Contrast-enhanced ultrasound liver imaging reporting and data system v2017: patient outcomes after treatment for early-stage hepatocellular carcinoma nodules with category 3-5 and category M.

OBJECTIVE: To evaluate correlation between contrast-enhanced ultrasonography Liver Imaging Reporting and Data System (CEUS LI-RADS; v. 2017) categories (LR 3-5 vs LR-M) and outcomes in patients with early-stage hepatocellular carcinoma (HCC) after initial therapy. METHODS: In this retrospective study, 272 patients with high risks for HCC and solitary clinically or pathologically confirmed HCC were identified between January 2010 and December 2015. Patients were initially treated by resection and radiofrequency ablation (RFA) according to the Barcelona Clinic Liver Cancer staging system and were followed up until December 31, 2018. Recurrence-free survival (RFS) and overall survival (OS) were compared between nodules assigned as LR 3-5 or LR M according to CEUS LI-RADS v. 2017 by using the Kaplan-Meier curve, log-rank test, and Cox proportional hazard model. RESULTS: Early washout is the key determinating whether a nodule is classed as LR-M. Treatment procedures and LI-RADS category showed an independent correlation with OS and RFS (p < 0.05). LR 3-5 category were more correlated with better OS (88.6 months and 74.2 months, respectively; p = 0.017) compared with LR-M. Surgical resection demonstrated longer OS and RFS than RFA in LR-M patients and longer OS in LR 3-5 patients (p < 0.05). Besides, there was no significantly difference in OS and RFS between two categories in resection (p > 0.05), while for patients treated with RFA, LR 3-5 patients showed significant longer OS and RFS than LR-M patients (p < 0.05). CONCLUSION: Patients with HCC assigned as LR-M showed worse RFS and OS and surgical resection tended to be a more effective treatment for these patients. ADVANCES IN KNOWLEDGE: Putting forward a theory that CEUS LI-RADS categories could independently predict the outcome for patients with solitary HCC at early-stage after initial treatment.

Surrogate endpoints for overall survival in anti-programmed death-1 and anti-programmed death ligand 1 trials of advanced melanoma.

BACKGROUND: We assessed the surrogacy of objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) for overall survival (OS) in anti-PD-1/PD-L1 trials of metastatic melanoma through a meta-analysis of randomized controlled trials (RCTs). METHODS: PubMed and EMBASE were searched for phase II/III RCTs till June 2019 investigating anti-PD-1/PD-L1 agents. Treatment effect (hazard ratio or odds ratio) on potential surrogates (ORR/DCR/PFS) and OS were collected. At trial level, we assessed the correlation between treatment effect on potential surrogates and OS, weighted by sample size, fixed and random effect models, and calculated the surrogate threshold effect (STE). Sensitivity analyses and leave-one-out cross-validation approach were performed to evaluate the robustness of our findings. RESULTS: We included 8 RCTs (4110 patients; 11 comparisons). We did not identify strong correlations between ORR [coefficient of determination (R 2): 0.09-0.25], DCR (0.41-0.57) and OS. However, we noted a strong correlation between PFS and OS, with R 2 of 0.82 in sample size, 0.75 in fixed effect and 0.72 in random effect model weighting, the robustness of which was further verified by leave-one-out cross-validation approach. Sensitivity analyses with restriction to trials with less than 50% crossover, phase III trials, large trials and first-line trials strengthened the correlation (0.78-0.94). The STE for PFS was 0.78. CONCLUSIONS: PFS may be the appropriate surrogate for OS in anti-PD-1/PD-L1 trials of metastatic melanoma. A future anti-PD-1/PD-L1 trial would need less than 0.78 for PFS of the upper limit of confidence interval to predict an OS benefit.

Disease-free survival as a surrogate endpoint for overall survival in adjuvant trials of pancreatic cancer: a meta-analysis of 20 randomized controlled trials.

BACKGROUND: We aimed to assess whether disease-free survival (DFS) could serve as a reliable surrogate endpoint for overall survival (OS) in adjuvant trials of pancreatic cancer. METHODS: We systematically reviewed adjuvant randomized trials for non-metastatic pancreatic cancer after curative resection that reported a hazard ratio (HR) for DFS and OS. We assessed the correlation between treatment effect (HR) on DFS and OS, weighted by sample size or precision of hazard ratio estimate, assuming fixed and random effects, and calculated the surrogate threshold effect (STE). We also performed sensitivity analyses and a leave-one-out cross validation approach to evaluate the robustness of our findings. RESULTS: After screening 450 relevant articles, we identified a total of 20 qualifying trails comprising 5170 patients for quantitative analysis. We noted a strong correlation between the treatment effects for DFS and OS, with coefficient of determination of 0.82 in the random effect model, 0.82 in the fixed effect model, and 0.80 in the sample size weighting; the robustness of this finding was further verified by the leave-one-out cross-validation approach. Sensitivity analyses with restriction to phase 3 trials, large trials, trials with mature follow-up periods, and trials with adjuvant therapy versus adjuvant therapy strengthened the correlation (0.75 to 0.88) between DFS and OS. The STE was 0.96 for DFS. CONCLUSIONS: Therefore, DFS could be regarded as a surrogate endpoint for OS in adjuvant trials of pancreatic cancer. In future similar adjuvant trials, a hazard ratio for DFS of 0.96 or less would predict a treatment impact on OS.

Development of prognostic index based on autophagy-related genes analysis in breast cancer.

BACKGROUND: Autophagy is a self-digesting process that can satisfy the metabolic needs of cells, and is closely related to development of cancer. However, the effect of autophagy-related genes (ARGs) on the prognosis of breast cancer remains unclear. RESULTS: We first found that 27 ARGs were significantly associated with overall survival in breast cancer. The prognosis-related ARGs signature established using the Cox regression model consists of 12 ARGs that can be divided patients into high-risk and low-risk groups. The overall survival of patients with high-risk scores (HR 3.652, 2.410-5.533; P < 0.001) was shorter than patients with low-risk scores. The area under the receiver operating characteristic (ROC) curve for 1-year, 3-year, and 5-year survival rates were 0.739, 0.727, and 0.742, respectively. CONCLUSION: The12-ARGs marker can predict the prognosis of breast cancer and thus help individualized treatment of patients at different risks. METHODS: Based on the TCGA dataset, we integrated the expression profiles of ARGs in 1,039 breast cancer patients. Differentially expressed ARGs and survival-related ARGs were evaluated by computational difference algorithm and COX regression analysis. In addition, we also explored the mutations in these ARGs. A new prognostic indicator based on ARGs was developed using multivariate COX analysis.

Evaluation of Contrast-enhanced US LI-RADS version 2017: Application on 2020 Liver Nodules in Patients with Hepatitis B Infection.

Background Use of contrast material-enhanced (CE) US Liver Imaging Reporting and Data System (LI-RADS) version 2017 has not been validated in large populations where hepatitis B virus (HBV) is endemic. Purpose To evaluate the diagnostic performance of CE US LI-RADS version 2017 in a population with a high prevalence of HBV infection. Materials and Methods In this retrospective study, liver nodules in patients with HBV who were evaluated from January 2004 to December 2016 were categorized as CE US LR-1 to LR-5 through LR-M. A subgroup of LR-M nodules was reclassified as LR-5, and additional analysis was performed. The reference standard consisted of histologic evaluation or composite imaging and clinical follow-up findings. Diagnostic performance was assessed with sensitivity, specificity, positive predictive value (PPV), and negative predictive value. Results A total of 2020 nodules in 1826 patients (median age, 54 years ± 12 [standard deviation]; 1642 men) were included. Of the 1159 LR-5 lesions, 1141 were hepatocellular carcinoma (HCC); three, intrahepatic cholangiocarcinomas; six, other malignancies; six, atypical hyperplasia; and three, benign lesions. The PPV of LR-5 for HCC was 98% (95% confidence interval [CI]: 98%, 99%). In LR-M nodules, 153 showed arterial phase hyperenhancement, early washout, and absence of punched-out appearance within 5 minutes, and 142 of 153 (93%; 95% CI: 89%, 97%) were HCC. If these nodules were reclassified as LR-5, LR-M specificity and PPV as a predictor of non-HCC malignancy increased from 88% (95% CI: 87%, 89%) and 36% (95% CI: 31%, 41%) to 96% (95% CI: 95%, 97%) and 58% (95% CI: 51%, 65%), respectively (P < .001). Despite reclassification, LR-5 specificity and PPV remained high (94% [95% CI: 92%, 96%] and 98% [95% CI: 97%, 99%], respectively). Conclusion The contrast-enhanced US Liver Imaging Reporting and Data System version 2017 category LR-5 is effectively predictive of the presence of hepatocellular carcinoma. In patients with hepatitis B virus infection, performance may be further improved by reclassification of category LR-M nodules with arterial phase hyperenhancement, early washout, and no punched-out appearance to LR-5. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Sidhu in this issue.

Comparison of long-term results between radiotherapy after breast-conserving surgery and postmastectomy radiotherapy in stage T1-2N1M0 breast cancer.

PURPOSE: Postoperative radiotherapy (RT) can improve survival for T1-2N1 breast cancer. However, there exists a concern whether BCS plus RT has the same or a superior therapeutic effect as that of mastectomy. In this study, we aimed to compare the long-term results between RT after BCS and postmastectomy RT in stage T1-2N1M0 breast cancer. PATIENTS AND METHODS: Totally 1816 pathological stage T1-2N1M0 breast cancer patients were analyzed. The propensity score matching (PSM) method was used to select 196 pairs of patients between BCS and mastectomy receiving postoperative RT. Five-year locoregional relapse (LRR), locoregional relapse-free survival (LRFS), distant metastasis (DM), distant metastasis-free survival (DMFS), disease-free survival (DFS), breast cancer-specific survival (BCSS) were analyzed as endpoints. RESULTS: In the whole group, significant differences were observed in all endpoints (P<0.05) between the no-RT and RT groups. For patients receiving mastectomy, DM, DMFS, DFS and BCSS rates had no differences between the two groups. For patients without RT in the multivariable analysis, the molecular subtype was associated with each endpoint (P<0.05). Age, primary tumor site, tumor size, and LVI status were significantly associated with DM. The analysis of 196 pairs of patients selected by PSM showed that BCS plus RT resulted in a significantly lower 5-year DM rate (P=0.015) and superior survival in terms of the 5-year DMFS (P=0.046), DFS (P=0.049) and BCSS (P=0.024) compared with mastectomy. CONCLUSIONS: Postoperative radiotherapy remarkably improved survival in T1-2N1M0 breast cancer but not in the mastectomy subgroup, except for LRR and LRFS. Patients with BCS plus RT had better survival compared with those with postmastectomy radiation in terms of DM, DMFS, DFS and BCSS.

Outcomes of adding induction chemotherapy to concurrent chemoradiotherapy for stage T3N0-1 nasopharyngeal carcinoma: a propensity-matched study.

OBJECTIVE: Our objective was to examine whether adding induction chemotherapy to concurrent chemoradiotherapy improved survival in stage III nasopharyngeal carcinoma (NPC) patients, especially in low-risk patients at stage T3N0-1. MATERIALS AND METHODS: We retrospectively analyzed 687 patients with stage T3N0-1 NPC treated with intensity-modulated radiation therapy (IMRT) plus concurrent chemotherapy (CC) with or without induction chemotherapy (IC). Propensity score matching (PSM) method was used to select 237 pairs of patients from two cohorts. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were assessed by using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: No significant survival differences were observed between IC plus CC and CC cohorts with similar 4-year OS (91.7% vs 92.6%, P=0.794), LRFS, (92.7% vs 96.8%, P=0.138), DMFS (93.5% vs 94.3%, P=0.582), and PFS (87.5% vs 91.1%, P=0.223). In a univariate analysis, lower Epstein-Barr virus deoxyribonucleic acid (EBV DNA; <4,000 copies/mL) significantly improved 4-year DMFS (95.5% vs 91.6%, P=0.044) compared with higher EBV DNA (≥4,000 copies/mL). No factors were associated with 4-year OS, LRFS, DMFS, and PFS in a multivariate analysis. IC plus CC group experienced higher rates of grade 3-4 leucopenia (P<0.001) and neutropenia (P<0.001). CONCLUSION: The addition of IC to CC in stage T3N0-1 NPC patients treated with IMRT did not significantly improve their survival. The IC group experienced higher rates of grade 3-4 hematological toxicities. Therefore, further investigation is required.

Retrospective Analysis of the Survival Benefit of Induction Chemotherapy in Stage IVa-b Nasopharyngeal Carcinoma.

PURPOSE: The value of adding induction chemotherapy to chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains controversial, yet high-risk patients with LA-NPC have poor outcomes after chemoradiotherapy. We aimed to assess the survival benefits of induction chemotherapy in stage IVa-b NPC. PATIENTS AND METHODS: A total of 602 patients with stage IVa-b NPC treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy with or without induction chemotherapy were retrospectively analyzed. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, log-rank test and Cox regression analysis. RESULTS: In univariate analysis, 5-year OS was 83.2% for induction chemotherapy plus concurrent chemotherapy and 74.8% for concurrent chemotherapy alone, corresponding to an absolute risk reduction of 8.4% (P = 0.022). Compared to concurrent chemotherapy alone, addition of induction chemotherapy improved 5-year DMFS (83.2% vs. 74.4%, P = 0.018) but not 5-year LRFS (83.7% vs. 83.0%, P = 0.848) or PFS (71.9% vs. 66.0%, P = 0.12). Age, T category, N category, chemotherapy strategy and clinical stage were associated with 5-year OS (P = 0.017, P = 0.031, P = 0.007, P = 0.022, P = 0.001, respectively). In multivariate analysis, induction chemotherapy plus concurrent chemotherapy was an independent favorable prognostic factor for OS (HR, 0.62; 95% CI, 0.43-0.90, P = 0.012) and DMFS (HR, 0.57; 95% CI, 0.38-0.83, P = 0.004). In subgroup analysis, induction chemotherapy significantly improved 5-year DMFS in stage IVa (86.8% vs. 77.3%, P = 0.008), but provided no significant benefit in stage IVb. CONCLUSIONS: In patients with stage IVa-b NPC treated with IMRT, addition of induction chemotherapy to concurrent chemotherapy significantly improved 5-year OS and 5-year DMFS. This study provides a basis for selection of high risk patients in future clinical therapeutic trials.