Shorter TTR Research Articles

Prognostic value of baseline MRI features in patients treated with thermal ablation for hepatocellular carcinoma

PurposeTo investigate prognostic value of baseline MRI features for time-to-recurrence (TTR) and local recurrence in patients with early hepatocellular carcinoma (HCC). MethodBaseline and follow-up images of 88 patients treated with thermal ablation followed by adjuvant sorafenib or matching placebo due to HCC within the phase II prospective randomized trial (SORAMIC) were included. Baseline MRI images were evaluated in terms of atypical enhancement (lack of wash-in or wash-out), lesion diameter, tumor capsule, peritumoral enhancement on arterial phase, intratumoral fat, irregular margin, satellite lesions, and peritumoral hypointensity on hepatobiliary phase. Prognostic value of these features for TTR and local recurrence were assessed with univariable and multivariable Cox proportional hazard models. ResultsRecurrence at any location was diagnosed during follow-up in 30 patients, and the median TTR was 16.4 (95% CI, 15 – NA) months. The presence of more than one lesion (p = 0.028) and peritumoral hypointensity on hepatobiliary phase images (p = 0.012) at baseline were significantly associated with shorter TTR in univariable analysis. AFP > 15 mg/dL (p = 0.084), and history of cirrhosis (p = 0.099) were marginally non-significant. Peritumoral hypointensity on hepatobiliary phase images was the only significant risk factor for recurrence in multivariable analysis (p = 0.003).Local recurrence (adjacent to thermal scar) was diagnosed in eleven (8.3%) out of 132 lesions that underwent thermal ablation. The only significant risk factor for local recurrence was a lesion diameter larger than 3 cm (22.2% vs. 4.5%, p = 0.007). ConclusionsPeritumoral hypointensity on hepatobiliary phase can serve as imaging biomarker to identify increased recurrence risk in patients undergoing thermal ablation for early-stage HCC.

Relative contribution of clinical and molecular features to outcome within low and high risk T and N groups in stage III colon cancer (CC).

3520 Background: Duration of adjuvant FOLFOX or CAPOX for stage III CC is being guided by pt stratification into low (T1-3N1) and high (T4 or N2) risk groups based on the IDEA study. We determined the relative contributions of clinical and molecular features for prediction of time-to-recurrence (TTR) and survival after recurrence (SAR) within each risk group. Methods: Stage III CC (N=5,430) from 2 trials of adjuvant FOLFOX ± cetuximab with similar outcome by study arm [NCCTG N0147 (Alliance), PETACC-8] were used. Tumors were analyzed for mismatch repair (dMMR vs pMMR), mutations in KRAS (exon 2) and BRAFV600E. Median pt follow-up was 83.4 months. Relative contributions to predicting outcome were assessed using χ2 (Harrell’s rms) based on multivariable (MV) Cox models. Results: N (50.8%) and T (31.8%) stage were the top two contributors to prediction of TTR which supports risk grouping. High risk (n=2566) vs low risk (n=2774) pts had poorer TTR (HR 2.7, 95% CI, 2.4-3.0) and SAR [HR 1.6 (1.4-1.9)], both p<.0001. TTR: KRAS contributed the most to predicting TTR among high (58.6%) and low (51.1%) risk pts (Table). Contribution of MMR (16%) to predicting TTR was limited to low risk pts. Contribution of BRAFV600E to TTR was nearly 3-fold increased in high vs low risk pts. SAR: BRAFV600E contributed the most to predicting SAR, especially in high vs low risk pts (2-fold increase). Tumor sidedness and performance status (PS) were key contributors to SAR, but not TTR. MV associations: TTR: low risk, KRAS [HR 1.7 (1.4-2.3], MMR [HR 0.55 (.35-.87), gender (M/F) [HR 1.3 (1.0-1.5)], all p<.04]; high risk: BRAF [HR 1.3 (1.1-1.7)], sidedness (R vs L) [HR 1.14 (1.0-1.3)], KRAS [HR 1.4 (1.2-1.6)], all p<.04]. SAR: BRAF, sidedness, PS (all p<.05). Conclusions: KRAS mutation was the strongest predictor of shorter TTR in both risk groups whereas BRAFV600E was the primary driver of SAR, especially in high risk pts. Support: U10CA180821, U10CA180882, U24CA196171; BMS, Pfizer, Sanofi. NCT00079274.[Table: see text]

1284P - HOXA-related long non-coding RNAs impact prognosis in early stage NSCLC patients

Background: HOX genes, grouped in four clusters in humans (HOXA-D), encode for transcription factors that are master regulators of embryonic development and oncogenesis. HOXA cluster, located in chromosome 7, play a critical role in the patterning of tissues with mesodermal components such as lungs. Long non-coding RNAs (lncRNAs) are especially abundant in the HOXA cluster (HOXA10-AS, HOXAS2, HOXAS3, HOXA11-AS, HOTAIRM1 and HOTTIP). We aimed to evaluate the prognostic role of HOXA-related lncRNAs in early stage non-small cell lung cancer (NSCLC). Methods: 100 early stage NSCLC patients resected in our center from June 2007 to November 2013 were studied. Patient characteristics: median age, 65 (32-84); 78% males; 74% stage I; 56% ADK; 23% received adjuvant treatment. With a mean follow-up of 28.7 months, 31% relapsed. As validation data set 200 NSCLC patients from TCGA Research Network were used (RNAseq data). Only stage I-II TCGA samples without prior malignancy or synchronous cancer that not received neoadjuvant treatment were included. Statistical analysis was performed using R and TANRIC. Results: HOTTIP and HOXA11AS impacted prognosis in our cohort of patients. HOTTIP was expressed in all samples and patients with high levels of HOTTIP had shorter TTR (78.3 vs 58 months; p = 0.048) and shorter OS (81.2 vs 61 months; p = 0.023). HOTTIP was overexpressed in SCC (p = 0.007) and in smokers (p = 0.018). HOXA11AS was expressed only in 9% of patients but the patients expressing HOXA11AS had shorter TTR (73.5 vs 32 months; p = 0.002). In the multivariate analysis HOXA11AS emerged as an independent prognostic marker for TTR (OR: 3.13, 95%CI: 1.3-7.3; p = 0.009), while HOTTIP (OR: 2.357, 95%CI: 1.1-5.2; p = 0.036) and age>65 (p = 0.022) for OS. In the validation data set HOXA11AS was validated as prognostic marker (p = 0.019). HOXA11AS expression correlated positively with development genes HOXA11, HOXA13, HOXA10, HOXA9, HOXA3, FOXD1, ZIC5 and miR-196b (HOXA cluster miRNA) and negatively with surfactant metabolism genes SFTPB and NAPSA or let-7a(p < 0.001). Interestingly, the high expression was associated to patients harboring RTN1 mutations (p < 0.0001). Conclusions: HOXA11AS expression in early stage NSCLC patients is a high-risk relapse marker. Legal entity responsible for the study: University of Barcelona, Barcelona, Spain Funding: None Disclosure: All authors have declared no conflicts of interest. Keywords: HOTTIP, NSCLC, lncRNA, HOXA11AS

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy.

Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

A Fast Blind Rendezvous Method by Alternate Hop-and-Wait Channel Hopping in Cognitive Radio Networks

Rendezvous is an essential operation for secondary users communicating in a cognitive radio network (CRN). Because it is infeasible to employ a common control channel in a licensed spectrum, blind rendezvous is an expected solution and generally estimated by the criteria of asynchronous rendezvous support, guaranteed rendezvous, asymmetric model support, heterogeneity of roles, and short time-to-rendezvous (TTR). Most existing blind rendezvous methods fail to fully satisfy these criteria or have considerable TTR significantly increased with the number of channels. This paper presents a new alternate hop-and-wait channel hopping method, called E-AHW, which can support fast blind rendezvous. By assigning each secondary user a unique alternate channel hopping sequence composed of HOP/WAIT-mode subsequences, all blind rendezvous criteria can be satisfied with shorter TTR. According to simulation results, the performance of E-AHW is better than existing methods. Moreover, using E-AHW, the average value and standard deviation of time intervals between two rendezvous are also less than other methods. Thus, E-AHW can provide an efficient and stable communication environment.

Long-term Prognosis of Combined Hepatocellular and Cholangiocarcinoma After Curative Resection Comparison With Hepatocellular Carcinoma and Cholangiocarcinoma

In this study, we attempted to evaluate the prognosis of combined hepatocellular and cholangiocarcinoma (cHCC-CC) with comparison to hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CC). The prognosis of cHCC-CC has not been fully elucidated. In this study, we attempted to evaluate the prognosis of cHCC-CC with comparison to HCC and CC. Consecutive patients who underwent curative resection for cHCC-CC at a single tertiary care center in Korea and their age, sex, and Child-Turcotte-Pugh class matched HCC and CC patients were included. We evaluated time-to-recurrence (TTR) and overall survival (OS) of cHCC-CC cases and compared them with HCC and CC patients. Thirty cHCC-CC, 60 HCC, and 60 CC patients were included. For cHCC-CC group, the median TTR and OS were 5.4 and 18.0 months. After adjustment for confounding factors, the cHCC-CC group had a shorter TTR than did HCC group [relative risk (RR), 2.76; P<0.001] and CC group (RR, 2.00; P=0.013), and a shorter OS than HCC group (RR, 4.70; P<0.001). Compared with the each stage I diseases, cHCC-CC had shorter TTR than HCC (RR, 4.59; P=0.001) and CC (RR, 2.74, P=0.015) and shorter OS than HCC (RR, 9.35; P=0.001). The results of this study indicated that cHCC-CC had a significantly poorer prognosis than HCC and CC even after curative resection.

Tumor suppressor gene CpG site methylation and outcome in surgically treated stage I-II non-small cell lung cancer patients

11035 Background: Five year survival in completely resected non small cell lung cancer (NSCLC) stage I-II patients approximates 60%. Presently, no adequate prognostic indicators accurately predict outcome. To explore epigenetic influences, promoter methylation (silencing) at multiple CpG dinucleotides of tumor suppressor genes with roles in metastasis and survival was analyzed. Methods: Methylation was quantified at specific CpG sites in p16, MGMT, DAPK, RASSF1, ECAD, LET7–3-a, NORE1(RASSF5) and PTEN promoters in assessable tumor tissue from 88 surgically treated NSCLC patients by pyrosequencing. Results: Overall average promoter methylation ranged from 9.27+6.04% (DAPK) to 71.3+10.5% (LET7–3-a). Of the genes analyzed, RASSF1 showed significant association between overall average promoter methylation and increased recurrence (p=0.024). Upon comparison of methylation at specific CpG sites and any recurrence, MGMT methylation at CpG position 17 in exon1 and DAPK methylation at CpG site -1503 (A of the first ATG codon = +1) were significantly associated with higher recurrence (p=0.030, p=0.031, respectively). NORE1 methylation at -224 and -244 were significantly associated with no recurrence (p=0.024, p=0.030, respectively). Kaplan-Meier survival analysis revealed significantly lower time to regression [TTR; 9.80 vs. 55.2 months (mo), Log Rank p=0.003] and overall survival (OS, p=0.001) with MGMT methylated at exon 1 position 17. Significantly lower TTR and OS were also observed with MGMT methylated at exon 1 position 24 (p=0.020, p=0.017, respectively). In contrast, methylation at -224 in the NORE1 promoter was associated with longer median TTR (p=0.053). Conclusions: These data support an influence of specific CpG site methylation and outcome after surgical resection for stage I and II NSCLC. Methylation was generally associated with shorter TTR and OS, however methylation of particular NORE1 sites was associated with better outcome in this patient group. The effects of methylation of specific promoter sites may reflect accessibility to methylases and/or an interaction of transcription factors required for control of expression of these genes, phenotypically impacting metastatic potential and recurrence. No significant financial relationships to disclose.

GRP78 as a Novel Predictor of Responsiveness to Chemotherapy in Breast Cancer

The discovery of predictive factors for chemoresistance is critical for improving adjuvant therapy for cancer patients. The 78-kDa glucose-regulated protein (GRP78), widely used as an indicator of the unfolded protein response (UPR), is induced in the tumor microenvironment. In vitro studies suggest that GRP78 confers chemoresistance to topoisomerase inhibitors, such as Adriamycin (doxorubicin). Here, we report on a retrospective cohort study of 127 stage II and III breast cancer patients who were treated with Adriamycin-based chemotherapy. Archival tumor specimens were available for analysis and the relationship of GRP78 expression level to "time to recurrence" (TTR), used as a surrogate marker for drug resistance, was examined. Our data show that 67% of the study subjects expressed high level of GRP78 in their tumors before the initiation of chemotherapy and suggest an association between GRP78 positivity and shorter TTR [hazard ratio (HR), 1.78; P = 0.16]. Interestingly, subgroup analysis reveals that the HR for the GRP78-positive group increased significantly among patients who did not receive further taxane treatment (HR, 3.00; P = 0.022) and among mastectomy patients (HR, 3.33; P = 0.027). The HR was even stronger among mastectomy patients who did not receive further taxane treatment (HR, 4.82; P = 0.010). The use of GRP78 as a predictor for chemoresponsiveness and the potential interaction of GRP78 and/or the UPR pathways with taxanes warrant larger studies.