Search

Introduction Although obesity is associated with adverse cancer outcomes in general, most retrospective clinical studies suggest a beneficial effect of obesity in NSCLC. Methods Hypothesizing that this “obesity paradox” arises partly from the limitations of using body mass index (BMI) to measure obesity, we quantified adiposity using preoperative computed tomography images. This allowed the specific determination of central obesity as abdominal visceral fat area normalized to total fat area (visceral fat index [VFI]). In addition, owing to the previously reported salutary effect of metformin on high-BMI patients with lung cancer, metformin users were excluded. We then explored associations between visceral obesity and outcomes after surgical resection of stage I and II NSCLC. We also explored potential immunologic underpinnings of such association using complimentary analyses of tumor gene expression data from NSCLC tumors and the tumor transcriptome and immune microenvironment in an immunocompetent model of lung cancer with diet-induced obesity. Results We found that in 513 patients with stage I and II NSCLC undergoing lobectomy, a high VFI is associated with decreased recurrence-free and overall survival. VFI was also inversely related to an inflammatory transcriptomic signature in NSCLC tumors, consistent with observations made in immunocompetent murine models wherein diet-induced obesity promoted cancer progression while exacerbating elements of immune suppression in the tumor niche. Conclusions In all, this study uses multiple lines of evidence to reveal the adverse effects of visceral obesity in patients with NSCLC, which align with those found in animal models. Thus, the obesity paradox may, at least in part, be secondary to the use of BMI as a measure of obesity and the confounding effects of metformin use.

Background A study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-). Patients and Methods A total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies. Results In this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002). Conclusions The real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p Disclosures No relevant conflicts of interest to declare.

Mediastinoscopy is considered the gold standard for preresectional staging of lung cancer. We sought to examine the effect of concomitant mediastinoscopy on postoperative pneumonia (POP) in patients undergoing lobectomy. All patients in our institutional database (2008–2015) undergoing lobectomy who did not receive neoadjuvant therapy were included in our study. The relationship between mediastinoscopy and POP was examined using univariate (Chi square) and multivariate analyses (binary logistic regression). In order to validate our institutional findings, lobectomy data in the National Surgical Quality Improvement Program (NSQIP) from 2005 to 2014 were analyzed for these associations. Of 810 patients who underwent a lobectomy at our institution, 741 (91.5%) surgeries were performed by video-assisted thoracic surgery (VATS) and 487 (60.1%) patients underwent concomitant mediastinoscopy. Univariate analysis demonstrated an association between mediastinoscopy and POP in patients undergoing VATS [odds ratio (OR) 1.80; p = 0.003], but not open lobectomy. Multivariate analysis retained mediastinoscopy as a variable, although the relationship showed only a trend (OR 1.64; p = 0.1). In the NSQIP cohort (N = 12,562), concomitant mediastinoscopy was performed in 9.0% of patients, with 44.5% of all the lobectomies performed by VATS. Mediastinoscopy was associated with POP in patients having both open (OR1.69; p

INTRODUCTION AND OBJECTIVES:To our knowledge, none of the studies published in the literature objectively measure the effect of art therapy on outcomes and convalescence of cancer patients. We soug...

Surveillance for long-term complications related to previous cancer therapy can help diagnose/manage chronic health conditions in childhood cancer survivors and improve survivor quality of life. However, a challenge to delivering long-term care to childhood cancer survivors is loss to follow-up; many patients discontinue care at specialized survivor care centers. The purpose of this study was to examine patterns of loss to follow-up among a cohort of childhood cancer survivors.This retrospective study examined follow-up patterns among a nonrandom representative sample of 370 childhood cancer survivors among 1116 patients from a single institution. The median age of patients at diagnosis was 10.2 years (range1-21). Factors potentially related to follow-up were utilized to evaluate patterns of follow-up across 5-year intervals following completion of active therapy. The association between patient characteristics and follow-up was evaluated using univariate and multivariate binomial regression models.The probability of follow-up 1-5 years post-treatment was 91.2% (89.7%-92.5%) but dropped to 68.5% (66.2%-70.8%) during years 6-10, 47.7% (45.0%-50.3%) during years 11-15, and continued to steadily decrease over time. Overall, white race, diagnoses at younger ages, patients with lymphomas/leukemias, and decade of diagnosis were each associated with somewhat better rates of follow-up.These findings highlight the lack of follow-up by adult survivors of childhood cancer with only approximately one-half of patients returning for follow-up 10 years after completion of therapy. Interventions focused on educating both patients and primary care physicians may help to increase long-term follow-up care among this at-risk population.

Background: Although first-line chemo-immunotherapy cures a significant number of diffuse large B-cell lymphoma (DLBCL) patients, long term survival is only observed in 30% or 41% of patients treated with second-line therapy followed with high dose chemotherapy and autologous stem cell support (HDC-ASCS) or chimeric antigen receptor anti-CD19 T-cell therapy (CART-19) respectively. The use of third-line therapy with chemotherapy drugs or current available small molecule inhibitors for relapsed/refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) is associated with a poor response rate and a median survival of 6.3 months, stressing the need to identify druggable biomarkers associated with therapy resistance and poor clinical outcomes. Methods: To this end, we identified patients with rel/ref DLBCL that failed at least 2 prior lines of therapy treated at our Institute. Demographic, clinical and pathological characteristics were identified. Archived pathological material from the biopsy performed at the second relapse/progression was obtained for each patient. Using the Nanostring nCounter Analysis System (Nanostring Technologies, Seattle, WA), gene expression profiling (GEP) was performed for each sample as previously described using a custom designed code set containing 770 genes. Analysis and normalization of the raw Nanostring data was performed using nSolver Analysis Software v1.1. Raw counts were normalized to internal levels of 7 reference genes: CNOT2, GAPDH, HPRT1, PHGDH, SUMO2, SYS1 and WDR45L. A background count level was estimated using the average count of the 8 negative control probes in every reaction plus 2 standard deviations. Correlation between clinical outcomes (response rate to third line therapy, progression free-survival [PFS] and overall survival [OS]) and IPI score, clinical characteristics and GEP. Subsequently and based on the GEP results, we evaluated the expression of Bcl-XL and other Bcl-2 family proteins in a panel of DLBCL cell lines. Immuno-precipitation (IP) studies were conducted to determine protein-protein interaction between Bcl-XL and other Bcl-2 related proteins. In addition, cell lines were exposed to A1331852, a novel Bcl-XL inhibitor at different doses alone or in combination with chemotherapy drugs. Cell viability was evaluated using Presto Blue assay and IC50 values were calculated using the GraphPad Prism6 software. Results: A total of 53 rel/ref DLBCL were identified that received third line therapy at our Institute. The median age was 59yrs. The median PFS and OS was 23 months and 21 months respectively. Over-expression of BCL-XL RNA levels was associated with a shorter OS (P=0.015, HR=1.17). Pre-clinically higher levels of Bcl-XL as determined by western blotting were found in lymphoma cell lines resistant to chemotherapy agents in vitro. IP studies demonstrated a strong interaction between Bcl-XL and BIM in chemotherapy resistant cell lines. In vitro exposure of DLBCL cell lines to A1331852 resulted in dose- and time-dependent cell death. Moreover, synergistic activity was observed when A1331852 was combined with chemotherapy drugs (doxorubicin, vincristine and etoposide). Conclusion: Our data suggests that high expression level of BCLxL was associated with inferior prognosis in the refractory and/or relapsed DLBCL patients. Inhibition of Bcl-XL results in cell death of rituximab-chemotherapy resistant lymphoma cell lines and potentiates the anti-tumor activity of chemotherapy agents. Selective targeting of Bcl-XL may be a novel therapeutic strategy for rel/ref aggressive B-cell lymphoma. Disclosures No relevant conflicts of interest to declare.

Glomerular filtration rate (GFR) is an essential clinical assessment of renal function post-renal transplantation. Creatinine clearance (CrCl) measured over 12 h and estimated GFR (e-GFR) (calculated by the Modification of diet in renal disease equation) were compared in 28 stable renal transplant recipients (RTRs). This single center study included 14 African American (AA) and 14 Caucasian (CC) recipients. The 12-h creatinine clearance (CrCl-12 h) was determined by monitored urine collection and by e-GFR on two occasions (two phases) separated by at least 2 weeks. Statistics included mixed model analysis of CrCl-12 h and e-GFR relative to race, phase, and difference between parameters. In the first phase, the e-GFR was higher in AA males (58.4 ± 14.8 mL/min) than the CC males (46.2 ± 10.2 mL/min) (p = 0.032), whereas the CrCl-12 h of AA males (70.8 ± 8.7 mL/min) and CC males (63.3 ± 21.7 mL/min) was not different (p = 0.740). During the second phase, the e-GFR in AA and CC RTRs was 55.4 ± 10.1 mL/min and 47.6 ± 10.7 mL/min (p = 0.117), respectively, whereas CrCl-12 h in AAs was 64.71 ± 17.9 mL/min and in CCs was 62.0 ± 14.9 mL/min (p = 1.000). The CrCl-12 h was higher than the e-GFR (p < 0.001) irrespective of race or phase. CrCl-12 h was not different on both occasions (p = 0.289) in all the patients. CrCl-12 h was consistently greater than e-GFR. The difference between these e-GFR estimates may have an importance in the care of RTRs.

Background Limited mycophenolic acid (MPA) data are available comparing racial influence on mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) pharmacokinetics. Methods Intrapatient MPA pharmacokinetics of MMF versus EC-MPS were compared in 13 male African American (AA) and 14 Caucasian (C) renal transplant recipients (RTRs). RTRs were switched to equivalent doses of the alternate formulation for at least 10 days prior to the second study. Mycophenolic acid clearance and dose-normalized area under the concentration-time curve(0-12) (AUC*) were determined. Mixed model statistics evaluated the main effects of race, drug formulation, and interaction of race and drug formulation (R × D) with albumin, cyclosporine trough, renal function, and diabetes and enterhepatic recirculation. Results Significant R × D was identified for MPA AUC* for EC-MPS (AA, 0.056 ± 0.029 [mg·h/L]/mg; C, 0.080 ± 0.044 [mg·h/L]/mg) compared with MMF (AA, 0.053 ± 0.019 [mg·h/L]/mg; C, 0.060 ± 0.025 [mg·h/L]/mg), P = .022. Significant R × D was identified with albumin in the model for MPA clearance for MMF (AA, 21.7 ± 8.9 L/h; C, 20.5 ± 10.8 L/h) compared with EC-MPS (AA, 22.2 ± 10.1 L/h; C, 16.2 ± 9.1 L/h), P = .032. Conclusions Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion.

Background Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. Methods Four isogenic cell lines C2/C2VHL and 786-O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2α knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student’s T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. Results Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2α is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERα) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated α-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. Conclusions Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2604-7) contains supplementary material, which is available to authorized users.

Renal transplant recipients exhibit variability in mycophenolic acid (MPA) and MPA glucuronide (MPAG) pharmacokinetics, which are influenced by clinical and demographic factors. Racial influence on MPA and MPAG pharmacokinetics was investigated in 53 patients: 17 African American males, 22 Caucasian males, and 14 females receiving mycophenolate mofetil (MMF) and cyclosporine. A 12-hour steady-state pharmacokinetic study was conducted. Enterohepatic circulation of MPA was characterized by a second plasma concentration peak and was included in a novel statistical model with MPAG. MPA clearance in African American males was 26.5 ± 14.4 L/h versus 17.9 ± 6.1 L/h in Caucasian males (P = .035) and 16.1 ± 4.6 L/h in Caucasian females (P = .024) with no difference noted in MPA troughs. Enterohepatic circulation occurred less frequently in African American males (23%) compared with Caucasian males (42%) and Caucasian females (50%) (P > .05). Cyclosporine exposure was correlated with MPA and MPAG pharmacokinetics, whereas creatinine clearance influenced MPAG pharmacokinetics. A racial difference was noted with more rapid MPA clearance in African American males compared with Caucasians. The results support differential MPA dosing and the role of therapeutic drug monitoring in addition to considering the influence of renal function and concurrent immunosuppressives on MPA and MPAG pharmacokinetics.

Introduction: Patients (pts) with limited stage (LS) aggressive large B-cell lymphoma (ALBCL) comprise 30-40% of ALBCLs and are usually treated with R-CHOP with or without consolidative involved field radiation therapy (IFRT). In pts with ALBCL, cytogenetic studies have identified a subset with high-risk disease who harbor MYC rearrangement (MYC-R) with or without BCL2 (BCL2-R) and/or BCL6 (BCL6-R) rearrangements. This has led to the adoption of intensive induction strategies in this population; however, it is unclear if such an approach is necessary in limited stage disease. Methods: We conducted a multi-center (15 US academic centers) retrospective study of MYC-R LS-ALBCL pts with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBL) morphology. LS was defined by stage I and II confined to a single radiation field as determined by the treating center. Pts diagnosed between 1/1/2005 and 3/1/2017 were included. All pts received either R-CHOP or more intensive immuno-chemotherapy (IIC) (i.e. R-DA-EPOCH, R-hyperCVAD/MA, or R-CODOX-M/IVAC) with or without IFRT. Baseline demographic, clinical, laboratory, pathology and outcomes data was collected by retrospective chart review. Stage-modified IPI (sm-IPI) score was calculated [stage II (vs 1), age >60, elevated LDH, and ECOG performance status ≥ 2]. Differences in overall response rate (ORR), complete remission (CR) rate, 2-year progression-free survival (PFS) and overall survival (OS) were compared in pts treated with R-CHOP vs IIC and in pts treated with IFRT vs no IFRT. Results: A total of 142 pts with MYC-R LS-ALBCL were identified, of which 105 fulfilled the inclusion criteria. Baseline characteristics included: median age 65 yrs (range 21-85), 66% male; 14% stage I, 32% stage IE, 28% stage II, 26% stage IIE disease; 17% bulky, 58% extra-nodal, 15% transformed disease, 40% elevated LDH. The majority of pts (70%) had germinal center B-cell phenotype. Eighty-two pts had data on BCL2-R and BCL6-R, of which 41 (50%) had double-hit lymphoma (DHL), including 4 pts with triple-hit lymphoma. Forty-five pts (43%) received R-CHOP, of which 56% had IFRT. Sixty pts (57%) received IIC, of which 42% had IFRT. R-DA-EPOCH was the most common IIC regimen used (85%), followed by R-hyperCVAD/MA (12%). Age (p=0.38), stage (p=0.32), extra-nodal disease (p=0.84), LDH (p=0.09), sm-IPI (p=0.24), morphology (p=0.44) and double-hit status (p=1.00) were similar between pts receiving R-CHOP and IIC. Median no. of cycles (NOC) (6 vs 6) and proportion of pts who received IFRT (56% vs 42%, p=0.17) did not differ in the 2 groups. Median NOC were lower in IFRT vs no IFRT group (4 vs 6; p=0.02). Pts receiving IIC (vs. R-CHOP) were more likely to undergo CNS prophylaxis (CNS-P) (75% vs 29%, p ORR was 90% (83% CR, 7% PR). Pts with DHL were less likely to achieve a CR compared to pts with MYC-R only (73% vs 98%; p=0.011). CR rate was higher in the IFRT vs no-IFRT group (92% vs. 75%, p=0.028). In the 27 pts who had relapsed/refractory disease, distant relapses were more common in the IFRT vs no-IFRT group (87% vs 33%, p=0.007). Median follow-up was 3.2 yrs; 35 (33%) pts progressed or died. Of the 23 deaths, 15 were due to progressive lymphoma, 1 due to treatment-related toxicity and 7 due to unrelated causes. 2-year PFS and OS were 78% and 86% for the entire cohort and 72% and 82% respectively for DHL pts. Sm-IPI ≥ 2 (HR: 2.81, p=0.02) and age ≥ 70 (HR: 4.07, P Conclusions: Outcomes of MYC-R LS-ALBCL pts are excellent with 2-year PFS and OS of 78% and 86% respectively. There was no benefit of choosing IIC over R-CHOP or using CNS prophylaxis in pts with MYC-R LS-ALBCL and LS-DHL in our study. While IFRT was effective in inducing CRs and preventing local relapses, distant relapses limited its benefit. Pts with LS-DHL had lower CR rates with similar PFS and OS when compared to those with MYC-R as the sole cytogenetic abnormality. Longer follow up is needed to assess the impact of upfront treatment strategies on late relapses. Disclosures Landsburg: Takeda: Consultancy; Curis: Consultancy, Research Funding. Maddocks:Teva: Honoraria; AstraZeneca: Honoraria; Pharmacyclics/Janssen: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; BMS: Research Funding. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Millenium: Other: Institutional Research Support. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Vose:Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Roche: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Acerta Pharma: Research Funding; Legend Pharmaceuticals: Honoraria. Cohen:Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Mehta:Seattle Genetics: Research Funding; Kite: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Merck: Research Funding; Spectrum: Consultancy; Epizyme: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Incyte: Research Funding; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Olszewski:Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding. Hill:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: The spectrum of FL varies from an indolent disease course spanning decades to early transformation and death. Longitudinal studies have identified a subset of high risk patients (pts) who progress within 24 months of frontline therapy. It is still unclear how best to treat these patients and as yet, there is no standard 2nd line therapy for FL. Given the multitude of treatments available and the heterogenous disease course, it is challenging to compare outcomes of 2nd line therapy. It is unclear if the efficacy of second-line therapy in FL is influenced by the type of therapy, disease biology (early vs. late progression) or both. We conducted a single institute, retrospective study to determine the clinical benefit of 2nd line therapy in FL and to evaluate if any particular type of therapy was associated with improved outcomes in FL patients with early progression (EP). Methods: All patients with relapsed/refractory FL treated at our Institute between 1990 and 2014 were included. Patients were included if they received anti-CD20 monoclonal antibody (mAb)-based therapy in the first-line setting and completed both, first-line and second-line therapy at our Institution. Demographic, clinical, pathological and outcomes data was collected by retrospective chart review. Clinical endpoints included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). Treatments were divided in two groups for comparison: immunotherapy alone (anti-CD20 mAb) (IT) or chemo-immunotherapy (CIT). Differences in clinical outcomes were analyzed between FL patients with early progression after 1st line therapy (EP, i.e. progression ≤ 2yrs) vs. FL with late relapse (LP, i.e. progression > 2yrs). Comparisons were made using the Mann-Whitney U and Person chi-square tests as appropriate. Survival outcomes were assessed using standard Kaplan-Meier methods. All analyses were conducted in SAS v9.4 (Cary, NC) at a significance level of 0.05. Results: A total of 537 newly diagnosed FL pts were identified of which 291 pts received 1st line therapy at our Institute. IT or CIT was given to 19.6% and 80.4% pts respectively. IT treated pts were older (median age: 61y vs 57y, p=0.033) and had lower FLIPI scores (1.5 vs 2.1, p Conclusion: FL pts with LR have excellent outcomes to 2nd line therapy and treatment selection could be determined by the agent(s) toxicity profile. In contrast, EP predicts poor clinical outcomes with short duration of response to standard IT or CIT. Therapeutic approaches incorporating clinically available targeted agents (i.e. immunomodulatory agents of B-cell receptor signaling inhibitors) or novel agents in the context of clinical trials, may provide a more effective disease control in this subgroup. Disclosures No relevant conflicts of interest to declare.

Limited mycophenolic acid (MPA) data are available comparing racial influence on mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) pharmacokinetics.Intrapatient MPA pharmacokinetics of MMF versus EC-MPS were compared in 13 male African American (AA) and 14 Caucasian (C) renal transplant recipients (RTRs). RTRs were switched to equivalent doses of the alternate formulation for at least 10 days prior to the second study. Mycophenolic acid clearance and dose-normalized area under the concentration-time curve(0-12) (AUC*) were determined. Mixed model statistics evaluated the main effects of race, drug formulation, and interaction of race and drug formulation (R × D) with albumin, cyclosporine trough, renal function, and diabetes and enterhepatic recirculation.Significant R × D was identified for MPA AUC* for EC-MPS (AA, 0.056 ± 0.029 [mg·h/L]/mg; C, 0.080 ± 0.044 [mg·h/L]/mg) compared with MMF (AA, 0.053 ± 0.019 [mg·h/L]/mg; C, 0.060 ± 0.025 [mg·h/L]/mg), P = .022. Significant R × D was identified with albumin in the model for MPA clearance for MMF (AA, 21.7 ± 8.9 L/h; C, 20.5 ± 10.8 L/h) compared with EC-MPS (AA, 22.2 ± 10.1 L/h; C, 16.2 ± 9.1 L/h), P = .032.Race influences MPA exposure between MMF and EC-MPS and may warrant therapeutic monitoring during formulation conversion.

The American Joint Committee on Cancer (AJCC) has proposed the inclusion of pretreatment serum carcinoembryonic antigen (CEA) levels (C stage) into the conventional TNM staging system of colon cancer. The latter proposal has yet to be widely adopted because of the lack of long-term survival estimates of after C-stage incorporation into AJCC staging.To evaluate whether long-term overall and cancer-specific survival is affected by inclusion of C stage into the standard AJCC TNM staging and to study the implications on survival estimates.We performed a retrospective study of all patients diagnosed as having histologically proven colonic adenocarcinoma from January 1, 2004, through December 31, 2005, from the National Cancer Institute's Surveillance, Epidemiology, and End Results database. We stratified each AJCC stage as C0 (normal) or C1 (elevated) based on the pretreatment serum CEA level. Median follow-up was 71 months.Five-year estimates of overall and disease-specific survival and hazard ratios (HRs) for estimates of risk of overall and disease-specific mortality.A total of 16 619 patients were evaluated, and of these, 8878 patients had C0 disease and 7741 had C1 disease. C1 stage was independently associated with a 51% and 59% increased risk of overall (HR, 1.51; 95% CI, 1.44-1.59; P .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.49-1.69; P . 001) at a median follow-up of 71 months. Analysis of survival of the AJCC stages subdivided as C0 or C1 revealed a significant worse prognosis of C1 AJCC stages compared with the respective C0 AJCC stages. The magnitude of change in survival was large enough to cause clustering of survival estimates of C1 vs C0 cancers across various AJCC stages. Analysis of patients with stage I, II, and III cancer revealed that node-negative C1 disease was associated with prognosis similar or worse than node-positive C0 disease.Inclusion of C stage into the AJCC TNM staging of colon cancer revealed significant differences dependent on C stage in terms of 5-year survival. C-stage inclusion resulted in substantial change in survival estimates, with C1 status portending a prognosis to certain stages similar to or worse than higher AJCC TNM stages with C0 status. We recommend routine pretreatment CEA testing as standard of care in colon cancer and use of C stage for multimodality treatment planning and risk stratification in prospective studies and randomized clinical trials.