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Abstract Background. Intracellular one-carbon transfer reactions are essential for nucleotide synthesis and methylation of biologic compounds including DNA. Previous studies have linked genetic variants in one-carbon metabolism genes with risk of developing NHL, but little is known regarding the impact of these variants on disease outcome. We evaluated the hypothesis that inherited genetic variation in genes involved in one-carbon metabolism is associated with overall survival in DLBCL. Methods. We genotyped 30 single nucleotide polymorphisms (SNPs) from 18 candidate one-carbon metabolism genes in 215 DLBCL patients who participated in a population-based case-control study conducted from 1998–2000 using the SEER (Surveillance, Epidemiology and End Results) cancer registries in the Detroit, Iowa, Los Angeles and Seattle. Stage, B-symptoms, first course of therapy, date of last follow-up and vital status through early 2005 were obtained from cancer registry files. Cox proportional hazards analysis was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for the association between individual SNPs and overall survival, adjusting for age, demographic and clinical factors. We also used parallel modeling strategies to identify the best summary multi-SNP risk score to predict survival. Results. The median age at diagnosis was 57 years (range, 20–74), and 50 (23%) of the patients died during follow-up, with a median follow-up of 57 months (range, 31–78 months) for surviving patients. After adjusting for demographic and clinical variables, SNPs in SHMT1 (rs1979276; HRCT/TT=2.47, 1.31–4.67), BHMT (rs585800; HRAT/TT=2.02, 1.16–3.54), and TCN1 (rs526934; HRTT=1.86, 1.04–3.33) were the strongest and most robust predictors of survival. A summary score of the number of deleterious genotypes (0–3) from these three genes was strongly associated with survival (p=7.9 x 10−5) after accounting for demographic and clinical variables (HR=2.58 per deleterious genotype, 95% CI 1.75–3.80). A risk score combining the three SNPs with clinical and demographic variables (score of 0 to 5) was even more strongly associated with survival (p=1.4 x 10−13); the Kaplan Meier survival curves are shown in the Figure. In a time-dependent ROC analysis, the combined risk score had a concordance index of 0.75 at 5 years of follow-up (95% CI 0.69–0.81). Conclusion: Host genetic variation in the one-carbon metabolism genes SHMT1, BHMT, and TCN1, individually and particularly in combination, was associated with overall DLBCL survival after accounting for clinical and demographic factors, supporting a role for this pathway in disease progression. Future work should evaluate interactions of genes from this pathway with dietary nutrients and therapeutic agents in DLBCL prognosis. Figure Figure

Objectives: To understand from the perspective of patients who did, and did not attend ICU recovery programs, what were the most important components of successful programs and how should they be organized. Design: International, qualitative study. Setting: Fourteen hospitals in the United States, United Kingdom, and Australia. Patients: We conducted 66 semi-structured interviews with a diverse group of patients, 52 of whom had used an ICU recovery program and 14 whom had not. Interventions: None. Measurements and Main Results: Using content analysis, prevalent themes were documented to understand what improved their outcomes. Contrasting quotes from patients who had not received certain aspects of care were used to identify perceived differential effectiveness. Successful ICU recovery programs had five key components: 1) Continuity of care; 2) Improving symptom status; 3) Normalization and expectation management; 4) Internal and external validation of progress; and 5) Reducing feelings of guilt and helplessness. The delivery of care which achieved these goals was facilitated by early involvement (even before hospital discharge), direct involvement of ICU staff, and a focus on integration across traditional disease, symptom, and social welfare needs. Conclusions: In this multicenter study, conducted across three continents, patients identified specific and reproducible modes of benefit derived from ICU recovery programs, which could be the target of future intervention refinement.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

Intracranial extension of rhinosinusitis is rare in children. We report a 9-year-old immunocompetent boy with central precocious puberty and obstructive sleep apnea-hypopnea syndrome who developed an intracranial epidural abscess secondary to rhinosinusitis while on continuous positive airway pressure (CPAP) treatment. A retrospective review of the medical record and imaging studies was performed. MEDLINE and Cochrane databases were searched for reports of epidural abscess developing in patients receiving CPAP treatment or in patients with precocious puberty. Intracranial extension of frontal rhinosinusitis is more common during puberty probably because of the active growth of the frontal sinuses and their rich blood supply. Controlled studies show no increase with rhinosinusitis in adults on CPAP; no published studies assess intracranial extension of rhinosinusitis in CPAP use. Patients with unexplained, severe headache and fever following CPAP use may require neuroimaging (magnetic resonance imaging [MRI] / contrast computed tomography) to rule out intracranial extension of sinusitis.

AbstractImmunochemotherapy followed by autologous transplant (ASCT) in CALGB/Alliance 59909 achieved a median progression‐free survival (PFS) in mantle cell lymphoma (MCL) of 5 years, but late recurrences occurred. We evaluated tolerability and efficacy of adding post‐transplant bortezomib consolidation (BC) or maintenance (BM) to this regimen in CALGB/Alliance 50403, a randomized phase II trial. Following augmented‐dose R‐CHOP/ methotrexate, high‐dose cytarabine‐based stem cell mobilization, cyclophosphamide/carmustine/etoposide (CBV) autotransplant, and rituximab, patients were randomized to BC (1.3 mg/m2 IV days 1, 4, 8, 11 of a 3‐week cycle for four cycles) or BM (1.6 mg/m2 IV once weekly × 4 every 8 weeks for 18 months) beginning day 90. The primary endpoint was PFS, measured from randomization for each arm. Proliferation signature, Ki67, and postinduction minimal residual disease (MRD) in bone marrow were assessed. Of 151 patients enrolled; 118 (80%) underwent ASCT, and 102 (68%) were randomized. Both arms met the primary endpoint, with median PFS significantly greater than 4 years (P < .001). The 8‐year PFS estimates in the BC and BM arms were 54.1% (95% CI 40.9%‐71.5%) and 64.4% (95% 51.8%‐79.0%), respectively. Progression‐free survival was significantly longer for transplanted patients on 50403 compared with those on 59909. Both the PFS and OS were significantly better for those who were MRD‐negative post‐induction. The high risk proliferation signature was associated with adverse outcome. Both BM and BC were efficacious and tolerable, although toxicity was significant. The comparison between studies 50403 and 59909 with long‐term follow up suggests a PFS benefit from the addition of BC or BM post‐ transplant.

e20046 Background: The immune system and VEGF may play a role in melanoma behavior. We prospectively collected data in 10 stage III and 22 stage IV melanoma patients to observe factors influencing outcomes. Methods: We assessed median survival (MS), LDH, BRAF, VEGF, Th1/Th2 ratio, regulatory T cells (Tregs) and CD4/CD8 ratio, which were measured upon enrollment. LDH and BRAF were measured in standard commercial labs; VEGF via ELISA at LVHN; Th1/Th2 ratio and CD4/CD8 ratio via flow cytometry at Mayo Clinic. Stage III patients were treated with resection and interferon or observation. Stage IV patients were treated with some or all of the following: resection +/- GM-CSF, IL-2, ipilimumab, vemurafenib, carboplatin/paclitaxel/bevacizumab and temazolamide. Results: MS for stage IV patients was 48 months using a Kaplan-Meier survival curve. The only variable associated with survival was LDH, (HR=1.0017, 95%CI: 1.0003-1.0032, p=0.02). In stage IV patients, there was a positive correlation between VEGF and Tregs (r=.485, n=22 p=0.022) and a negative correlation between Tregs and Th1/Th2 (r=-.470, n=22, p=0.027). In stage III/IV patients who were alive at study completion, there was a positive correlation between CD4/CD8 and VEGF (r=.792, n=10, p=0.006). In patients who died, there was a negative correlation between Tregs and Th1/Th2 (r=-.660, n=12, p=0.02). 7 of the stage IV patients are currently disease free, including 5 of the 10 who received IL-2 +/- metastectomy. Conclusions: While a median survival of 48 months was provocative for stage IV patients, it may reflect referral selection at an IL-2 center. Recent advances such as ipilimumab (which lowers Tregs), BRAF inhibitors, and immunotherapy/aggressive resection as initial therapy may have impacted survival. The literature suggests that an elevated CD4/CD8 ratio predicts better outcomes. Higher VEGF levels have also been associated with lower overall survival in patients treated with IL-2. We found an association between higher VEGF levels and increased Tregs in deceased patients but not in living patients. In patients still alive, higher VEGF was balanced by a higher CD4/CD8 ratio. We did not find a correlation between baseline VEGF and survival.

1033 Background: MA.32 investigates effects of Metformin vs. Placebo, in addition to standard care, on invasive disease free survival and other outcomes. Metformin may improve obesity and metabolic factors [insulin, glucose, leptin, C-reactive protein (CRP)] that have been associated with poor BC outcomes. Maintaining blinding of investigators to outcomes, we conducted a planned, DSMB approved, analysis of the effect of Metformin vs. Placebo on weight and metabolic factors at 6 months, including examination of interactions with baseline body mass index (BMI), in the first 498 subjects with paired fasting plasma samples. Methods: 498 non-diabetic subjects with T1-3, N0-3, M0 BC meeting defined entry criteria who had completed surgery and adjuvant chemo (if given) provided fasting blood samples at randomization and 6 months (while on study drug). Glucose was measured locally; blood was aliquoted, frozen and stored at -80°C then shipped to NCIC CTG (Kingston, Canada). Paired plasma aliquots were shipped to Mount Sinai Hospital (Toronto, Canada) for analysis of Insulin (Dako), hsCRP (Roche Elecsys) and leptin (Luminex). Statistical analysis used the Wilcoxon signed rank test. Results: Mean age was 52.4 ±9.2 years. Arms were balanced for ER/PgR (63% pos), BMI, prior adjuvant chemo (89%), T and N status, grade, mastectomy/lumpectomy and radiation. Conclusions: Metformin significantly improved weight, insulin, glucose, leptin and CRP at 6 months. Effects did not vary by baseline BMI. Funded by: NIH, CCSRI, CBCF, BCRF, Apotex Canada (drug & placebo - in kind). Clinical trial information: NCT01101438. [Table: see text]

e21112 Background: Metastatic malignant melanoma is difficult to treat and has a poor prognosis. Systemic therapy for metastatic melanoma has had limited success and novel drug combinations need to be tested. To that end, we have combined anti-angiogenic therapy (bevacizumab) with chemotherapy in clinical trials and have shown some clinical efficacy. Vascular endothelial growth factor (VEGF) is increasingly seen as an immunosuppressive factor that hampers dendritic cell maturation and reduces antigen presentation. We have recently shown that tumor-derived VEGF plays a role in Th-2 driven systemic chronic inflammation seen in advanced melanoma patients. Therefore, our data suggest that blocking tumor derived VEGF with the monoclonal antibody bevacizumab may impact immunity in such a way that augments anti-tumor immunity enhancing clinical efficacy. Methods: In order to understand the immune status in metastatic melanoma patients on chemotherapy (n=55) or chemotherapy plus bevacizumab (n=73), we measured levels of 42 cytokines, chemokines and growth factors in plasma by a mulit-plex bead assay. Matched pairs analysis was performed to determine if the average responses of the measured cytokines were different between the patients that received chemotherapy with bevacizumab or chemotherapy alone. The pre-treatment levels were compared with levels drawn four weeks after the first treatment. Results: There were significant differences in IL-1a, IL-1ra, IL-6, IL-8 and IP-10 between patients treated with chemotherapy alone relative to patients treated with chemotherapy plus bevacizumab. In all cases of patients treated with chemotherapy plus bevacizumab, the levels of these cytokines all decreased relative to pre-treatment samples. In patients treated with chemotherapy alone the levels of these cytokines increased relative to pre-treatment samples. Conclusions: Our data suggest that treating patients with the anti-angiogenic drug bevacizumab may affect the plasma cytokine milieu by reducing the level of many key inflammatory cytokines. Therefore, the use of bevacizumab in combination with chemotherapy may augment host immunity and elicit a more effective anti-tumor immune response.

8599 Background: Chemotherapy resistance is a common, difficult problem for melanoma patients needing long term care and those suffering from recurrence. Neural growth factor receptor (NGFR), also known as CD271, is commonly expressed on mesenchymal stem cells and is important for development, survival and differentiation of cells. This has previously shown to be expressed on melanoma stem cells. We hypothesized that treatment with carboplatin enriches the population of tumor cells for cancer stem cells (CSC) as a mechanism of chemotherapy resistance. Methods: Core tumor samples from 118 patients with metastatic melanoma were obtained from formalin-fixed paraffin embedded specimens. Slides were stained using an anti-CD271 antibody for IHC. A375 melanoma cells were treated with increasing concentrations of carboplatin for approximately 1 year. WT, 6 mg/mL and 10 mg/mL resistant cells were tagged with CD271-PE antibody and run on a flow cytometer. These cells were then tested for gene expression by microarray using an Affymetrix human 133 plus 2.0 chip, and analyzed on Partek software. Pathway analysis of these carboplatin resistant cells was preformed using Ingenuity. Results: Virtually all melanoma tumor samples stained positively for CD271 by IHC, with a median of 50% cells within tumor samples expressing the cytoplasmic marker. Flow cytometry demonstrated an increase in the percentage of cells expressing CD271 as resistance to carboplatin increased. Wild type A375 cells contained 30% positive CD271, A375 6mg/mL resistant contained 42% positive and A375 10mg/mL resistant showed 66% positive. Microarray also exhibited a direct correlation between CD271 gene expression with increasing carboplatin resistance. Functional ontology enrichment revealed development and regulation of the EMT pathway as an important process impacted by our resistant cell line. Conclusions: The data suggests that as melanoma cells become resistant to certain chemotherapy drugs they essentially loose their differentiated phenotype and become more stem cell-like. Monitoring melanoma expression of CD271 could help individualize therapy and anticipate chemotherapeutic resistance in this high-risk group of patients.