Search

PurposeMolecular profiling has been used to select patients for targeted therapy and determine prognosis. Noninvasive strategies are critical to hepatocellular carcinoma (HCC) given the challenge of obtaining liver tissue biopsies.Experimental designWe analyzed blood samples from 206 patients with HCC using comprehensive genomic testing (Guardant Health) of circulating tumor DNA (ctDNA).ResultsA total of 153/206 (74.3%) were men; median age, 62 years (range, 18-91 years). A total of 181/206 patients had ≥1 alteration. The total number of alterations was 680 (nonunique); median number of alterations/patient was three (range, 1-13); median mutant allele frequency (% cfDNA), 0.49% (range, 0.06%-55.03%). TP53 was the common altered gene [>120 alterations (non-unique)] followed by EGFR, MET, ARID1A, MYC, NF1, BRAF, and ERBB2 [20-38 alterations (nonunique)/gene]. Of the patients with alterations, 56.9% (103/181) had ≥1 actionable alterations, most commonly in MYC, EGFR, ERBB2, BRAF, CCNE1, MET, PIK3CA, ARID1A, CDK6, and KRAS. In these genes, amplifications occurred more frequently than mutations. Hepatitis B (HBV)-positive patients were more likely to have ERBB2 alterations, 35.7% (5/14) versus 8.8% HBV-negative (P = 0.04).ConclusionsThis study represents the first large-scale analysis of blood-derived ctDNA in HCC in United States. The genomic distinction based on HCC risk factors and the high percentage of potentially actionable genomic alterations suggests potential clinical utility for this technology.

Background Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. Methods Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. Results We identified 383 patients with HCC with imaging and survival outcomes, n  = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. Conclusions Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC. [ABSTRACT FROM AUTHOR]

BackgroundA high pretreatment β2 -microglobulin (B2M) level is associated with inferior survival outcomes in patients with chronic lymphocytic leukemia. However, to the authors' knowledge, the prognostic and predictive significance of changes in B2M during treatment have not been reported to date.MethodsThe authors analyzed 83 patients treated with ibrutinib-based regimens (66 with recurrent/refractory disease) and 198 treatment-naive patients who were treated with combined fludarabine, cyclophosphamide, and rituximab (FCR) to characterize changes in B2M and their relationship with clinical outcomes.ResultsB2M rapidly decreased during treatment with ibrutinib; on multivariable analysis, patients who received FCR (odds ratio, 0.40; 95% confidence interval [95% CI], 0.18-0.90 [P = .027]) were less likely to have normalized B2M at 6 months than patients treated with ibrutinib. On univariable analysis, normalization of B2M was associated with superior progression-free survival (PFS) from the 6-month landmark in patients treated with ibrutinib-based regimens and FCR. On multivariable analysis, failure to achieve normalized B2M at 6 months of treatment was associated with inferior PFS (hazard ratio, 16.9; 95% CI, 1.3-220.0 [P = .031]) for patients treated with ibrutinib, after adjusting for the effects of baseline B2M, stage of disease, fludarabine-refractory disease, and del(17p). In contrast, in patients treated with FCR, negative minimal residual disease status in the bone marrow was the only variable found to be significantly associated with superior PFS (hazard ratio, 0.28; 95% CI, 0.12-0.67 [P = .004]).ConclusionsNormalization of B2M at 6 months in patients treated with ibrutinib was found to be a useful predictor of subsequent PFS and may assist in clinical decision-making.

B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.

Introduction: Circulating inflammatory cytokines play critical roles in tumor-associated inflammation and immune responses. Recent data have suggested that several interleukins (ILs) mediate carcinogenesis in hepatocellular carcinoma (HCC). However, the predictive and prognostic value of circulating ILs is yet to be validated. Our study aimed to evaluate the association of the serum ILs with overall survival (OS) and clinicopathologic features in a large cohort of HCC patients. Methods: We prospectively collected data and serum samples from 767 HCC patients treated at the University of Texas MD Anderson Cancer Center between 2001 and 2014, with a median follow-up of 67.4 months (95% confidence interval [CI]: 52.5, 83.3). Biomarker association with OS was evaluated by the log-rank method. Results: The median OS in this cohort was 14.2 months (95% CI: 12, 16.1 months). Clinicopathologic features were more advanced, and OS was significantly inferior in patients with high circulating levels of IL1-R1, IL-6, IL-8, IL-10, IL-15, IL-16, and IL-18. Conclusion: Our study shows that several serum IL levels are valid prognostic biomarker candidates and potential targets for therapy in HCC. [ABSTRACT FROM AUTHOR]

Introduction: Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients. Objectives: Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS). Methods: We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution. Results: Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46–48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0–1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively. Conclusion: In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted. [ABSTRACT FROM AUTHOR]

Background: The RAINBOW trial established ramucirumab combined with paclitaxel as a second-line option in metastatic gastric and gastroesophageal junction (GEJ) adenocarcinoma. Ramucirumab was given on days 1 and 15 with paclitaxel on days 1, 8, and 15 of a 28-day cycle. The median overall survival (OS) was significantly longer with ramuciru-mab plus paclitaxel (p = 0.017), and it led to 41% grade 3 or higher neutropenia. We review our experience with both ramucirumab plus paclitaxel given biweekly (mRAINBOW) to assess efficacy and safety. Objectives: The primary objective was to assess OS. Secondary end points were progression-free survival (PFS), overall response, and safety. Methods: We identified 129 patients retrospectively from our database between November 2014 and May 2017. Patients were included if they were followed up at our institution. Results: Median doses given were ramucirumab 8 mg/kg i.v. plus paclitaxel 110 mg/m2 i.v. given once every 2 weeks. The median performance status was 1, and ∼60% had poorly differentiated histology; 55.8% had progression in < 6 months on first-line therapy, and the majority had measurable cancer. Median overall OS and PFS for the entire cohort was 9.4 months (95% CI: 8.05–10.74) and 3.68 months (95% CI: 2.73–4.5), respectively. Median OS was 9.46 months (95% CI: 8.05–14.95) and median PFS was 4.14 months (95% CI: 2.96–5.29) in those patients that received ramucirumab plus paclitaxel in the second-line setting. Conclusion: Biweekly administration of ramucirumab plus paclitaxel did not compromise efficacy. Delays, adjustments, or doses held were similar to the RAINBOW trial, with 31% requiring a dose or schedule modification. [ABSTRACT FROM AUTHOR]

Purpose: F-fluorodeoxyglucose positron emission tomopraphy/computed tomography (FDGPET/CT) has been proven to be useful for imaging many types of cancer; however, its role is not well defined in hepatocellular carcinoma (HCC). We assessed the prognostic value of metabolic imaging biomarkers as established by baseline pretreatment FDG PET/CT in patients with HCC. Methods: We retrospectively analyzed the records of patients with HCC who underwent FDG PET/CT before initial treatment from May 2013 through May 2014. Four PET/CT parameters were measured: maximum standardized uptake value (SUV), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and tumor-to-normal-liver SUV ratio (TNR). Optimal cut-off values for the PET/CT parameters to stratify patients in terms of overall survival (OS) were determined. Multivariate analysis was performed to determine whether the PET/CT parameters could add to the prognostic value of the Cancer of the Liver Italian Program (CLIP) scoring system and the Barcelona-Clinic Liver Cancer (BCLC) staging system. Results: The analysis included 56 patients. Univariate analysis of the association between OS and continuous variables, including the PET/CT parameters SUV, TLG, tumor size, total bilirubin level, and alkaline phosphatase level were significant predictors of OS. SUV ≥ 11.7, TLG ≥ 1,341, MTV ≥ 230 mL, and TNR ≥ 4.8 were identified as cut-off values. Multivariate analysis revealed that SUV ≥ 11.7 and TNR ≥ 4.8 were independent factors predicting a poor prognosis in both the CLIP scoring system and the BCLC staging system, as was TLG in the BCLC staging system. Conclusion: Pretreatment FDG PET/CT in patients with HCC can add to the prognostic value of standard clinical measures. Incorporation of imaging biomarkers derived from FDG PET/CT into HCC staging systems should be considered. [ABSTRACT FROM AUTHOR]

Background: In patients with localized gastric adenocarcinoma (LGAC) who receive preoperative therapy, tools to predict response or prognosticate outcome before therapy are lacking. We used initial standardized uptake value (iSUV) of positron emission tomography (PET) to evaluate its association with overall survival (OS). Methods: We identified 60 patients with confirmed LGAC who were treated with preoperative chemoradiation and had a baseline PET in addition to other routine staging. Fisher's exact test and Wilcoxon's rank sum test were used to determine the association between iSUV and other variables, and the log-rank test and Cox proportional hazards model were used for survival analysis. Results: The median iSUV was 6 (range, 0-28). The presence of signet ring cells in pretreatment biopsies correlated highly with low iSUV (≤6; p = 0.0017). Patients with a high iSUV (>6) had a longer OS compared to those with a low iSUV (≤6; p = 0.0344). iSUV was not an independent predictor (p = 0.12); however, the risk of death was reduced for patients with an iSUV >6 (hazard ratio = 0.26). Conclusion: Our novel findings show that among LGAC patients treated with preoperative chemoradiation and surgery, those with a high iSUV have longer OS than patients with a low iSUV. iSUV appears to have a predictive role in patients with LGAC when treated with preoperative chemoradiation. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Hepatocellular carcinoma (HCC) staging systems were developed using data predominantly from patients who had hepatitis and cirrhosis. Given the recent change in prevalence of viral hepatitis and cirrhosis at oncology centers, which has altered the natural history of HCC, we aimed at comparing the accuracy of HCC staging systems in patients with or without hepatitis and cirrhosis. Methods: A total of 438 patients were enrolled. Baseline clinicopathologic parameters, Barcelona Clinic Liver Cancer stage, Cancer of the Liver Italian Program score, TNM (6th edition) stage, Okuda stage, and Chinese University Prognostic Index score were prospectively obtained for all patients, and retrospectively analyzed. Kaplan-Meier analysis was used to determine overall survival (OS), Cox regression analyses were performed, and Harrell's Correspondence Index compared the staging systems' ability to predict OS duration. Subgroup analyses of patients with or without hepatitis or cirrhosis were performed. Results: Median patient OS was 13.9 months; 165 patients (37.7%) had no cirrhosis and 256 patients (58.4%) had no hepatitis. Overall, all staging systems were significantly less predictive of OS in patients who did not have cirrhosis or hepatitis. Conclusion: Our results advocate the need to further stratify HCC based on cirrhosis and hepatitis status, which may change patient risk-stratification and, ultimately, treatment decisions. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Background: The presence of malignant lymph nodes (+ypNodes) in the surgical specimen after preoperative chemoradiation (trimodality) in patients with oesophageal cancer (EC) portends a poor prognosis for overall survival (OS) and disease-free survival (DFS). Currently, none of the clinical variables highly correlates with +ypNodes. We hypothesised that a combination of clinical variables could generate a model that associates with high likelihood of +ypNodes after trimodality in EC patients. Methods: We report on 293 consecutive EC patients who received trimodality therapy. A multivariate logistic regression analysis that included pretreatment and post-chemoradiation variables identified independent variables that were used to construct a nomogram for +ypNodes after trimodality in EC patients. Results: Of 293 patients, 91 (31.1%) had +ypNodes. OS (p =0.0002) and DFS (p <0.0001) were shorter in patients with +ypNodes compared to those with –ypNodes. In multivariable analysis, the significant variables for +ypNodes were: baseline T-stage (odds ratio [OR], 7.145; 95% confidence interval [CI], 1.381–36.969; p =0.019), baseline N-stage (OR, 2.246; 95% CI, 1.024–4.926; p =0.044), tumour length (OR, 1.178; 95% CI, 1.024–1.357; p =0.022), induction chemotherapy (OR, 0.471; 95% CI, 0.242–0.915; p =0.026), nodal uptake on post-chemoradiation positron emission tomography (OR, 2.923; 95% CI, 1.007–8.485; p =0.049) and enlarged node(s) on post-chemoradiation computerised tomography (OR, 3.465; 95% CI, 1.549–7.753; p =0.002). The nomogram after internal validation using the bootstrap method (200 runs) yielded a high concordance index of 0.756. Conclusion: Our nomogram highly correlates with the presence of +ypNodes after chemoradiation, however, considerably more refinement is needed before it can be implemented in the clinic. [Copyright &y& Elsevier]

Background: In patients with localized gastric cancer (LGC) who are unfit for surgery, decline surgery, or have unresectable cancer, chemoradiotherapy may provide palliation; however, data in the literature are sparse. Methods: We identified 66 LGC patients who had definitive chemoradiation but no surgery. All patients had baseline and postchemoradiation staging including an endoscopic biopsy. Multiple statistical methods were used to analyze outcomes. Results: Most patients were men and most had stage III or IV cancer. Five patients were surgery eligible but declined to have surgery. The median follow-up time was 33.9 months (95% CI 18.3-49.6). The median survival time (MST) for 66 patients was only 14.5 months (95% CI 10.8-19.7) and the median relapse-free survival (RFS) was 5.03 months (95% CI 4.67-6.40). The estimated overall survival (OS) and RFS rates at 3 years were 22.6% (95% CI 13.7-37.3) and 7.7% (95% CI 3.2-18.6), respectively. Twenty-three (35%) patients who achieved a clinical complete response (cCR; negative postchemoradiation biopsy and no progression by imaging) fared better than those who achieved less than cCR (