Early Relapse Group Research Articles

Development and validation of a novel mRNA signature for predicting early relapse in non-small cell lung cancer.

Recurrence after initial primary resection is still a major and ultimate cause of death for non-small cell lung cancer patients. We attempted to build an early recurrence associated gene signature to improve prognostic prediction of non-small cell lung cancer. Propensity score matching was conducted between patients in early relapse group and long-term survival group from The Cancer Genome Atlas training series (N=579) and patients were matched 1:1. Global transcriptome analysis was then performed between the paired groups to identify tumour-specific mRNAs. Finally, using LASSO Cox regression model, we built a multi-gene early relapse classifier incorporating 40 mRNAs. The prognostic and predictive accuracy of the signature was internally validated in The Cancer Genome Atlas patients. A total of 40 mRNAs were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high-risk group and a low-risk group. Relapse-free survival was significantly different between the two groups in both discovery (HR: 3.244, 95% CI: 2.338-4.500, P<0.001) and internal validation series (HR 1.970, 95% CI 1.181-3.289, P=0.009). Further analysis revealed that the prognostic value of this signature was independent of tumour stage, histotype and epidermal growth factor receptor mutation (P<0.05). Time-dependent receiver operating characteristic analysis showed that the area under receiver operating characteristic curve of this signature was higher than TNM stage alone (0.771 vs 0.686, P<0.05). Further, decision curve analysis curves analysis at 1year revealed the considerable clinical utility of this signature in predicting early relapse. We successfully established a reliable signature for predicting early relapse in stage I-III non-small cell lung cancer.

Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy

Rituximab is an important second line therapy in difficult nephrotic syndrome (NS), especially given toxicity of long-term glucocorticoid or calcineurin inhibitor (CNI) use. However, clinical response to rituximab is heterogenous. We hypothesized that this was underpinned by immunological differences amongst patients with NS. We recruited a cohort of 18 subjects with glucocorticoid-dependent or glucocorticoid-resistant childhood-onset minimal change NS who received rituximab either due to CNI nephrotoxicity, or due to persistent glucocorticoid toxicity with inadequate response to cyclophosphamide or CNIs. Immunological subsets, T-cell activation assays and plasma cytokines were measured at baseline and 6-months post-rituximab. Time to relapse was bifurcated: 56% relapsed within one year ("early relapse"), while the other 44% entered remission mainly lasting ≥3 years ("sustained remission"). At baseline, early relapse compared to sustained remission group had lower regulatory T-cells (Tregs) [2.94 (2.25, 3.33)% vs 6.48 (5.08, 7.24)%, P<0.001], PMA-stimulated IL-2 [0.03 (0, 1.85)% vs 4.78 (0.90, 9.18)%, P=0.014] and IFNγ [2.22 (0.18, 6.89)% vs 9.47 (2.72, 17.0)%, P=0.035] levels. Lower baseline Treg strongly predicted early relapse (ROC-AUC 0.99, 95% CI 0.97-1.00, P<0.001). There were no differences in baseline plasma cytokine levels. Following rituximab, there was significant downregulation of Th2 cytokines in sustained remission group (P=0.038). In particular, IL-13 showed a significant decrease in sustained remission group [-0.56 (-0.64, -0.35)pg/ml, P=0.007)], but not in the early relapse group. In conclusion, early relapse following rituximab is associated with baseline reductions in Treg and T-cell hyporesponsiveness, which suggest chronic T-cell activation and may be useful predictive biomarkers. Sustained remission, on the other hand, is associated with downregulation of Th2 cytokines following rituximab.

123I metaiodobenzylguanidine (MIBG) uptake predicts early relapse of neuroblastoma using semi-quantitative SPECT/CT analysis

Objective123I metaiodobenzylguanidine (MIBG) scintigraphy is a useful tool for the diagnosis of neuroblastoma (NB). MIBG uptake is correlated with norepinephrine transporter expression; hence, it is expected that high-MIBG tumors would be more highly differentiated and have a better prognosis than those with lower expression. We have introduced a method of assessing MIBG accumulation semi-quantitatively using SPECT/CT fusion images. The purpose of this study was to evaluate the relationship of 123I MIBG uptake measured by semi-quantitative values of SPECT/CT and early relapse of NB.MethodsWe studied the cases of 11 patients (5 males and 6 females, age 5–65 months, median age 20 months) with histopathologically proven NB between April 2010 and March 2015. The early-relapse group was defined as patients who had relapsed within 3 years after the first 123I MIBG SPECT/CT exam. Other patients were classified as the delay-relapse group. Uptake of MIBG was evaluated using the count ratio of tumor and muscles. T/Mmax and T/Mmean were defined as follows: T/Mmax = max count of tumor/max count of muscle, T/Mmean = mean count of tumor/mean count of muscle.ResultsThe average T/Mmean values of the early-relapse group and delay-relapse group were 2.65 ± 0.58 and 7.66 ± 2.68, respectively. The T/Mmean values of the early-relapse group were significantly lower than those of delay-relapse group (p < 0.05). The average T/Mmax of the early-relapse group and delay-relapse group were 8.86 ± 3.22 and 16.20 ± 1.97, respectively. There was no significant difference in T/Mmax values between the two groups.ConclusionsLow 123I MIBG uptake using semi-quantitative SPECT/CT analysis was correlated with early relapse of NB.

Cerrahi Sınır Negatif Radikal Prostatektomili Hastalarda Biyokimyasal Nüks ile İnsülin Benzeri Büyüme Faktör-1 Arasında İlişki Var mıdır?

Objective: Levels of insulin-like growth factor 1 (IGF-1) have been associated with prostate carcinoma. We have investigated whether IGF-1 level has an early predictive value for the biochemical relapse in the prostate carcinoma patients with a negative surgical margin who underwent curative surgery. Materials and Methods: We retrospectively analyzed 82 patients who were followed-up regularly and did not receive neoadjuvant or adjuvant chemotherapy. We classified patients as having Gleason scores ≥7 and &lt;7, PSA values ≥10 ng/ml and &lt;10, biochemical relapse positive or negative, T stages ≥T2 and &lt;T2, tumor burden in less or more than 50% pathologic specimens, respectively. PSA cut-off value accepted was as 0.2 ng/ml. According to average values in the literature, time to PSA relapses was considered early if it was less than 18 months and late if more than 18 months. We measured PSA and IGF-1 levels at each routine control visit. Results: During 60-month follow-up, 66 (80.4%) patients had no relapse, while in 8 (9.8%) patients had early, and other 8 (9.8%) patients had a late biochemical relapse. There was no statistically significant difference between these 3 groups of patients according to their age, tPSA levels, and BMI parameters. We compared IGF-1 levels with tumor burden, tPSA levels, tumor grade, and Gleason scores without any significant difference between these parameters. When we accepted IGF-1 cut-off values as 60 ng/ml, we observed higher Gleason scores (≥ 7 and more) in these patients. There was a weak relationship between IGF-1 levels of non-relapse and early relapse patients (p:0.078). However, when we evaluated IGF-1 levels among patients with relapse, the early relapse group had significantly higher IGF-1 levels (p: 0.006). When the cut-off value of IGF-1 was accepted as 60 ng/ml, which was found to be significant for Gleason score, the early relapse group had significantly higher IGF-1 levels compared to the non-relapse group (p:0.023). Conclusions: According to our study, the IGF-1 level has a predictive value for showing biochemical recurrence after surgery. Nevertheless, considering the number of patients, we need randomized controlled trials with a large number of patients.

Early Relapse After Autologous Stem Cell Transplantation in Multiple Myeloma is Still Prognostic in The Era of Novel Agents

Significant improvements in the prognosis of Multiple Myeloma(MM) have recently observed in the era of novel agents. Induction treatment, including new agents followed by conditioning regimen and upfront autologous stem cell transplantation(ASCT), has been accepted as the standard treatment approach for newly diagnosed eligible MM patients. Despite novel agents, upfront ASCT is still superior to conventional chemotherapy alone. Previous studies revealed that the duration between ASCT and relapse had predicted overall survival(OS), and meantime, it was widely used to determine the potential benefit from a second ASCT. However, the majority of the data collected reflects the treatment modalities before novel agents. In this study, we aimed to investigate the impact of post-transplantation early relapse(ER) on survival in the era of novel agents. The results of 155 MM patients that underwent ASCT at our center between January 2010 and May 2018 were analyzed retrospectively. The median follow-up duration was 20 months in the ER group, 27 months in the non-ER group, and 24 months in all patients. 33.3% of patients in the ER group and 71.4% of patients in the non-ER group were alive at the time of analysis. Median OS was 20.77±3.66 months in the ER group and 40.89±4.21 months in the non-ER group. We found a statistically significant relationship between the ER and the poor OS (p:&lt;0.001). Our study reveals that in the era of novel agents, ER still related to poor survival. Therefore, comprehensive studies needed to develop new strategies for early relapsed patients.

Early Relapse After Autologous Stem Cell Transplantation in Multiple Myeloma is Still Prognostic in The Era of Novel Agents

Significant improvements in the prognosis of Multiple Myeloma(MM) have recently observed in the era of novel agents. Induction treatment, including new agents followed by conditioning regimen and upfront autologous stem cell transplantation(ASCT), has been accepted as the standard treatment approach for newly diagnosed eligible MM patients. Despite novel agents, upfront ASCT is still superior to conventional chemotherapy alone. Previous studies revealed that the duration between ASCT and relapse had predicted overall survival(OS), and meantime, it was widely used to determine the potential benefit from a second ASCT. However, the majority of the data collected reflects the treatment modalities before novel agents. In this study, we aimed to investigate the impact of post-transplantation early relapse(ER) on survival in the era of novel agents. The results of 155 MM patients that underwent ASCT at our center between January 2010 and May 2018 were analyzed retrospectively. The median follow-up duration was 20 months in the ER group, 27 months in the non-ER group, and 24 months in all patients. 33.3% of patients in the ER group and 71.4% of patients in the non-ER group were alive at the time of analysis. Median OS was 20.77±3.66 months in the ER group and 40.89±4.21 months in the non-ER group. We found a statistically significant relationship between the ER and the poor OS (p:&lt;0.001). Our study reveals that in the era of novel agents, ER still related to poor survival. Therefore, comprehensive studies needed to develop new strategies for early relapsed patients.

Prognostic Factors for Postrelapse Survival after ex Vivo CD34+-Selected (T Cell-Depleted) Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma.

Allogeneic hematopoietic cell transplantation (alloHCT) for multiple myeloma (MM), with its underlying graft-versus-tumor capacity, is a potentially curative approach for high-risk patients. Relapse is the main cause of treatment failure, but predictors for postrelapse survival are not well characterized. We conducted a retrospective analysis to evaluate predictors for postrelapse overall survival (OS) in 60 MM patients who progressed after myeloablative T cell-depleted alloHCT. The median patient age was 56 years, and 82% had high-risk cytogenetics. Patients received a median of 4 lines of therapy pre-HCT, and 88% achieved at least a partial response (PR) before alloHCT. Of the 38% who received preemptive post-HCT therapy, 13 received donor lymphocyte infusions (DLIs) and 10 received other interventions. Relapse was defined as very early (<6 months; 28%), early (6 to 24 months; 50%), or late (>24 months; 22%). At relapse, 27% presented with extramedullary disease (EMD). The median postrelapse overall survival (OS) by time to relapse was 4 months for the very early relapse group, 17 months for the early relapse group, and 72 months for the late relapse group (P=.002). Older age, relapse with EMD, <PR before alloHCT, <PR by day +100, and no maintenance were prognostic for inferior postrelapse OS on univariate analysis. On multivariate analysis adjusted for age and sex, very early relapse (hazard ratio [HR], 4.37; 95% confidence interval [CI], 1.42 to 13.5), relapse with EMD (HR, 5.20; 95% CI, 2.10 to 12.9), and DLI for relapse prevention (HR, .11; 95% CI, 2.10 to 12.9) were significant predictors for postrelapse survival. Despite their shared inherent high-risk status, patients with MM have significantly disparate post-HCT relapse courses, with some demonstrating long-term survival despite relapse.

The lack of selection criteria for surgery in patients with non-colorectal non-neuroendocrine liver metastases

BackgroundThe benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM.MethodsData for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence < 1 year postoperatively who did not benefit from surgery (N = 28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥ 5 years postoperatively and benefited from surgery (N = 20). Clinicopathologic parameters, the Association Française de Chirurgie (AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups.ResultsThe majority of patients were female and a majority had an ASA score ≤ 2 at the time of liver surgery. The median age was 55 years. Almost half of the patients (46%) presented with a single-liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and 10-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were the size of liver metastases > 50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (scores 3–4) was predictive for the poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor, and the size of liver metastases was significantly higher in the ER group.ConclusionIn patients with resectable NCRNNELM, no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit.

Differences in disease status between patients with progression after first-line chemotherapy versus early relapse after adjuvant chemotherapy who undergo second-line chemotherapy for gastric cancer: Exploratory analysis of the randomized phase III TRICS trial

BackgroundSecond-line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Patients receiving SLC are categorized into two disease status groups: tumour progression after first-line chemotherapy and early recurrence after adjuvant chemotherapy. Differences between these groups have not yet been clarified. Patients and methodsA total of 163 eligible patients registered in the randomized phase III TRICS trial evaluating SLC for patients with AGC was classified into the progressive disease (PD) group (n = 55) or the early relapse (ER) group (n = 108). We compared overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). ResultsThe ER group had a lower median age than the PD group (66 vs. 72 years; P = 0.016), performance status (PS) 0 was more frequently seen in the ER group (87% vs. 71%; P = 0.012). The adjusted median OS was 13.7 months in the ER group and 13.6 months in the PD group (IPTW hazard ratio [HR]: 1.023; P = 0.854). The adjusted median PFS was 4.9 months in the ER group and 4.4 months in the PD group (IPTW HR: 0.707; P = 0.004). ORR was significantly better in the ER group than the PD group (21.3% vs. 4.9%; P = 0.020). No significant differences were observed in the incidence of adverse events. ConclusionsER was associated with improved PFS and better ORR than PD, although no difference in survival was demonstrated. From the viewpoint of treatment outcome, it seems appropriate to treat patients with ER in the same way as patients with PD. Clinical trial registrationUMIN 000002571.

Treatment of relapsed acute leukemia by Ara C plus donor lymphocyte infusion using CD34＋ cells reserved at the time of allogeneic transplantation.

Currently, there is no standard therapy available for relapsed acute leukemia after allogeneic hematopoietic cell transplantation (allo-HCT). In this study, we evaluated the efficacy of cytoreduction with cytarabine followed by granulocyte colony-stimulating factor (G-CSF)-primed donor lymphocyte infusion (DLI) for patients with acute leukemia who relapsed after allo-HCT. We retrospectively reviewed 255 patients who had received allo-HCT for acute leukemia/myelodysplastic syndrome. Patients were divided into two groups based on the CD34＋ cell dose they received during the initial transplantation; patients in the lower CD34＋ group received a dose lower than 6×106 cells/kg and those in the higher CD34＋ group received a dose higher than 6×106 cells/kg. No significant differences were noted between two groups with respect to overall survival, relapse-free survival, or graft-versus-host disease (GVHD)-free/relapse-free survival. Patients who relapsed after allo-HCT (n＝93) were assigned into early or late relapse groups using the median time to relapse as the threshold. Among the 93 patients with relapse, 39 received G-CSF-primed DLI. The median dose of CD3＋ cells was 2.82×107 cells/kg (range: 0.05-10.1). In the late relapse group, one-year overall survival was significantly higher in patients receiving DLI than that in patients not receiving DLI (53.4% ±7.4% vs. 26.7% ±7.4%; P＝0.039), whereas no DLI effect was detected within the early relapse group. In addition, the incidence of DLI-induced GVHD did not differ between the two groups. In conclusion, treatment with G-CSF-primed DLI after allo-HCT with a limited CD34＋ cell dose constitutes a feasible and effective option, which could replace second HCT in treatment of late-relapse patients.

Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial

Characterization of Relapse and Second-Line Therapy in Lenalidomide-Refractory, Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma: A Subanalysis of the Phase 3 First Trial

The metabolic clinical risk score as a new prognostic model for surgical decision-making in patients with colorectal liver metastases.

Selection for surgery in patients with colorectal liver metastases (CRLM) remains inaccurate. We evaluated if CRLM baseline metabolic characteristics, assessed by [18]F-fluorodeoxyglucose-positron emission tomography/computed tomography (18 FDG-PET/CT), could predict postoperative outcomes. In a retrospective series of patients undergoing surgery for CRLM, we defined two groups: the long-term survival (LTS) and early relapse (ER) groups, where the postoperative recurrence-free survivals were ≥5 years or <1 year, respectively. We analyzed the patients in whom baseline 18 FDG-PET/CT was available. Clinicopathologic parameters, clinical risk score (CRS), and baseline 18 FDG-PET/CT characteristics were compared between LTS and ER groups. A metabolic CRS (mCRS) was implemented, adding one point to the standard five-point CRS when the highest tumor standardized uptake values (SUVmax )/normal liver mean SUV (SUVmean(liver) ) ratios were >4.3, defining low- and high-risk mCRS by scores of 0 to 2 and 3 to 6, respectively. From a series of 450 patients operated for CRLM (mean follow-up of 58 months), we included for analysis 23 and 30 patients in the LTS and ER groups, respectively. Clinicopathologic parameters and CRS were similar in the LTS and ER groups. Median SUVmax /SUVmean(liver) ratios were higher in ER vs LTS patients (4.2 and 2.8, P = .008, respectively). mCRS was increased in ER patients (P = .024); 61% of LTS patients had low-risk mCRS and 73% of the ER patients had high-risk mCRS (P = .023). 18 FDG-PET/CT characteristics combined with traditional CRS may represent a new tool to improve selection for surgery in patients with CRLM.

Network-based analysis of prostate cancer cell lines reveals novel marker gene candidates associated with radioresistance and patient relapse.

Radiation therapy is an important and effective treatment option for prostate cancer, but high-risk patients are prone to relapse due to radioresistance of cancer cells. Molecular mechanisms that contribute to radioresistance are not fully understood. Novel computational strategies are needed to identify radioresistance driver genes from hundreds of gene copy number alterations. We developed a network-based approach based on lasso regression in combination with network propagation for the analysis of prostate cancer cell lines with acquired radioresistance to identify clinically relevant marker genes associated with radioresistance in prostate cancer patients. We analyzed established radioresistant cell lines of the prostate cancer cell lines DU145 and LNCaP and compared their gene copy number and expression profiles to their radiosensitive parental cells. We found that radioresistant DU145 showed much more gene copy number alterations than LNCaP and their gene expression profiles were highly cell line specific. We learned a genome-wide prostate cancer-specific gene regulatory network and quantified impacts of differentially expressed genes with directly underlying copy number alterations on known radioresistance marker genes. This revealed several potential driver candidates involved in the regulation of cancer-relevant processes. Importantly, we found that ten driver candidates from DU145 (ADAMTS9, AKR1B10, CXXC5, FST, FOXL1, GRPR, ITGA2, SOX17, STARD4, VGF) and four from LNCaP (FHL5, LYPLAL1, PAK7, TDRD6) were able to distinguish irradiated prostate cancer patients into early and late relapse groups. Moreover, in-depth in vitro validations for VGF (Neurosecretory protein VGF) showed that siRNA-mediated gene silencing increased the radiosensitivity of DU145 and LNCaP cells. Our computational approach enabled to predict novel radioresistance driver gene candidates. Additional preclinical and clinical studies are required to further validate the role of VGF and other candidate genes as potential biomarkers for the prediction of radiotherapy responses and as potential targets for radiosensitization of prostate cancer.

SERPINB12 as a possible marker of steroid dependency in children with eosinophilic esophagitis: A pilot study

BackgroundTopical steroids are effective in eosinophilic esophagitis (EoE), but patients often show different tendencies to relapse. We assessed whether gene expression is associated with a sort of steroid dependency in EoE children. MethodsBiopsy samples were prospectively collected on EoE children responding to topical steroids. Patients treated with viscous budesonide for 24 weeks were subsequently classified as early (6 months) or late (>6 months) relapsing. RNA was isolated from esophageal biopsies at the time of the relapse and analyzed by NGS for transcriptome profiling. ResultsOf 40 patients, 22 patients were considered for mRNA expression profile. Thirteen were included in the early-relapse group, and 9 were in the late-relapse. No significant difference was observed in the two groups for clinical, endoscopic or histological features. Using the mRNA expression profile we performed supervised clustering using the 10 top differentially expressed genes between early and late relapsing patients. The heatmap and PCA show a proper segregation among patients. SERPINB12 is the only gene attaining a significant differential expression between the two groups (FDR < 0.05). ConclusionsDifferent tendencies to relapse in EoE children responding to topical steroids might be related to altered mRNA expressions. SERPINB12 presented a significantly higher expression in the late relapse group and it deserves further investigations.

Development and Validation of an Autophagy Score Signature for the Prediction of Post-operative Survival in Colorectal Cancer.

Background: Survival rates for Colorectal cancer (CRC) patients who experienced early relapse have usually been relatively low. Our study aims at developing an autophagy signature that could help to detect early relapse cases in CRC.Methods: Propensity score matching analysis was carried out between patients from the early relapse group and the long-term survival group from GSE39582. For both groups, respectively, global autophagy expression changes were then analyzed to identify the differentially expressed prognostic autophagy related genes by conducting Linear Models for Microarray data method analysis. Then, the multi-gene signature was validated in TCGA and Fudan University Shanghai Cancer Center (FUSCC) cohorts. Time-dependent ROC were used to test the efficiency of this signature feature in predicting the prognosis of CRC patients.Results: 5 autophagy genes were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into low- or high-risk group. Time-dependent ROC analyses proved its prognostic accuracy, with AUC 0.841 and 0.803 at 1 and 3 years, respectively. Then, we validated its prognostic value in two external validation series (GSE17538 and GSE33113) and proved that the result is indeed significant irrespective of datasets in two external independent validation cohorts (TCGA and FUSCC cohorts). A nomogram was constructed to guide individualized treatment of patients with CRC.Conclusions: The identification of robust autophagy-related features can effectively classify CRC patients into groups with low and high risk of early relapse. This signature may be used to help select high-risk CRC patients who require more aggressive treatment interventions.

Risk Factors and Outcomes of Early Relapse After Curative Resection of Intrahepatic Cholangiocarcinoma.

Early relapse after hepatectomy for intrahepatic cholangiocarcinoma (ICC) has a tremendous influence on the long-term survival outcomes of ICC patients. The purpose of our study was to investigate risk factors for early tumor relapse and confirm whether early relapse was correlated with ICC patients' long-term survival outcomes. Three hundred and twenty-two consecutive ICC patients undergoing partial hepatectomy at Liver Surgery Department of Zhongshan Hospital (Fudan University, Shanghai, China) between January 2005 and December 2011 were included in this retrospectively study. The definition of early relapse had been described as tumor relapse within 24 months after hepatectomy in ICC patients. We identified a total of 168 ICC patients with early relapse and 23 ICC patients with late relapse after hepatectomy. From the time of relapse, the long-term survival outcomes were worse among patients who had early vs. late relapse (median OS 16.5 vs. 44.7 months, respectively; P < 0.0001). The overall survival of the early relapse group was lower than that of the late relapse group (P < 0.0001). Multivariate Cox regression analysis indicated that multiple tumors (hazard ratio [HR], 1.951; 95% CI, 1.382–2.755; P < 0.001), lymphonodus metastasis (HR, 1.517; 95% CI, 1.061–2.168; P = 0.022), and higher serum CA19-9 levels (HR, 1.495; 95% CI, 1.095–2.039; P = 0.011) were independent risk factors of early relapse. Moreover, multiple tumors (HR, 1.641; 95% CI, 1.120–2.406; P = 0.011), lymphonodus metastasis (HR, 2.008; 95% CI, 1.367–2.949; P < 0.001), elevated NLR (HR, 1.921; 95% CI, 1.331–2.774; P < 0.001) and higher serum CA19-9 levels (HR, 1.990; 95% CI, 1.409–2.812; P < 0.001) were independent predictors of overall survival for ICC patients with early relapse. Collectively, our findings demonstrated that multiple tumors, lymphonodus metastasis, and higher serum CA19-9 levels were associated with the increased risks of early relapse and worse prognoses of ICC after curative-intent resection.

The metabolic clinical risk score (mCRS) as a new prognostic model for surgical decision in patients with colorectal liver metastases.

e15094 Background: Selection for surgery in patients with colorectal liver metastases (CRLM) remains poorly accurate. We evaluated if baseline metabolic characteristics of CRLM, as assessed by [18]-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18FDG-PET/CT), may predict the postoperative outcome in patients operated for CRLM. Methods: In a series of 450 patients operated for CRLM, we retrospectively identified 2 groups: The long-term survival (LTS), as defined by postoperative recurrence-free survival (RFS)≥5 years, and the early relapse groups (ER), as defined by RFS &lt; 1 year. Clinicopathologic characteristics, Clinical Risk Score (CRS) and baseline 18FDG-PET/CT metabolic parameters were analyzed. Baseline 18FDG-PET/CT was performed at the time of diagnosis of CRLM, before any preoperative treatment. Low and high-risk CRS were defined by scores of 0 to 2 and 3 to 5, respectively. Metabolic CRS (mCRS) was implemented, using 1 additional point to the standard CRS when the highest tumor standardized uptake value (SUVmax) and normal liver mean SUV (SUVmean(liver)) ratio was &gt; 4.3. Low and high-risk mCRS were defined by scores of 0 to 2 and 3 to 6, respectively. Results: We analyzed 53 patients. No difference was observed between LTS (n = 23) and ER (n = 30) groups for clinicopathologic parameters related to the primary tumor and CRLM, CRS and rates of low/high risk CRS. All metabolic parameters analyzed, including SUVmax and SUVpeak, at the exception of metabolic tumor volume, were significantly increased in ER group. Median SUVmax/SUVmean(liver) ratio was significantly increased in the ER vs LTS, respectively of 4.2 and 2.8 (p = 0.008). mCRS was significantly higher in ER as compared to LTS patients (p = 0.024), while 61% of the LTS patients had a low-risk mCRS and 73% of the ER patients had a high-risk mCRS (p = 0.023). Conclusions: Baseline 18FDG-PET/CT characteristics demonstrate an increased tumor glucose uptake in patients who rapidly recur after curative-intent surgery for CRLM. The introduction of these data into clinical risk model may represent a new tool to improve selection for surgery in patients with CRLM.

Prognostic and predictive value of an autophagy-related signature for early relapse in stages I-III colon cancer.

We postulated that expression differences of autophagy-related genes are instrumental in stratifying the risk of early relapse after surgery and evaluating the prognosis of patients with stages I-III colon cancer. Therefore, propensity score matching analysis was performed between patients in early relapse group and long-term survival group from GSE39582 test series and internal validation series. Using Cox regression model, a nine-autophagy-related signature (CAPN2, ATG16L2, TP63, SIRT1, RPS6KB1, PEX3, ATG5, UVRAG, NAF1) was established to classify patients into those at high risk of early relapse (high-risk group), and those at low risk of early relapse (low-risk group). Relapse-free survival (RFS) was significantly different between the two groups in test [hazard ratio (HR): 2.019, 95% confidence interval (CI): 1.362-2.992, P < 0.001], internal validation (HR: 2.464, 95% CI: 1.196-5.079, P < 0.001) and another two external validation series (GSE14333-HR: 2.250, 95% CI: 1.227-4.126, P = 0.007; GSE33113-HR: 5.552, 95% CI: 2.098-14.693, P < 0.001). Then, based on RFS, we developed a nomogram, integrating the nine-autophagy-related classifier and four clinicopathological risk factors to evaluate prognosis of stages I-III colon cancer patients. Time-dependent receiver operating curve at 2 years showed that the integrated signature (area under curve = 0.758) had better prognostic accuracy than American Joint Committee on Cancer TNM stage (area under curve = 0.620). In conclusion, we identified and built a nine-autophagy-related signature, a credible approach to early relapse prediction in stages I-III colon cancer patients, which can assist physicians in devising more efficient therapeutic strategies.

Low Relapse Rate after 2 Years in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP and Achieved Complete Response

Introduction: Patients with DLBCL usually relapse early after the first treatment but some relapse after 2 years (defined as late relapses). In a previous study, patients with DLBCL who achieved event free survival at 24 months had a subsequent overall survival equivalent to the general population. We analyzed the time of relapse and clinical characteristics of late relapse in patients with DLBCL who achieved complete response (CR) after frontline R-CHOP.Methods: We retrospectively reviewed prospectively collected lymphoma registry of the Asan Medical Center in Seoul, Korea, between 2002 and 2015. We found 1,047 DLBCL patients who have been treated with R-CHOP as the first line modality. Among 1,047 patients, 859 (82.0%) patients achieved CR. Chi-square or Fisher's exact test was used for comparison of categorical variables and Student's t-test or Mann-Whitney U-test for continuous variables, as appropriate. Two-sided p-value of <0.05 was considered significant.Results: Among 859 patients, 182 (21.2%) patients relapsed and 51 (5.9%) patients had late relapse after 2 years from the end of treatment evaluation that confirmed CR. For patients who had a late relapse, median time from diagnosis to relapse was 4.0 years (range, 2.0 to 10.0 years), median age was 61 years old (range, 39-78), and 27 (52.9%) patients were male. Twenty-six (51%) patients had stage I-II, and 36 (70.6%) patients had low/low-intermediate International Prognostic Index (IPI) score at diagnosis. Compared with early relapses (n=131, 12.5%), late relapses were associated with low IPI score (median, 2 vs. 3; p = 0.001), low LDH (median, 244 vs. 337 IU/L; p < 0.001), low beta-2-microglobulin (median, 2.4 vs. 2.6 mg/L p = 0.002), higher germinal center phenotype rate (30.6% vs. 15%; p=0.05). Median overall survival from the end of treatment evaluation that confirmed CR was significantly higher in the late relapse group compared with early relapse group [112.6 months (95% CI 73.1-152.0) vs. 19.9 months (95% CI 15.3-24.4); p<0.001 by log rank].Conclusion: Our study demonstrated that relapse rate after 2 years was low (5.9%) in patients with DLBCL who achieved CR after R-CHOP. Patient with late relapse showed favorable clinical characteristics and survival outcomes compared with patients with early relapse. DisclosuresNo relevant conflicts of interest to declare.

A Novel Messenger RNA Signature as a Biomarker for Predicting Early Relapse in Non-Small Cell Lung Cancer

Background: High throughput gene expression profiling has showed great promise in providing insight into molecular mechanisms. Recurrence-related mRNAs may potentially enrich genes with the ability to predict cancer recurrence and survival, therefore we attempted to build an early recurrence-associated gene signature to improve prognostic prediction of lung cancer. Methods: Propensity score matching was conducted between patients in early relapse group and long-term survival group from TCGA training series (N=579) and patients were matched 1:1. Global transcriptome analysis was then performed between the paired groups to identify tumor specific mRNAs. Finally, using LASSO Cox regression model, we built a multi-gene early relapse classifier incorporating forty mRNAs. The prognostic and predictive accuracy of the signature was internally validated in another 193 lung cancer patients. Results: Forty mRNAs were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high-risk group and a low-risk group. Relapse free survival was significantly different between the two groups in both discovery (HR: 3.126, 95% CI: 2.249-4.346, P<0.001) and internal validation (HR 1.806, 95% CI 1.077-3.030, P=0.025). Further analysis revealed that the prognostic value of this signature was independent of tumor stage, histotype and EGFR mutation (P<0.05). Receiver operating characteristic (ROC) analysis showed that the area under ROC curve of this signature was higher than TNM stage alone (0.771 vs 0.686, P<0.05). Conclusions: Our forty-mRNA-based classifier provides a reliable model for predicting early recurrence in non-small cell lung cancer after surgery. This model may facilitate personalized therapy-decision making for these patients. Funding Statement: This research was supported by the National Science Foundation of China (No. 81802374). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Declaration of Interests: The authors have declared no conflicts of interests. Ethics Approval Statement: The study has been approved by the Institutional Review Boards of Huashan Hospital, Fudan University.