Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase ...inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II.
Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response.
Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036).
Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.
Objectives
MRI can detect early-stage nasopharyngeal carcinoma (NPC), but the detection is more challenging in early-stage NPCs because they must be distinguished from benign hyperplasia in the ...nasopharynx. This study aimed to determine whether intravoxel incoherent motion diffusion-weighted imaging (IVIM DWI) MRI could distinguish between these two entities.
Methods
Thirty-four subjects with early-stage NPC and 30 subjects with benign hyperplasia prospectively underwent IVIM DWI. The mean pure diffusion coefficient (
D
), pseudo-diffusion coefficient (
D
*), perfusion fraction (
f
) and apparent diffusion coefficient (ADC) values were calculated for all subjects and compared between the 2 groups using Student’s
t
test. Receiver operating characteristics with the area under the curve (AUC) was used to identify the optimal threshold for all significant parameters, and the corresponding diagnostic performance was calculated. A
p
value of < 0.05 was considered statistically significant.
Results
Compared with benign hyperplasia, early-stage NPC exhibited a significantly lower
D
mean (0.64 ± 0.06 vs 0.87 ± 0.11 × 10
−3
mm
2
/s), ADC
0–1000
mean (0.77 ± 0.08 vs 1.00 ± 0.13 × 10
−3
mm
2
/s), ADC
300–1000
(0.63 ± 0.05 vs 0.86 ± 0.10 × 10
−3
mm
2
/s) and a higher
D
* mean (32.66 ± 4.79 vs 21.96 ± 5.21 × 10
−3
mm
2
/s) (all
p
< 0.001). No significant difference in the
f
mean was observed between the two groups (
p
= 0.216). The
D
and ADC
300–1000
mean had the highest AUC of 0.985 and 0.988, respectively, and the D mean of < 0.75 × 10
−3
mm
2
/s yielded the highest sensitivity, specificity and accuracy (100%, 93.3% and 96.9%, respectively) in distinguishing early-stage NPC from benign hyperplasia.
Conclusion
DWI has potential to distinguish early-stage NPC from benign hyperplasia and
D
and ADC
300–1000
mean were the most promising parameters.
Key Points
• Diffusion-weighted imaging has potential to distinguish early-stage nasopharyngeal carcinoma from benign hyperplasia in the nasopharynx.
• The pure diffusion coefficient, pseudo-diffusion coefficient from intravoxel incoherent motion model and apparent diffusion coefficient from conventional diffusion-weighted imaging were significant parameters for distinguishing these two entities in the nasopharynx.
• The pure diffusion coefficient, followed by apparent diffusion coefficient, may be the most promising parameters to be used in screening studies to help detect early-stage nasopharyngeal carcinoma.
There are limitations in using radiologic evaluation to assess the treatment outcome of patients with hepatocellular carcinoma (HCC). The use of serial alpha-fetoprotein (AFP) in monitoring response ...has not been rigorously evaluated. We aimed to study the clinical value of AFP trend in an attempt to validate AFP as a surrogate serologic end point.
Participants from a phase III randomized trial of systemic chemotherapy in HCC were studied. Serum AFP was prospectively collected in parallel with clinical and radiologic outcome. AFP response was defined as a decrease in AFP of more than 20% after a minimum of two cycles of chemotherapy. We studied the relationship between AFP response and treatment outcome in terms of radiologic response and overall survival.
Of 188 patients, 117 patients with elevated serum AFP (> 20 microg/L) and documented radiologic evaluation had received at least two cycles of chemotherapy. A total of 47 AFP responders were identified. AFP responders had better survival than nonresponders (13.5 v 5.6 months, respectively; P < .0001), and AFP response was strongly associated with radiologic response (P < .0001). Multivariate analysis suggested that AFP response was significantly associated with survival (hazard ratio, 0.413; 95% CI, 0.273 to 0.626; P < .0001). AFP responses were frequently observed in patients with radiologically stable disease (SD) and tended to identify a subgroup of SD patients with better survival.
Serial AFP measurement is useful in prognostication and monitoring treatment response in HCC patients undergoing systemic chemotherapy. Incorporation of AFP response into the criteria evaluating treatment outcome should be considered in clinical practice and clinical trials of novel agents in HCC.
Because of the uneven geographic distribution and small number of randomized trials available, the value of additional induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) in ...nasopharyngeal carcinoma (NPC) remains controversial. This study performed an individual patient data (IPD) pooled analysis to better assess the precise role of IC + CCRT in locoregionally advanced NPC.
Four randomized trials in endemic areas were identified, representing 1,193 patients; updated IPD were obtained. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary endpoints, respectively.
Median follow-up was 5.0 years. The HR for PFS was 0.70 95% confidence interval (CI), 0.56-0.86;
= 0.0009; 9.3% absolute benefit at 5 years in favor of IC + CCRT versus CCRT alone. IC + CCRT also improved OS (HR = 0.75; 95% CI, 0.57-0.99;
= 0.04) and reduced distant failure (HR = 0.68; 95% CI, 0.51-0.90;
= 0.008). IC + CCRT had a tendency to improve locoregional control compared with CCRT alone (HR = 0.70; 95% CI, 0.48-1.01;
= 0.06). There was no heterogeneity between trials in any analysis. No interactions between patient characteristics and treatment effects on PFS or OS were found. After adding two supplementary trials to provide a more comprehensive overview, the conclusions remained valid and were strengthened. In a supplementary Bayesian network analysis, no statistically significant differences in survival between different IC regimens were detected.
This IPD pooled analysis demonstrates the superiority of additional IC over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly associated with improved distant control.
.
•Incorporation of advanced extranodal extension (ENE), which infiltrates into adjacent muscle/skin/salivary glands to the current stage N3 outperformed the other five different modifications for ...predicting outcomes in nasopharyngeal carcinoma (NPC).•Incorporation of advanced ENE achieved a significantly higher c-index for 5-year DFS from 0.69 to 0.72 in the internal cohort and from 0.65 to 0.72 in the external cohort when compared with that of N8th staging system.•By adding advanced ENE to the current N3 increased the sensitivity for predicting disease recurrence from 22.4% to 47.1% in the internal cohort and from 14.0% to 41.9% in the external cohort.•Results from two centre cohorts confirmed that the radiological advanced ENE should be considered as a criterion for stage N3 disease in NPC.
Extranodal extension (ENE) has the potential to add value to the current nodal staging system (N8th) for predicting outcome in nasopharyngeal carcinoma (NPC). This study aimed to incorporate ENE, as well as cervical nodal necrosis (CNN) to the current stage N3 and evaluated their impact on outcome prediction. The findings were validated on an external cohort.
Pre-treatment MRI of 750 patients from the internal cohort were retrospectively reviewed. Predictive values of six modified nodal staging systems that incorporated four patterns of ENE and two patterns of CNN to the current stage N3 for disease-free survival (DFS) were compared with that of N8th using multivariate cox-regression and concordance statistics in the internal cohort. Performance of stage N3 for predicting disease recurrence was calculated. An external cohort of 179 patients was used to validate the findings.
Incorporation of advanced ENE, which infiltrates into adjacent muscle/skin/salivary glands outperformed the other five modifications for predicting outcomes (p < 0.01) and achieved a significantly higher c-index for 5-year DFS (0.69 vs 0.72) (p < 0.01) when compared with that of N8th staging system. By adding advanced ENE to the current N3 increased the sensitivity for predicting disease recurrence from 22.4 % to 47.1 %. The finding was validated in the external cohort (5-year DFS 0.65 vs. 0.72, p < 0.01; sensitivity of stage N3 increased from 14.0 % to 41.9 % for disease recurrence).
Results from two centre cohorts confirmed that the radiological advanced ENE should be considered as a criterion for stage N3 disease in NPC.
•Pre-treatment IVIM-DWI predicts outcome in nasopharyngeal carcinoma (NPC).•High D predicts poor local relapse-free survival and disease-free survival.•Low D* predicts poor regional relapse-free ...survival.•None of the diffusion parameters predicts distant metastases-free survival.
To evaluate whether pre-treatment intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) can predict treatment outcome after 2 years in patients with nasopharyngeal carcinoma (NPC).
One hundred and sixty-one patients with newly diagnosed NPC underwent pre-treatment IVIM-DWI. Univariate Cox regression analysis was performed to evaluate the correlation of the mean values of the pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction and apparent diffusion coefficient with local relapse-free survival (LRFS), regional relapse-free survival (RRFS), distant metastases-free survival (DMFS) and disease-free survival (DFS). Significant diffusion parameters, together with staging, age, gender and treatment as confounding factors, were added into a multivariate model. The area under the curves (AUCs) of significant parameters for disease relapse were compared using the Delong test.
Disease relapse occurred in 30 % of the patients at a median follow-up time of 52.1 months. The multivariate analysis showed that high D and T-staging were correlated with poor LRFS (p = 0.042 and 0.020, respectively) and poor DFS (p = 0.023 and 0.001, respectively); low D* and high T-staging with poor RRFS (p = 0.020 and 0.033, respectively); and high N-staging with poor DMFS (p = 0.006). D with the optimal threshold of ≥0.68 × 10−3 mm2/s and T-staging showed similar AUCs (AUC = 0.614 and 0.651, respectively; p = 0.493) for predicting disease relapse.
High D and low D* were predictors of poor locoregional outcome but none of the diffusion parameters predicted DMFS in NPC.
To evaluate the effect of combining circulating Epstein-Barr viral (EBV) DNA load data with TNM staging data in pretherapy prognostication of nasopharyngeal carcinoma (NPC).
Three hundred seventy-six ...patients with all stages of NPC were studied. Pretreatment plasma/serum EBV DNA concentrations were quantified by a polymerase chain reaction assay. Determinants of overall survival were assessed by multivariate analysis. Survival probabilities of patient groups, segregated by clinical stage (I, II, III, or IV) alone and also according to EBV DNA load (low or high), were compared.
Pretherapy circulating EBV DNA load is an independent prognostic factor for overall survival in NPC. Patients with early-stage disease were segregated by EBV DNA levels into a poor-risk subgroup with survival similar to that of stage III disease and a good-risk subgroup with survival similar to stage I disease.
Pretherapy circulating EBV DNA load is an independent prognostic factor to International Union Against Cancer (UICC) staging in NPC. Combined interpretation of EBV DNA data with UICC staging data leads to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. Validation studies are awaited.
Objective To study rates of relapse in remitted patients with first episode psychosis who either continued or discontinued antipsychotic drugs after at least one year of maintenance treatment.Design ...12 month randomised, double blind, placebo controlled trial.Setting Early psychosis outpatient clinics in Hong Kong.Participants 178 patients with first episode psychosis who had received at least one year of antipsychotic drug treatment between September 2003 and July 2006 and had no positive symptoms of psychosis.Interventions Patients received either maintenance treatment with quetiapine (400 mg/day) or placebo and were followed up for the next 12 months or until a relapse occurred.Main outcome measure Relapse assessed monthly and defined as re-emergence of psychotic symptoms (delusions, conceptual disorganisation, hallucinations, suspiciousness, and unusual thought content) according to predefined thresholds.Results 178 patients were randomised (89 to quetiapine and 89 to placebo). The Kaplan-Meier estimate of the risk of relapse at 12 months was 41% (95% confidence interval 29% to 53%) for the quetiapine group and 79% (68% to 90%) for the placebo group (P<0.001). Although quetiapine was generally well tolerated, the rate of discontinuation due to adverse or serious adverse events was greater in the quetiapine group (18%; 16/89) than in the placebo group (8%; 7/89) (relative risk 2.29, 95% confidence interval 0.99 to 5.28; χ2=3.20, df=1; P=0.07).Conclusion In a group of asymptomatic patients with first episode psychosis and at least one year of previous antipsychotic drug treatment, maintenance treatment with quetiapine compared with placebo resulted in a substantially lower rate of relapse during the following year.Trial registration Clinical trials NCT00334035.
Ribociclib is a specific cyclin dependent kinase (Cdk) 4/6 inhibitor that induces G
arrest by blocking the formation of cyclin D1-Cdk4/6 complex and inhibiting retinoblastoma (RB) phosphorylation. ...Cyclin D1 is overexpressed in over 90% of nasopharyngeal carcinoma (NPC) and CCND1 gene activation plays a critical role in NPC pathogenesis. This study evaluated the preclinical activities of ribociclib in NPC cell lines and patient derived xenograft (PDX) models. Over 95% cell growth inhibition was observed at 96 hours after ribociclib treatment. (IC
concentrations: HK1 = 1.42 ± 0.23 µM; HK1-LMP1 = 2.18 ± 0.70 µM and C666-1 = 8.26 ± 0.92 µM). HK1 and C666-1 cells were chosen for analysis of ribociclib on kinase signaling, apoptosis and cell cycle. Treatment with ribociclib for 48 hours consistently showed a dose-dependent reduction in phosphorylated and total RB expression and G
cycle arrest was only observed. Combining ribociclib with the alpha-specific PI3K inhibitor alpelisib showed a synergistic effect in two NPC PDX models in nude mice. The co-treatment induced a significant reduction in tumor volume in both xeno-666 and xeno-2117 compared with ribociclib treatment alone and control (p < 0.01). In summary, ribociclib is active in NPC models and the effect on growth inhibition was augmented when combined with alpelisib. This study supports the clinical evaluation of ribociclib in NPC.
Abstract
A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)–based approaches to screen for early stage nasopharyngeal ...carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.
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