Prognostic MicroRNA Fingerprints Predict Recurrence of Early-Stage Hepatocellular Carcinoma Following Hepatectomy.

Tu1041 Post-Chemoembolization Pre-Transplant AFP-L3% Is a Useful Biomarker for Predicting HCC Recurrence After Liver Transplantation

Tu1042 Post Pancreatectomy Hemorrage Endovascular Management: Single Instution Experience Using Covered Stents

BackgroundEpidermal growth factor-like domain 7 (Egfl7), a recently identified secreted protein, was significantly increased in patients with HCC by our previous studies. However, its efficacy in the diagnosis of early HCC remains unknown. In this study, we therefore evaluate the efficacy of serum Egfl7 for early HCC diagnosis and compare it with alpha-fetoprotein (AFP).MethodsSerum Egfl7 levels in testing cohort (1081 participants) and validation cohort (476 participants) were measured by a sandwich enzyme-linked immunoassay (ELISA). The cut-off value of Egfl7 was determined by Youden’s index and the efficacies of Egfl7 and AFP in diagnosing early HCC were estimated by receiver operating characteristic (ROC).ResultsSerum Egfl7 was significantly elevated in patients with early HCC than all non-HCC controls in whatever Testing Cohort or Validation Cohort. In the Testing Cohort, ROC curves showed the optimum cut-off value of Egfl7 was 2610 ng/mL and Egfl7 showed a significantly higher sensitivity than AFP in discriminating early HCC from healthy individuals (77.4% vs. 65.3%, P = 0.0013) but the area under ROC (AUROC) and accuracy of Egfl7 and AFP were similar (0.860 vs. 0.868, P = 0.704; 80.2% vs. 83.8%, P = 0.184). In distinguishing patients with early HCC from patients with chronic liver disease (CLD), the AUROC, sensitivity, specificity and accuracy of Egfl7 were 0.800, 75.2, 71.7 and 73.5%, which were all significantly higher than AFP (0.675, 61.8, 62.0 and 61.9% in order). Egfl7 also showed a significant higher sensitivity and accuracy than AFP (76.6% vs. 64.0%, P = 0.0031; 79.9% vs. 66.1%, P < 0.0001) in differentiating early HCC patients from non-HCC individuals. Additionally, 70.8% of early HCC patients with negative AFP could be diagnosed by Egfl7 and the combined use of Egfl7 and AFP increased the sensitivity to 91.0%. These results were confirmed by a validation cohort.ConclusionEgfl7 is a valuable serum marker in the diagnosis of early HCC and could complement the efficacy of AFP, especially in distinguishing early HCC from CLD and identifying patients with AFP-negative early HCC.

Introduction: Novel biomarkers reflecting liver fibrosis and the immune microenvironment may correlate with the risk of hepatocellular carcinoma (HCC) recurrence. This study aimed to evaluate the prognostic value of serum biomarkers in predicting HCC recurrence. Methods: Serum biomarkers, including M2BPGi, IL-6, IL-10, CCL5, VEGF-A, soluble PD-1, PD-L1, TIM-3, and LAG-3, were measured in 247 patients with HCC undergoing surgical resection. Factors associated with recurrence-free survival (RFS) and overall survival (OS) were evaluated. The ERASL-post model and IMbrave050 criteria were used to define HCC recurrence risk groups. Results: Serum M2BPGi levels significantly correlated with FIB-4 score, aspartate transaminase-to-platelet ratio index, ALBI score, alpha-fetoprotein (AFP), alanine transaminase, aspartate transaminase, IL-10, CCL5, VEGF-A, soluble PD-1, PD-L1, TIM-3, and LAG-3 levels. M2BPGi, VEGF-A, soluble PD-1, and TIM-3 levels significantly correlated with RFS. In multivariate analysis, M2BPGi >1.5 COI (hazard ratio [HR] = 2.100, p < 0.001), tumor size >5 cm (HR = 1.859, p = 0.002), multiple tumors (HR = 2.562, p < 0.001), AFP >20 ng/mL (HR = 2.141, p < 0.001), and microvascular invasion (HR = 1.954, p = 0.004) were independent predictors of RFS. M2BPGi levels significantly stratified the recurrence risk in ERASL-post and IMbrave050 risk groups. An M2BPGi-based model could significantly discriminate RFS in the overall cohort as well as in the IMbrave050 low- and high-risk groups. M2BPGi >1.5 COI was also an independent predictor of OS after resection (HR = 2.707, p < 0.001). Conclusion: Serum M2BPGi levels significantly correlated with surrogate markers of liver fibrosis, liver function, and immunology. M2BPGi is a significant predictor of HCC recurrence and survival after resection and could be incorporated into recurrence-prediction models. Introduction: Novel biomarkers reflecting liver fibrosis and the immune microenvironment may correlate with the risk of hepatocellular carcinoma (HCC) recurrence. This study aimed to evaluate the prognostic value of serum biomarkers in predicting HCC recurrence. Methods: Serum biomarkers, including M2BPGi, IL-6, IL-10, CCL5, VEGF-A, soluble PD-1, PD-L1, TIM-3, and LAG-3, were measured in 247 patients with HCC undergoing surgical resection. Factors associated with recurrence-free survival (RFS) and overall survival (OS) were evaluated. The ERASL-post model and IMbrave050 criteria were used to define HCC recurrence risk groups. Results: Serum M2BPGi levels significantly correlated with FIB-4 score, aspartate transaminase-to-platelet ratio index, ALBI score, alpha-fetoprotein (AFP), alanine transaminase, aspartate transaminase, IL-10, CCL5, VEGF-A, soluble PD-1, PD-L1, TIM-3, and LAG-3 levels. M2BPGi, VEGF-A, soluble PD-1, and TIM-3 levels significantly correlated with RFS. In multivariate analysis, M2BPGi >1.5 COI (hazard ratio [HR] = 2.100, p < 0.001), tumor size >5 cm (HR = 1.859, p = 0.002), multiple tumors (HR = 2.562, p < 0.001), AFP >20 ng/mL (HR = 2.141, p < 0.001), and microvascular invasion (HR = 1.954, p = 0.004) were independent predictors of RFS. M2BPGi levels significantly stratified the recurrence risk in ERASL-post and IMbrave050 risk groups. An M2BPGi-based model could significantly discriminate RFS in the overall cohort as well as in the IMbrave050 low- and high-risk groups. M2BPGi >1.5 COI was also an independent predictor of OS after resection (HR = 2.707, p < 0.001). Conclusion: Serum M2BPGi levels significantly correlated with surrogate markers of liver fibrosis, liver function, and immunology. M2BPGi is a significant predictor of HCC recurrence and survival after resection and could be incorporated into recurrence-prediction models.

The Presence of Philadelphia Chromosome Does Not Confer Poor Prognosis in Adult Pre-B Acute Lymphoblastic Leukemia in the Tyrosine Kinase Inhibitor Era - a Surveillance, Epidemiology, and End Results Database Analysis

Background: In literature-based meta-analyses of cancer prognostic studies, methods for extracting summary statistics from published reports have been extensively employed. However, no assessment of the magnitude of bias produced by these methods or comparison of their influence on fixed vs. random effects models have been published previously. Therefore, the purpose of this study is to empirically assess the degree of bias produced by the methods used for extracting summary statistics and examine potential effects on fixed and random effects models. Methods: Using published data from cancer prognostic studies, systematic differences between reported statistics and those obtained indirectly using log-rank test p-values and total number of events were tested using paired t tests and the log-rank test of survival-agreement plots. The degree of disagreement between estimates was quantified using an information-based disagreement measure, which was also used to examine levels of disagreement between expressions obtained from fixed and random effects models. Results: Thirty-four studies provided a total of 65 estimates of lnHR and its variance. There was a significant difference between the means of the indirect lnHRs and the reported values (mean difference = -0.272, t = -4.652, p-value &lt;0.0001), as well as between the means of the two estimates of variances (mean difference = -0.115, t = -4.5556, p-value &lt;0.0001). Survival agreement plots illustrated a bias towards under-estimation by the indirect method for both lnHR (log-rank p-value = 0.031) and its variance (log-rank p-value = 0.0432). The magnitude of disagreement between estimates of lnHR based on the information-based measure was 0.298 (95% CI: 0.234 – 0.361) and, for the variances it was 0.406 (95% CI: 0.339 – 0.470). As the disagreement between variances was higher than that between lnHR estimates, this increased the level of disagreement between lnHRs weighted by the inverse of their variances in fixed effect models. In addition, results indicated that random effects meta-analyses could be more prone to bias than fixed effects meta-analyses as, in addition to bias in estimates of lnHRs and their variances, levels of disagreement as high as 0.487 (95% CI: 0.416 – 0.552) and 0.568 (95% CI: 0.496 – 0.635) were produced due to between-studies variance calculations. Conclusions: Extracting summary statistics from published studies could introduce bias in literature-based meta-analyses and undermine the validity of the evidence. These findings emphasise the importance of reporting sufficient statistical information in research articles and warrant further research into the influence of potential bias on random effects models.

HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.

BackgroundHepatocellular carcinoma (HCC) has a high predilection for portal vein invasion, and the prognosis of HCC with malignant portal vein invasion is extremely poor. The objective of this study was to investigate the outcomes and the prognostic factor of recurrence in HCC patients with malignant portal vein invasion.MethodsWe retrospectively reviewed the clinicopathologic data and outcomes of 83 HCC patients with malignant portal vein invasion and 1,056 patients without portal vein invasion who underwent liver resection.ResultsIncreased serum alkaline phosphatase (ALP) levels, increased maximum tumor size, and intrahepatic metastasis were predisposing factors for malignant portal vein invasion by multivariate analysis. The median disease-free survival and overall survival of HCC patients with malignant portal vein invasion was 4.5 months and 25 months, respectively. The 1-year, 2-year, and 3-year disease-free survival rates were 30.6%, 26.1%, and 21.2%, respectively, and the overall survival rates for HCC patients with malignant portal vein invasion were 68.6%, 54.2%, and 41.6%, respectively. The initial detection site was the lung in HCC patients with portal vein invasion and the liver in HCC patients without portal vein invasion. C-reactive protein (CRP) was a significant independent predictor of tumor recurrence in HCC with malignant portal vein invasion after surgery.ConclusionsIncreased ALP levels, increased maximum tumor size, and intrahepatic metastasis were independent predictors of malignant portal vein invasion in HCC. CRP level was closely associated with the predisposing factor of tumor recurrence in HCC patients with malignant portal vein invasion after a surgical resection, and lung metastasis was common.

Background: A small, but not negligible, proportion of breast cancers in young women are detected in association with childbearing. While pregnancy usually is a period of intense medical observation, signs and symptoms of a malignancy may be overlooked or misinterpreted as pregnancy-related, resulting in diagnostic and treatment delays. Also, a delayed diagnosis in pregnant women has been suggested as a reason for the more advanced disease and poorer outcomes in women with pregnancy-associated breast cancer. Material and Methods: For the purpose of the present study, pregnancy-associated breast cancer (PABC) was defined as an invasive breast tumor diagnosed during pregnancy and up to two years post-delivery (non-PABC cases were diagnosed outside this time window, or nulliparous). Based on a systematic review of medical records for women aged 15-44 years at diagnosis with PABC and non-PABC identified in Swedish health care registers, chart information was retrieved by trained nurses for a total of 570 women (285 PABC women and 285 age and hospital matched non-PABC women) treated at 11 hospitals across Sweden between 1992 and 2009. Median waiting times from initial signs or symptoms in days to start of treatment, and time periods within, were computed using the Kaplan-Meier method and compared using the logrank test for the Kaplan-Meier curves. Dates on first symptoms were available for 122 matched PABC/non-PABC pairs, in total 244 patients. Full dates to assess and compare times between first health care contact – diagnosis – start of treatment, were available for 246 PABC/non-PABC pairs, in total 492 women. Objective: To examine and compare lengths of several defined waiting times within the time period from initial symptoms to start of treatment in women diagnosed with PABC and non-PABC. Results: Patient delay-time between first symptom and first point of contact with health care provider. Median time between first symptoms and first contact with health care was 36 days and 45 days for women with PABC and non-PABC, respectively (logrank test p-value 0.48). Time between first health care contact and diagnosis Median time between first contact and diagnosis was 7 days for both PABC and non-PABC women (logrank test p-value 0.16). Time between diagnosis and start of treatment The median waiting time from date of diagnosis to initiation of treatment was shorter in women with PABC (22 days) compared to non-PABC women (26 days) (logrank test p-value 0.14). Time between first contact and start of treatment The median delay of start of treatment from first contact with a health care provider was 34 days in PABC women and 37 days in non-PABC women. (logrank test p-value 0.14). Conclusions: Patients' delay and the time between first contact with health care and start of treatment was shorter in women with PABC compared to non-PABC. Taken together, the present results do not support the notion that diagnostic and treatment delays are more common in women diagnosed with breast cancer during or shortly after pregnancy. Citation Format: Lambe M, Fredriksson I, Johansson ALV. Pregnancy associated breast cancer (PABC); no evidence of patients' or doctors' delays. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-08.

8119 Background: This expanded access program provided access to Pemetrexed (P) alone or P plus a platinum (Cis or Cb) for 3311 MPM patients (pts) in 13 countries. In a subset analysis of chemonaive pts, this study confirmed the activity of P+Cis and P+Cb and demonstrated similar effectiveness of the two treatments (Santoro et al, ASCO 2007), while therapy assignment was based on the investigator’s clinical evaluation. Methods: In this post-hoc regression analysis, prognostic factors were built into a Cox regression model. Prognostic factors were then used to categorize pts into more homogenous subgroups and to compare clinical outcome - overall survival (OS) and time to progressive disease (TTPD) - between the two treatments. Results: A total of 1404 and 1405 pts were available for the OS and TTPD analyses, respectively, with about 700 pts in each treatment group. In the regression analysis, performance status (ECOG PS at baseline 0–1 vs. >1 or KPS 80–100 vs. 50–70) was identified as the only statistically significant factor for OS and TTPD in this study population. In the OS analysis, the HR for PS was 0.43 [95% CI 0.30, 0.63] and in the TTPD analysis, the HR was 0.57 [CI 0.43, 0.76]; (p <0.0001). Interestingly, neither gender nor age was identified as statistically significant factors (p>0.1). Patient subgroups based on PS were: Group 1 with ECOG PS 0–1 or KPS ≥80 (88% of pts), and group 2 with ECOG PS >1 or KPS 50–70 (12% of pts). Notably, approximately half of pts were treated with P+Cis and the other half with P+Cb; this ratio remained the same within each PS subgroup. Within the PS subgroups, a comparison between treatments did not reveal a statistically significant difference in OS and TTPD: In group 1, the logrank test p-value was 0.92 for OS and 0.46 for TTPD; in group 2, the logrank test p-value was 0.07 for OS and 0.67 for TTPD. Conclusions: PS was identified as the strongest prognostic factor in this patient population. Comparing P+Cis- and P+Cb-treated pts within the PS subgroups did not reveal a clinically relevant difference in either OS or TTPD. The investigator’s choice for P+Cis or P+Cb did not appear to be influenced by the baseline PS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly, Seminar presentations Eli Lilly Eli Lilly

Early Allogeneic Stem Cell Transplantation and Use of Asparaginase during Induction Chemotherapy Appear to Improve Otherwise Poor Outcomes in Adult T-Cell Acute Lymphoblastic Leukemia/Lymphoma (T-ALL/T-LBL) Patients: A Multi-Institutional Review

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent malignancies within the digestive system, characterized by alarmingly high incidence and mortality rates. Early screening and diagnosis play a crucial role in the treatment and prognosis of HCC patients. We investigated whether the detection of serum glutathione reductase (GR) can serve as an effective complement to traditional tumor biomarkers in clinical laboratory medicine for patients with HCC.MethodsWe analyzed the positive rates and levels of serum GR, alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ), carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in 330 patients with HCC, 160 patients with benign liver tumors (BLT), 260 patients with chronic hepatitis B (CHB), 220 patients with liver cirrhosis (LC), and 280 healthy controls (HCs). The diagnostic performance of five biomarkers and their combinations for HCC patients and AFP-negative HCC patients was evaluated using receiver operating characteristic (ROC) curves and area under the curve (AUC) analysis. Additionally, we investigated the correlation between the levels of GR, PIVKA-Ⅱ or AFP and the clinicopathological parameters of patients with HCC.ResultsThe positive rates and levels of GR, AFP, PIVKA-II, CEA, and CA19-9 were significantly higher in the HCC group, the early HCC group, and the advanced HCC group than in the control group (p < 0.001). In the advanced HCC group, the positivity rates and levels of GR, AFP, and PIVKA-Ⅱ were markedly higher than those in the early HCC group (p < 0.01). PIVKA-Ⅱ exhibited the highest AUC and sensitivity for HCC diagnosis, at 0.873 (95% CI 0.853–0.891) and 72.7%, respectively, with a specificity of 94.9%. GR demonstrated exceptional diagnostic capability for patients with AFP-negative HCC, AFP-negative early HCC, and AFP-negative advanced HCC, with AUC values ranging from 0.864 to 0.881, sensitivity between 46.4% and 71.4%, and specificity of 97.7% (p < 0.001). Among all possible combinations, the combined detection of the five biomarkers yielded the highest AUC and sensitivity for diagnosing HCC, at 0.922 (95% CI 0.906–0.936) and 90.3%, respectively. The levels of GR, AFP, and PIVKA-Ⅱ exhibited varying degrees of correlation with the clinicopathological parameters of HCC patients.ConclusionsThe detection of serum GR can serve as an effective complement to traditional tumor biomarkers in clinical laboratory medicine for HCC patients, particularly those with AFP-negative HCC. The combined detection of GR, AFP, PIVKA-Ⅱ, CEA, and CA19-9 can significantly enhance the diagnostic performance of HCC patients.

A new model based on gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts prognostic outcome after curative resection of solitary hepatocellular carcinoma

e14541 Background: Anti-VEGF antibody Bevacizumab (Avastin: Roche Pharma AG) is the recommended drug for recurrent glioma. Multiple low-cost bio-similars of this drug are now available however their clinical efficacy has never been compared against the original molecule. The aim of the current analysis is to compare the overall survival (OS) between recurrent glioma patients with bio-similar and innovator molecule. Methods: Adult recurrent glioma patients treated with bevacizumab from 1st July 2015 to 30th July 2019 were identified from the Neuro-Medical Oncology database. These patients were either offered Avastin or Bevacizumab biosimilar (BevaciRel: Reliance Life sciences or Bryta: Zydus Oncosciences) depending upon the financial affordability. The primary endpoint of the study was OS. It was defined as the time in months from the start of bevacizumab to death. Progression-free survival (PFS) was defined as the time in months from the start of bevacizumab to progression or death. The time to event variables was estimated using Kaplan Meier method. The median with its 95% confidence interval (CI) was calculated using Brookmeyer and Crowley method. The estimates were compared between the original and bio-similar bevacizumab cohort using the log-rank test. The hazard ratio was calculated using COX regression analysis. Results: There were 82 patients, out of which 57 received innovator and 25 received bio-similar bevacizumab. At median follow up of 26 months, 76 patients had an event for progression. The median PFS was 3.66 (95% CI 2.08 to 5.25) and 3.3 months (95% CI 2.38 to 4.21) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.072). The hazard ratio for progression was 0.61 (95% CI 0.35 to 1.05; P-value = 0.075). At the time of data cutoff, there were 69 deaths. The median OS was 5.53 (95% CI, 5.07 to 5.99) vs 7.33 months (95% CI, 5.63 to 9.03) in innovator and bio-similar arm respectively (Log-rank test P-value = 0.51). The hazard ratio for death was 1.21 (95% CI, 0.67 to 2.17; p-value = 0.51). Conclusions: In the brain tumor patients, both innovator and bio-similar bevacizumab seem to have similar clinical efficacy.

Colorectal cancer can be grouped into Dukes A, B, C, and D stages based on its developments. Generally speaking, more advanced patients have poorer prognosis. To integrate progression stage prediction systems with recurrence prediction systems, we proposed an ensemble prognostic model for colorectal cancer. In this model, each patient was assigned a most possible stage and a most possible recurrence status. If a patient was predicted to be recurrence patient in advanced stage, he would be classified into high risk group. The ensemble model considered both progression stages and recurrence status. High risk patients and low risk patients predicted by the ensemble model had a significant different disease free survival (log-rank test p-value, 0.0016) and disease specific survival (log-rank test p-value, 0.0041). The ensemble model can better distinguish the high risk and low risk patients than the stage prediction model and the recurrence prediction model alone. This method could be applied to the studies of other diseases and it could significantly improve the prediction performance by ensembling heterogeneous information.