A significantly greater proportion of patients with plasmablastic morphology had abnormal cytogenetics compared with those with nonplasmablastic classification (73% v 31%, respectively; P = .003). The overall survival rate measured from the time of transplantation was significantly worse in patients with plasmablastic morphology compared with those without (median survival time, 5 months v 24 months, respectively; P < .001). Progression-free survival time was shortened also, with a median time of 4 months compared with 12 months, respectively (P < .001). In the multivariate analysis, plasmablastic classification was the most powerful prognostic factor after transplantation for both overall (P = .001) and progression-free survival rates (P < .001). We also identified three risk groups based on plasmablastic morphology: plasma-cell labeling index, lactate dehydrogenase, and cytogenetics. The median overall survival time was 38 months when none of these factors was abnormal, 17 months with one abnormal factor, and 8 months with two or more abnormal factors (P < .001). CONCLUSION: Plasmablastic morphology is a powerful independent predictor of poor survival rate after autologous stem-cell transplantation for relapsed or primary refractory myeloma.

PURPOSE: Previous studies in patients with non-Hodgkin’s lymphoma (NHL) and other malignancies have suggested that the presence of host infiltrates in the tumors of these patients may predict a better outcome. This study was undertaken to determine the prognostic importance of the presence of T cells in the biopsy specimens of patients with B-cell NHL.PATIENTS AND METHODS: Seventy-two patients with diffuse large B-cell NHL were prospectively evaluated at a single institution between 1987 and 1994. The percentage of CD3+, CD3+/HLA-DR+, CD4+, CD8+, and natural killer cells was determined by flow cytometry in the pretreatment diagnostic biopsy specimen and correlated with patient outcome.RESULTS: An increase in the percentage CD4+ T cells in the pretreatment tumor biopsies significantly correlated with patient outcome. The percent of CD4+ T cells was also highly correlated with CD3+/HLA-DR+, CD45RO+, and low l-selectin (CD62L) expression, indicating that the CD4+ T cells are activated memory T-helper cells. Those patients with increased numbers of CD4+ T cells, compared with other patients, had a significantly longer 5-year failure-free survival (72% v 43%, respectively; P = .04), as well as a significantly longer 5-year overall survival (65% v 38%, respectively; P = .05). When evaluated in a multivariate model, the International Prognostic Index and more than 20% infiltrating CD4+ T cells in the pretreatment biopsy were significant independent predictors of relapse-free and overall survival.CONCLUSION: The presence of increased numbers of activated CD4+ cells in the area of B-cell diffuse large-cell NHL predicts a better prognosis. This finding provides a strong rationale for the investigation of cellular immunotherapy in B-cell NHL.