Citations

7554 Background: Predicting early clinical failure in patients with untreated FL is important but difficult. Lymphoma involvement of EN sites is better detected by FDG-PET/CT than CT alone, but PET parameters are not part of the usual predictive indices. We aimed to determine the incidence and patterns of spleen and EN disease using PET/CT, and learn if they are useful in predicting early clinical failure. Methods: PET/CT images from 613 cases of newly diagnosed FL between 2003 – 2016 were retrospectively reviewed. The location, pattern, and number of EN sites, as well as splenic involvement, were recorded. Associations with outcomes were assessed using event-free survival (EFS) and overall survival (OS). Results: 49% (301/613) of patients had PET/CT-detected EN involvement, and 28% (171/613) had spleen involvement. Presence of ≥2 EN sites, spleen, bone, or soft tissue involvement, as well as a multifocal on diffuse pattern of bone involvement by imaging, were univariate predictors of EFS; presence of ≥2 EN sites and bone involvement pattern were also predictive of OS. In a multivariate analysis with FLIPI-2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (Table). When the multivariate analysis was performed using PRIMA-PI factors, the presence of ≥2 EN sites was an adverse independent prognostic factor for OS (HR 2.28; 95% CI 1.01-5.18; p=0.05). Conclusions: Baseline PET/CT identifies EN and spleen sites of disease that can predict early clinical failure of FL. These results may be useful to better identify high-risk patients and guide appropriate therapy. [Table: see text]

7514 Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R2) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R2, and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]

8522 Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2 complexes. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with advanced DLBCL, MM and select solid tumors were enrolled in parallel expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 35 subjects were enrolled including DLBCL (21) and MM (14). Results in solid tumor cohorts are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, hyperglycemia, rash, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (2), pneumonitis (1), renal insufficiency (2), pancreatitis (1) and thrombocytopenia (1). CC-223 dose reduction was required in 9 subjects (27%), usually during cycle 1 or 2, and 4 additional subjects with DLBCL dropped out during cycle 1 due to toxicity. Systemic exposure was similar between the two tumor cohorts and was associated with inhibition of TORC1 (p4EBP1) and TORC2 (pAKT) biomarkers in blood cells. Reduction in glucose uptake (32 – 98% decrease) on PET imaging at day 15 was observed in 7/7 DLBCL subjects with results currently available. Three of 17 evaluable subjects with DLBCL had partial responses (PR) after 2 cycles; two with rapid and near complete regression (> 90%) of target lesions by CT and PET with PR confirmed and treatment ongoing at 6 and 8 cycles. Both had failed multiple prior treatment regimens (5 and 3, respectively), including autologous stem cell transplant (ASCT). No responses were observed in 10/14 evaluable subjects with MM although 2 subjects have prolonged stable disease (SD) with treatment ongoing at 12 and 14 cycles. Conclusions: Encouraging signals of biomarker and clinical activity were observed in DLBCL, including two near complete responses, which are ongoing. Due to dose reductions and interruptions, a starting dose of 30 mg QD is recommended for future studies. Clinical trial information: NCT01177397.

3639 Background: The first phase of the multi-center prospectively specified retrospective study Validating Indicators To Associate Recurrence (VITAR), assessing the relationship between GCC gene expression in formalin fixed (FFPE) LNs and time to recurrence (TTR) in stage II CC pts not treated with adjuvant chemotherapy (Sargent, Annals Surg Onc 2011), showed promising initial results. Here we report a validation set of 463 new stage II CC pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs from untreated T3N0 CC pts diagnosed from 1999-2008 with at least 12 LNs examined , blinded to clinical outcomes. Patients were classified by GCC LN ratio (LNR) (high risk: LNR > 0.1; low risk: LNR ≤ 0.1), with LNR defined as ratio of GCC positive to GCC informative LNs. Cox regression models tested the relationship between GCC and the primary endpoint of TTR, adjusted for age, tumor grade, number of LN examined pathologically, and lymphovascular invasion. Mismatch repair (MMR) status was also assessed. All primary analyses and cut-points were pre-specified. Results: 46pts (10%) recurred (rec), median follow-up was 65 months, median LNs examined was 20, and 42% (195/463) were classified high risk. Overall, TTR was not significantly associated with binary GCC LNR risk class (HR=1.47, p=.208) or DFS (HR= 1.39, p=.097). One site’s (n=97) tissue grossing method precluded appropriate LN assessment with existing GCC qualification methods. Excluding this site resulted in a TTR HR=1.91, p=0.051 (multivariate). In a post-hocanalysis excluding this site and using a 3-level GCC risk group of high (LNR > 0.20), intermediate (0.10 < LNR < 0.20) and low (LNR < 0.10), high risk group pts had a 5-yr rec risk of 22% versus 8% in low risk (HR 2.72, p=0.006). MMR status was not significantly associated with TTR (multivariate p=0.30). Conclusions: GCC status is a promising prognostic factor in appropriately staged stage II CC pts not treated with adjuvant therapy independent of traditional histopathology risk factors, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Outcome associations were strengthened when considering a 3-level GCC categorization.

Abstract Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods In a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation. Results 7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels &lt;120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. Conclusions None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.

Background: Suprascapular nerve (SSN) block using bone reference points (BARO) is a technique that in principle is accessible to practitioners without experience in locoregional anesthesia or ultrasound guidance. The primary objective was to validate the feasibility of SSN BARO by an orthopedic surgeon. The secondary objective was to provide a description of the path of the sensory branches from the SSN to the shoulder. Methods: A BARO was performed on 15 cadaveric shoulders by an intern in orthopedic surgery. Ten ml of methylene blue and 0.75% ropivocaine were injected around the SSN. 2.5ml of a red latex solution were also injected to identify the injection site. The distribution of the sensory branches of the NSS was also described. Results: The average distance between the SSN and the injection site was 1.5cm (0-4.5cm). The most frequent injection site was the proximal third of the scapular neck. Fifteen SSNs were marked upstream of the origin of the sensory branches. The 15 SSN produced 3 sensory branches that innervate the posterior glenohumeral capsule, the subacromial bursa, and the coracoclavicular and acromioclavicular ligaments. Conclusion: SSN BARO by an orthopedic surgeon is a simple, reliable, and accurate technique. Injection near the suprascapular notch is recommended to mark the SSN upstream of its three sensory branches.

PURPOSE The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers. PATIENTS AND METHODS Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location. RESULTS Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic ( BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors ( BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant ( P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors. CONCLUSION The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.