Citations

343 Background: Alliance/CALGB 80802, a randomized phase III trial, evaluated sorafenib plus doxorubicin vs. doxorubicin in pts with HCC and showed no improvement in median overall survival (OS) (HR[95CI] 1.05[0.83-1.31]) or PFS (HR[95CI] 0.93[0.75-1.16]). In HCC surrogacy of tumor response with OS remains controversial, in part due to varying criteria used for response evaluation (e.g., RECIST1.1 and mRECIST). We evaluated the performance of several models to predict OS using pretreatment clinical and radiomic variables. Methods: In CALBG 80802, we segmented all measurable tumor lesions on sequential CT scans. A lesion’s imaging phenotype was deciphered with 23 uncorrelated quantitative imaging features measured at baseline and week (wk) 10 (first follow-up). An OS landmark survival analysis was conducted at wk 10. Patients were randomly assigned (3:1) to training (n = 92) and validation (n = 37) sets. In a training set, 6 random forest predictive models (6 signatures) used features that best predicted OS using 3 sets of variables: radiomics only (n = 23), clinical only (n = 9), radiomics and clinical (n = 32). Two time points (baseline only or baseline + wk 10) were assessed. Each signature's output was an individualized prediction and a continuous value ranging from 0 to 1 (from most to least favorable predicted OS). The primary endpoint was to compare these models' performance to predict OS using error rate (Harrell's concordance-index) in the validation set. Results: Of the 6 training signatures evaluated, the one achieving the highest performance in the validation set was an 8-feature signature combining radiomics and clinical variables measured at two time points (baseline + wk 10) with an error rate of 35.6%. The variables [rank of importance] (table) selected by the signature included baseline clinical features (albumin[1], AFP[2], Child-Pugh[4]), baseline radiomics features (component 17[3], component 1[5], component 9[7], tumor volume[8]) and wk 10 radiomics features (delta tumor volume[6]). Variable delta tumor volume [6] used a more enhanced estimation of tumor burden at baseline and a delta tumor volumetric measurement; compared to RECIST1.1 measurement of percentage change in unidimensional measurement of a subset of target lesions. The four quartiles of the signature were significantly associated with OS (Log-Rank, P < 0.0001). Conclusions: The selected combined radiomic and clinical composite signature provided the best prediction for OS in the 80802 study patients’ population. It is a suggested way forward to go beyond single anatomic measurement techniques such as RECIST or mRECIST. [Table: see text]

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as < 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p < 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]

10 Background: In colon cancer, tumor deposits (TD) have been associated with worse prognosis, but they are included in the TNM staging system only in the absence of lymph node metastasis (i.e., stage III pN1c tumors). Here we aimed at evaluating the prognostic value of TD and the impact of the addition of TD in the count of lymph node metastases in patients with stage III colon cancer from the CALGB/SWOG 80702 phase III trial (NCT01150045). Methods: Pathological reports of all patients were reviewed for the presence and the count of TD, primary tumor sidedness, lymphovascular invasion and perineural invasion. Cases without available pathological report or without specific information of TD were excluded. Prognostic associations were evaluated by multi-variable Cox models adjusting for treatment arm, T-stage, N-stage, lymphovascular invasion, perineural invasion and lymph node ratio. Results: Overall, 2028 patients were included, with 524 (26%) TD-positive and 1504 (74%) TD-negative stage III tumors. Of the TD-positive patients, 80 (15.4%) were node negative (i.e., pN1c), 239 (46.1%) were pN1a/b and 200 (38.55%) were pN2. 17.2% and 37.0% of all pN1a/b and pN2 tumors had TD. Overall median follow-up was 69.3 months. The presence of TD was associated with poorer DFS (adjusted hazard ratio (aHR) = 1.59, 95%CI 1.28-1.91) and OS (aHR = 1.52, 95%CI 1.18-1.95) in the overall population. The negative effect of TD on DFS and OS was observed for both pN1a/b and pN2 groups and confirmed in multivariate Cox model. Among TD-positive patients, the number of TD had a linear negative effect on DFS and OS. Adding TD to the count of lymph node metastases, 104 of 1570 (6.6%) patients initially considered as pN1 were re-staged as pN2. Re-staged pN2 patients experienced worse DFS (3-year DFS rate: 65.5% versus 80.3%, P = .0003) and OS (5-year OS rate: 69.1 versus 87.8%, P = .0005) than patients confirmed as pN1. Re-staged pN2 patients had similar DFS than patients initially staged as pN2 (3-year DFS rate: 65.5% versus 63.1%, P = .1992). OS curves of these 2 groups crossed, with better outcomes during the first 3 years of follow-up but poorer 5-year estimates for re-staged pN2 patients (5-year OS rate: 69.1% versus 74.8%, P = .0436). Conclusions: TD are found in more than one fourth of stage III colon cancer specimens. The number of TD has a linear deleterious effect on patients’ prognosis. Adding the number of TD to the count of lymph node metastases improves the prognostication accuracy of the TNM staging. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01150045.

AbstractBackgroundPlasma NfL is a sensitive marker of axonal injury that is elevated in symptomatic FTLD and asymptomatic carriers of FTLD‐associated genetic mutations at short‐term risk of phenoconversion to mild behavioral or cognitive impairment or dementia. In carriers of FTLD‐associated genetic mutations, NfL is associated with clinical measures of disease severity.MethodPlasma NfL was measured using single molecule array technology in baseline blood samples from 290 participants in the ARTFL/LEFFTDS consortia. Participants included 181 asymptomatic mutation carriers (C9orf72, GRN, and MAPT); 45 with mild impairment (MBI/MCI), and 64 with dementia. 103 family members without FTLD‐associated mutations served as asymptomatic controls. Social cognition scales were obtained through clinical evaluation at baseline, year 1, and year 2. Stepwise linear regressions assessed NfL relationships with baseline social cognition measures. Linear mixed models were used to test the ability of baseline NfL to predict longitudinal changes. Analyses corrected for age, sex, and genotype.ResultAt baseline, plasma NfL correlated with all measures of social cognition, regardless of genotype. Associations were strongest for the Revised Self‐monitoring Scale (RSMS;β = ‐.50, p < .001), total score of the Social Norms questionnaire (β= .48, p < .001), and caregiver burden (Zarit burden;β = .55, p < .001). Regardless of disease severity, baseline NfL related to worse RSMS scores over time (‐3.7 points at year 2/ LogNfL unit increase, 95% CI ‐1.7 to ‐5.7, p < .001). In MBI/MCI, higher baseline NfL was associated with worse longitudinal scores on the Social Norms questionnaire (‐5.9 points at year 2/LogNfL unit increase, 95% CI ‐1.1 to ‐10.7, p = .016). No associations were seen in asymptomatic non‐carriers.ConclusionIn this familial FTLD cohort, plasma NfL is correlated with clinical measures of social cognition and caregiver burden. Higher baseline plasma NfL concentrations are associated with worsening self‐monitoring and social norms scores over time. These associations suggest that NfL is correlated with clinically meaningful measures that may be relevant to therapeutic development.

AbstractBackgroundIt is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials.MethodAs part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020.ResultAs of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection.ConclusionThe data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity &lt; .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend &lt; .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend &lt; .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

Pediatric aggressive mature B-cell lymphomas are the most common types of non-Hodgkin lymphoma in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). These diseases are highly aggressive but curable, the treatment is complex, and patients may have many complicated supportive care issues. The NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL.