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•HBsAg− patients (anti-HBc+ but anti-HBs−) are at increased risk of HBsAg seroreversion after corticosteroid therapy.•The peak daily dose of corticosteroid is a more important risk ...factor for hepatitis flares than treatment duration.•In contrast, dose and duration of corticosteroid use are not associated with the risk of HBsAg reversion.
Systemic corticosteroids may cause HBV reactivation, but the impact on patients with previous HBV exposure is poorly defined. We aimed to study the risk of HBsAg seroreversion and hepatitis flare in patients with previous HBV exposure.
Patients who were negative for HBsAg and received corticosteroids between 2001–2010 were included. Patients who were positive for antibody to HBsAg (anti-HBs) and/or to HBcAg (anti-HBc) were defined as having previous HBV exposure. The primary endpoint was HBsAg seroreversion; the secondary endpoint was hepatitis flare (alanine aminotransferase >80 U/L) at 1 year.
A total of 12,997 patients fulfilled the inclusion criteria: anti-HBs positive only (n = 10,561); anti-HBc positive only (n = 970); anti-HBs & anti-HBc positive (n = 830) and anti-HBs & anti-HBc negative (n = 636). HBsAg seroreversion occurred in 165 patients. Patients who were anti-HBc positive only had a higher risk of HBsAg seroreversion (1-year incidence 1.8%) than those negative for both anti-HBs & anti-HBc (0%; p = 0.014). Patients with previous HBV exposure had a similarly low risk of liver failure as unexposed individuals (1.1% vs. 0.9%). The risk of a hepatitis flare started to increase in those receiving corticosteroids at peak daily doses of 20–40 mg (adjusted hazard ratio HR 2.19, p = 0.048) or >40 mg (aHR 2.11, p = 0.015) prednisolone equivalents for <7 days, and was increased at treatment durations of 7–28 days and >28 days (aHR 2.02–3.85; p <0.001–0.012).
In HBsAg-negative patients who were only anti-HBc positive, high peak daily doses of corticosteroids increased the risk of hepatitis flare, but not seroreversion. The rate of liver failure was low and similar in HBV exposed and unexposed individuals; there were no deaths, nor any requirement for liver transplantation.
It is important to know the hepatitis B virus (HBV) status before starting corticosteroid therapy. Patients with resolved HBV infection without detectable immunity are at an increased risk of HBV surface antigen seroreversion after corticosteroid therapy. High peak daily doses of corticosteroids (>40 mg prednisolone equivalents) increase the risk of hepatitis flare, but not seroreversion, in patients with previous exposure to HBV, irrespective of the duration of treatment. Interval monitoring of liver biochemistries is essential for the early detection of hepatitis flares in these patients.
Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) for non-metastatic locoregionally advanced nasopharyngeal carcinoma (NPC) has gained considerable attention. However, the ...most efficacious IC regimens remain investigational. We aimed to compare the survival benefits of all available IC regimens followed by CCRT in this network meta-analysis.
All randomized-controlled trials of CCRT with or without IC in non-metastatic locoregionally advanced NPC were included, with an overall nine trials of 2,705 patients counted in the analysis. CCRT alone was the reference category. Eight IC regimens followed by CCRT were analyzed: docetaxel + cisplatin (DC), gemcitabine + carboplatin + paclitaxel (GCP), gemcitabine + cisplatin (GP), mitomycin + epirubicin + cisplatin + fluorouracil + leucovorin (MEPFL), cisplatin + epirubicin + paclitaxel (PET), cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX) and cisplatin + fluorouracil (PF), cisplatin + capecitabine (PX). Fixed-effects frequentist network meta-analysis models was applied and P-score was used to rank the treatments.
DC, GP, and PX were the top three IC regimens with the highest probability of benefit on overall survival (OS). Their corresponding hazard ratios (HRs) (95% CIs) compared with CCRT alone were of 0.24 (0.08-0.73), 0.43 (0.24-0.77), and 0.54 (0.27-1.09) and the respective P-scores were 94%, 82%, and 68%. The first three IC regimens showing significantly improved progression-free survival (PFS) were PX, followed by GP and DC with respective HRs of 0.46 (0.24-0.88), 0.51 (0.34-0.77), and 0.49 (0.20-1.20), and P-scores of 82%, 78%, and 74%. Among the studies in the intensity-modulated radiation therapy (IMRT) era, GP and PX were the best performed IC regimens, whilst DC performed the best among non-IMRT studies. Doublet and gemcitabine-based IC regimens had better survival benefits compared to triplet and taxane-based IC regimens, respectively.
Given its consistent superiority in both OS and PFS, DC, GP, and PX ranked among the three most efficacious IC regimens in both the overall and subgroup analysis of IMRT or non-IMRT studies. Exploratory analyses suggested that doublet and gemcitabine-based IC regimens showed better survival performance.
Tuberculosis (TB) reactivation has been increasingly identified following immune checkpoint inhibitor (ICI) therapy for cancer patients. However there has been no report on TB reactivation in the ...gastrointestinal tract. In the report, we describe a patient who developed TB ileitis after pembrolizumab for her metastatic nasopharyngeal carcinoma (NPC). Rechallenge with pembrolizumab after its temporary interruption together with anti-TB therapy produced continuous tumor response but without further TB reactivation. To date, this is the first gastrointestinal TB reactivation after ICI therapy for cancer. Guidelines to screen for TB before initiation of ICIs in endemic areas should be established.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction:
The prognostic role of plasma Epstein–Barr virus (EBV) DNA clearance when intensity-modulated radiotherapy (IMRT) and the 8th edition of American Joint Committee on Cancer (AJCC)/Union ...for International Cancer Control (UICC) TNM Staging Classification are fully implemented remains undeciphered. We investigated if its half-life clearance during radical treatment for non-metastatic nasopharyngeal carcinoma (NPC) was an early prognosticator.
Patients and methods:
Patients with previously untreated non-metastatic NPC were prospectively treated with radical IMRT and concurrent chemotherapy +/– induction/adjuvant chemotherapy from 2014 to 2018. Their plasma EBV DNA was measured immediately before treatment followed by weekly schedules until 0 copy/ml in two consecutive measurements. Cox regression models were employed to identify prognostic factors.
Results:
Forty-five patients were prospectively recruited and analyzed. After a median follow-up of 30.3 months, 2 (4.5%), 1 (2.3%), and 6 (13.6%) patients experienced local, regional, and distant relapses, respectively. The median half-life clearance of plasma EBV DNA was 7.92 days. Those with half-life clearance of >15 days had a worse 3-years progression-free survival (PFS) (79.5 vs. 25.0%,
p
= 0.005), distant metastasis-free survival (DMFS) (85.0 vs. 31.3%,
p
= 0.009), and overall survival (OS) (91.3 vs. 75.0%,
p
= 0.024) when compared to those with a shorter half-life. Multivariable analyses demonstrated that only half-life (>15 days) was prognostic of DMFS HR (95% CI): 4.91 (1.31; 18.39),
p
= 0.01 and OS HR (95% CI): 5.24 (1.06; 26.05) while half-life (>15 days) HR (95% CI): 5.14 (1.28; 22.73),
p
= 0.02 and sum of pretreatment gross tumor volumes of the primary nasopharyngeal tumor and the radiologically positive neck nodes (GTV_P+N) HR (95% CI): 1.01 (1.00; 1.03),
p
= 0.02 were prognostic of PFS.
Conclusion:
The half-life clearance of plasma EBV DNA was prognostic in non-metastatic NPC staged and treated in the contemporary era. Earlier biomarker surveillance during treatment should be considered.
Clinical Trial Registration:
This study has been registered with
ClinicalTrials.gov
(Identifier: NCT03830996).
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were ...examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3. Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.
Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, ...cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4
T cells, and CD8
T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.
Background: The Dundee Ready Educational Environment Measure (DREEM) was specifically designed to measure the undergraduate medical educational environment. This study seeks to review the adoption of ...DREEM internationally, and its association with different learning contexts and learner factors in order to better support our learners and facilitate future applications and research.
Method: A systematic literature review was conducted on all articles that adopted and reported data using the DREEM from 1997 to April 2017.
Results: Overall, the majority of 106 included studies from over 30 countries were conducted in Asia and Europe (76.4% of studies) within medical, dental, and nursing programs (86.8% of studies). Seventy-nine out of 98 studies (80.6%) which reported DREEM scores observed a mean total DREEM score within the range of "more positive than negative" (101-150 out of maximum 200 points). Higher DREEM scores were associated with better past academic achievement, quality of life, resilience, positive attitudes towards course, mindfulness, preparedness for practice, less psychological distress, and greater peer support.
Conclusions: Future studies may want to examine other correlates of DREEM such as coping styles, personality profiles, burnout level, and DREEM scores can be incorporated into reviews of learning environments to ascertain longitudinal changes following educational interventions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antiviral treatment is known to improve survival in patients with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC). Yet, the treatment uptake in CHB patients remains low. We aimed to ...report the secular trend in antiviral treatment uptake from 2007–2017, and to compare the effect of different nucleos(t)ide analogue (NA) initiation times (before vs. after HCC diagnosis) on survival.
A 3-month landmark analysis was used to compare overall survival in patients not receiving NA treatment (i.e. no NA), patients receiving NAs after their first HCC treatment (i.e. post-HCC NA), and patients receiving NAs ≤3 months before their first HCC treatment (i.e. pre-HCC NA). A propensity score-weighted Cox proportional hazards model was used to balance clinical characteristics between the 3 groups and to estimate hazard ratios (HRs).
The uptake of antiviral treatment in HCC patients increased from 47.3% in 2007 to 98.3% in 2017. The pre-HCC NA group contributed mostly to the uptake rate, which increased from 72.7% to 96.0% in the past decade. In addition, 3,843 CHB patients (407 no NA; 2,932 pre-HCC NA; 504 post-HCC NA) with HCC, receiving at least 1 type of HCC treatment, were included in the analysis. Lack of NA treatment at the time of HCC diagnosis increased the risk of death (weighted HR 3.05; 95% CI 2.70–3.44; p <0.001). The impact of the timing of NA treatment was insignificant (weighted HR 0.90; 95% CI 0.78–1.04; p = 0.161).
The uptake of antiviral treatment in HCC patients increased over the past decade. NA treatment, regardless of whether it was initiated before or after HCC diagnosis, improved survival. It is never too late to initiate NA treatment, even after HCC diagnosis.
More and more patients who have hepatitis B-related liver cancer received antiviral treatment over the past decade. The timing of starting antiviral treatment, regardless of whether it was before or after liver cancer happens, does not really matter in terms of survival benefits.
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•Antiviral treatment improves survival in patients with chronic hepatitis B-related HCC.•The uptake of antiviral treatment in HCC patients was suboptimal in the past (47.3% in 2007), but dramatically improved to 98.3% in 2017.•The timing of antiviral treatment (before or after HCC occurrence) does not matter that much in terms of patient survival.•Antivirals should be started soon after HCC has been diagnosed in patients with chronic hepatitis B who are not already on them.
Chromatin assembly factor 1 (CAF-1) is a replication-dependent epigenetic regulator that controls cell cycle progression and chromatin dynamics. In this study, we aim to investigate the ...immunomodulatory role and therapeutic potential of the CAF-1 complex in HCC.
CAF-1 complex knockout cell lines were established using the CRISPR/Cas9 system. The effects of CAF-1 in HCC were studied in HCC cell lines, nude mice, and immunocompetent mice. RNA-sequencing, ChIP-Seq, and assay for transposase accessible chromatin with high-throughput sequencing (ATAC-Seq) were used to explore the changes in the epigenome and transcriptome. CAF-1 complex was significantly upregulated in human and mouse HCCs and was associated with poor prognosis in patients with HCC. Knockout of CAF-1 remarkably suppressed HCC growth in both in vitro and in vivo models. Mechanistically, depletion of CAF-1 induced replicative stress and chromatin instability, which eventually led to cytoplasmic DNA leakage as micronuclei. Also, chromatin immunoprecipitation sequencing analyses revealed a massive H3.3 histone variant replacement upon CAF-1 knockout. Enrichment of euchromatic H3.3 increased chromatin accessibility and activated the expression of endogenous retrovirus elements, a phenomenon known as viral mimicry. However, cytosolic micronuclei and endogenous retroviruses are recognized as ectopic elements by the stimulator of interferon genes and dsRNA viral sensing pathways, respectively. As a result, the knockout of CAF-1 activated inflammatory response and antitumor immune surveillance and thereby significantly enhanced the anticancer effect of immune checkpoint inhibitors in HCC.
Our findings suggest that CAF-1 is essential for HCC development; targeting CAF-1 may awaken the anticancer immune response and may work cooperatively with immune checkpoint inhibitor treatment in cancer therapy.
To examine the acceptability of a board game newly developed through a co-design process for promoting end-of-life care discussion among Chinese older adults.
A multi-centre mixed method study, ...including a one group pre-test post-test study and focus group interviews, was conducted. Thirty older adults participated in a one-hour game session in a small group format. Acceptability was assessed by attrition rate and satisfaction with the game. Participants’ experiences with the game were explored qualitatively. Within-subject changes in self-efficacy and readiness for advance care planning (ACP) behaviours were also examined.
The players generally had positive experiences with the game, giving a low attrition rate. A significantly higher level of self-efficacy in sharing end-of-life care preferences with surrogates was reported after the game session (p = 0.008). There was a slight increase in the proportion of players indicated that they would complete ACP behaviours in the coming months immediately after the intervention.
A serious game is acceptable by Chinese older adults to raise discussions regarding end-of-life matters.
A game can be an ice-breaking tool to increase self-efficacy towards communicating end-of-life care preferences with surrogates, but follow-up support is needed to facilitate the uptake of ACP behaviours.
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