Chronic inflammation is an aberrantly prolonged form of a protective response to a loss of tissue homeostasis and it is involved in several steps of the carcinogenesis process. As a result, many ...cancers are inflammation-related. The systemic inflammatory response is associated with survival in advanced and localized cancers. Two categories of scores have been proposed to monitor the systemic inflammatory response, those derived from protein measurement and those based on counting inflammatory cells. This review aims to provide a critical appraisal of these 2 categories of surrogate markers. The 3 scale modified Glasgow prognostic score (mGPS) is based on the combination of C-reactive protein and albumin and is graded 0 to 2. It has been validated worldwide showing an independent prognostic value in patients with cancer in a variety of tumour types and tumour stages. Leukocytes-based scores are mainly neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR). Elevated NLR and/or PLR and lower LMR seem to be associated with decreased survival, but the studies about these markers are very heterogeneous. The main limit is the variety of thresholds used to dichotomize patients, so that reproducibility and reliability of leukocytes-based scores can be questioned. Hence, there is no sufficient evidence to support their use in clinical practice. Comprehensive management of patients with operable and advanced cancer should integrate the host systemic inflammatory response by calculating the mGPS. It could be a helpful tool to tailor patients' management.
Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with ...5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer.
This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1–14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13.
Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37–60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6–59·1) in the capecitabine group compared with 36·4 months (29·7–44·5) in the observation group (adjusted hazard ratio HR 0·81, 95% CI 0·63–1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55–0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30–44) in the observation group (adjusted HR 0·75, 95% CI 0·58–0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6–35·9) in the capecitabine group and 17·5 months (12·0–23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8–46·3) in the capecitabine group and 17·4 months (12·0–23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related.
Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting.
Cancer Research UK and Roche.
The transcription factor Nrf2 regulates the basal and inducible expression of a battery of cytoprotective genes. Whereas numerous Nrf2-inducing small molecules have been reported, very few chemical ...inhibitors of Nrf2 have been identified to date. The quassinoid brusatol has recently been shown to inhibit Nrf2 and ameliorate chemoresistance in vitro and in vivo. Here, we show that brusatol provokes a rapid and transient depletion of Nrf2 protein, through a posttranscriptional mechanism, in mouse Hepa-1c1c7 hepatoma cells. Importantly, brusatol also inhibits Nrf2 in freshly isolated primary human hepatocytes. In keeping with its ability to inhibit Nrf2 signaling, brusatol sensitizes Hepa-1c1c7 cells to chemical stress provoked by 2,4-dinitrochlorobenzene, iodoacetamide, and N-acetyl-p-benzoquinone imine, the hepatotoxic metabolite of acetaminophen. The inhibitory effect of brusatol toward Nrf2 is shown to be independent of its repressor Keap1, the proteasomal and autophagic protein degradation systems, and protein kinase signaling pathways that are known to modulate Nrf2 activity, implying the involvement of a novel means of Nrf2 regulation. These findings substantiate brusatol as a useful experimental tool for the inhibition of Nrf2 signaling and highlight the potential for therapeutic inhibition of Nrf2 to alter the risk of adverse events by reducing the capacity of nontarget cells to buffer against chemical and oxidative insults. These data will inform a rational assessment of the risk:benefit ratio of inhibiting Nrf2 in relevant therapeutic contexts, which is essential if compounds such as brusatol are to be developed into efficacious and safe drugs.
•Nrf2 regulates the expression of numerous cytoprotective genes.•We show that the quassinoid brusatol rapidly and transiently inhibits Nrf2 signaling.•Brusatol sensitizes mammalian cells to chemical stress provoked by electrophiles.•Brusatol inhibits Nrf2 independent of its key regulatory mechanisms.•Therapeutic inhibition of Nrf2 could enhance drug-induced adverse effects.
Activating mutations in KRAS have been suggested as potential predictive and prognostic biomarkers. However, the prognostic impact of specific point mutations remains less clear. This study assessed ...the prognostic impact of specific KRAS mutations on survival for patients with colorectal cancer.
Retrospective review of patients KRAS typed for advanced and recurrent colorectal cancer between 2010 and 2015 in a UK Cancer Network.
We evaluated the impact of KRAS genotype in 392 patients. Mutated KRAS was detected in 42.9% of tumours. KRAS mutations were more common in moderate vs well-differentiated tumours. On multivariate analysis, primary tumour T stage (HR 2.77 (1.54-4.98), P=0.001), N stage (HR 1.51 (1.01-2.26), P=0.04), curative intent surgery (HR 0.51 (0.34-0.76), P=0.001), tumour grade (HR 0.44 (0.30-0.65), P=0.001) and KRAS mutation (1.54 (1.23-2.12), P=0.005) were all predictive of overall survival. Patients with KRAS codon 12 mutations had worse overall survival (HR 1.76 (95% CI 1.27-2.43), P=0.001). Among the five most common codon 12 mutations, only p.G12C (HR 2.21 (1.15-4.25), P=0.01) and p.G12V (HR 1.69 (1.08-2.62), P=0.02) were predictive of overall survival.
For patients with colorectal cancer, p.G12C and p.G12V mutations in codon 12 were independently associated with worse overall survival after diagnosis.
The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the ...long-term data and novel exploratory subgroup analyses.
This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m
twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13.
Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex.
This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.
Griffithsin (GRFT) is a broad-spectrum antiviral protein that is effective against several glycosylated viruses. Here, we have evaluated the
in vitro
and
in vivo
antiviral activities of GRFT against ...Japanese encephalitis virus (JEV) infection.
In vitro
experiments showed that treatment of JEV with GRFT before inoculation of BHK-21 cells inhibited infection in a dose-dependent manner, with 99 % inhibition at 100 μg/ml and a 50 % inhibitory concentration
(
IC
50
) of 265 ng/ml (20 nM). Binding assays suggested that binding of GRFT to JEV virions inhibited JEV infection.
In vivo
experiment showed that GRFT (5 mg/kg) administered intraperitoneally before virus infection could completely prevent mortality in mice challenged intraperitoneally with a lethal dose of JEV. Our study also suggested that GRFT prevents JEV infection at the entry phase by targeting the virus. Collectively, our data demonstrate that GRFT is an antiviral agent with potential application in the development of therapeutics against JEV or other flavivirus infections.
The application of primary human hepatocytes following isolation from human tissue is well accepted to be compromised by the process of dedifferentiation. This phenomenon reduces many unique ...hepatocyte functions, limiting their use in drug disposition and toxicity assessment. The aetiology of dedifferentiation has not been well defined, and further understanding of the process would allow the development of novel strategies for sustaining the hepatocyte phenotype in culture or for improving protocols for maturation of hepatocytes generated from stem cells. We have therefore carried out the first proteomic comparison of primary human hepatocyte differentiation. Cells were cultured for 0, 24, 72 and 168 h as a monolayer in order to permit unrestricted hepatocyte dedifferentiation, so as to reveal the causative signalling pathways and factors in this process, by pathway analysis. A total of 3430 proteins were identified with a false detection rate of <1 %, of which 1117 were quantified at every time point. Increasing numbers of significantly differentially expressed proteins compared with the freshly isolated cells were observed at 24 h (40 proteins), 72 h (118 proteins) and 168 h (272 proteins) (
p
< 0.05). In particular, cytochromes P450 and mitochondrial proteins underwent major changes, confirmed by functional studies and investigated by pathway analysis. We report the key factors and pathways which underlie the loss of hepatic phenotype in vitro, particularly those driving the large-scale and selective remodelling of the mitochondrial and metabolic proteomes. In summary, these findings expand the current understanding of dedifferentiation should facilitate further development of simple and complex hepatic culture systems.
Liver-limited recurrence after resection of colorectal liver metastases is a frequent occurrence, and can in some cases be treated with curative intent. Although surgical re-resection remains ...standard of care, there is growing interest in the role of ablation in this setting. The aim of this study was to compare the outcomes after curative-intent ablation and resection in patients with recurrent colorectal liver metastases.
We retrospectively analysed data from 366 consecutive patients who underwent liver resection for colorectal liver metastases between June 2010 and August 2015. Sixty-four developed liver-limited recurrence which was treated with curative intent, thirty-three (51.6%) by ablation and 31 (48.4%) by repeat resection.
Patient groups were well matched, with surgically resected patients showing higher pre-operative carcinoembryonic antigen levels and larger metastases. There were fewer post-operative complications and shorter length of stay in the ablation group (p < 0.02). After a median follow-up of 36.2 months, median overall survival was the same for both the resected and ablated groups at 33.3 months. Median progression-free survival was longer for patients treated with surgery (10.2 months) compared to ablation (4.3 months) (p = 0.002).
Ablation or resection for liver-limited recurrence after surgery for colorectal liver metastases is associated with improved overall survival compared with systemic chemotherapy alone, and should always be considered for patients with resectable liver recurrence. Although ablation seemed to be associated with a shorter progression-free survival, post-procedure morbidity was significantly lower. The choice between ablation and resection should therefore be made on a personalised basis.
Older age is a risk factor for the development of HCC. However, the treatment options available for older patients with HCC, their safety, efficacy and utility, are poorly understood resulting in ...challenging decision-making. In this review, we aim to report the best available evidence to facilitate optimal decision making for older patients with HCC. We report that surgical resection for HCC is equally safe (90-day mortality ~3%) and effective (five-year disease free survival ~40%) for older patients as it is for younger patients. Five-year survival after ablation therapy for HCC is in excess of 50% in older patients, whilst morbidity rates are in the region of 3%. Survival rates of 30% after chemoembolisation reflects its role as a non-curative treatment. Transplantation is an option that may be helpful for a minority of patients, but the high risks of in-hospital mortality and lower likelihood of receiving a transplant should be duly considered before committing to this approach. We therefore advocate an individualised assessment for older patients based on these risk profiles and probabilities of optimal outcomes. In patients with a projected life-span ≥ 3 years, and who have sufficient physiological and functional reserve, surgical resection should be the treatment of choice. Patients with a projected life-span < 3 years are better served with loco-regional therapies, and tumour size, at a threshold of 3 cm, should guide the choice between ablation and chemoembolisation therapies.
Abstract Aims Long-term survival has been demonstrated for patients with irresectable colorectal liver metastases who are brought to resection by chemotherapy. However, it remains unclear whether ...improved long-term outcome seen with modern therapies translates to increased rates of secondary resection and whether response rates correlate with rates of secondary liver resection. Methods A systematic review of literature published between January 1998 and September 2013 was performed. Phase II/III trials were included if they reported the rate of objective response and the rate of secondary resection of initially irresectable metastases. For the phase III trials, the ratio between response and resection rates within the trials was investigated as well as the correlation for both parameters in all trials. Results Twenty-five studies were identified. Response rate demonstrated a strong correlation with rates of secondary resection ( R2 = 0.44, p = 0.008). Ratios of response/resection between both arms of 10 randomised control trials (RCTs) were calculated to control for selection bias, and showed that in a randomised setting response rates correlate with increased rates of secondary resection in an intra-trial comparison ( R2 = 0.87, p = 0.002). Linear regression analysis demonstrated a significant difference between studies where criteria for resectability were defined (median 39.5%), and those where it was not (median 11%) ( p = 0.006). Conclusion There is a clear correlation between radiological response and rates of secondary resection, with studies that define resectability achieving much higher rates. All trials investigating first line treatment in patients with metastatic colorectal cancer should have criteria for resection, with conversion to secondary resection as a defined study end-point.
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