Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second ...most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.
Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the ...Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow‐up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician‐diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age‐ and multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow‐up (4,488,410 person‐years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98‐7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57‐5.60) for 0‐<2 years; 6.08 (95% CI, 2.96‐12.50) for 2‐<10 years; and 7.52 (95% CI, 3.88‐14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1‐fold increased HCC risk (95% CI, 2.48‐26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 95% CI, 0.69‐6.09 and HR, 1.45 95% CI, 0.69‐3.07, respectively). Conclusion: T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797‐1806)
Prospective data on the risk of hepatocellular carcinoma (HCC) according to dose and duration of aspirin therapy are limited.
To examine the potential benefits of aspirin use for primary HCC ...prevention at a range of doses and durations of use within 2 prospective, nationwide populations.
Pooled analysis of 2 prospective US cohort studies: the Nurses' Health Study and the Health Professionals Follow-up Study. Data were accessed from November 1, 2017, through March 7, 2018. A total of 133 371 health care professionals who reported data on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men were included. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.
Cox proportional hazards regression models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for HCC.
Of the 133 371 participants, 87 507 were women and 45 864 were men; in 1996, the median time of follow-up, the mean (SD) age was 62 (8) years for women and 64 (8) years for men. Over more than 26 years of follow-up encompassing 4 232 188 person-years, 108 incident HCC cases (65 women, 43 men) were documented. Compared with nonregular use, regular aspirin use (≥2 standard-dose 325-mg tablets per week) was associated with reduced HCC risk (adjusted HR, 0.51; 95% CI, 0.34-0.77). This benefit appeared to be dose related: compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 standard-dose tablets per week, 0.51 (95% CI, 0.30-0.86) for more than 1.5 to 5 tablets per week, and 0.49 (95% CI, 0.28-0.96) for more than 5 tablets per week (P for trend = .006). Significantly lower HCC risk was observed with increasing duration (P for trend = .03); this decrease was apparent with use of 1.5 or more standard-dose aspirin tablets per week for 5 or more years (adjusted HR, 0.41; 95% CI, 0.21-0.77). In contrast, use of nonaspirin nonsteroidal anti-inflammatory drugs was not significantly associated with HCC risk (adjusted HR, 1.09; 95% CI, 0.78-1.51).
This study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against HCC.
Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we develop a quantitative method, exploiting local tissue-specific cell-free DNA ...(cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions is strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients. Using compact targeted sequencing (<25 kb) of predictive regions, we demonstrate how the approach could enable quantitative low-cost tracking of ctDNA dynamics and disease progression.
Obesity in adulthood has been associated with increased risk of liver-related mortality. Whether higher levels of physical activity counteract the excess risk conferred by obesity remains unknown. We ...simultaneously evaluated the long-term impact of physical activity and adiposity on liver-related mortality, within 2 nationwide populations.
We conducted a prospective cohort study of 77,238 women and 48,026 men, with detailed, validated assessments of weekly physical activity (metabolic equivalent task MET-hours), adiposity (body mass index BMI, waist circumference), and diet, alcohol use and clinical comorbidities, biennially from 1986 through 2012. Using Cox proportional hazards regression models, we calculated multivariable-adjusted hazard ratios (aHRs) and 95% CIs for liver-related mortality, including death from hepatocellular carcinoma (HCC) and other complications of cirrhosis.
Over 1,856,226 person-years, we recorded 295 liver-related deaths (108 HCC; 187 cirrhosis). Risk of liver-related mortality increased monotonically with higher BMI during adulthood (ptrend<0.0001) and with weight gain during early adulthood (ptrend <0.0001). The risk of liver-related mortality also declined progressively, with increasing physical activity (ptrend = 0.0003); the aHRs across increasing physical activity quintiles were: 1.0, 0.70 (95% CI 0.51–0.96), 0.59 (95% CI 0.42–0.84), 0.52 (95% CI 0.36–0.74) and 0.46 (95% CI 0.31–0.66). Compared to lean-active adults (BMI <25; ≥18 MET-hours/week), the aHRs for obese-active, lean-sedentary, and obese-sedentary adults were: 1.04 (95% CI 0.73–1.37), 2.08 (95% CI 1.21–3.33) and 3.40 (95% CI 2.06–5.56), respectively. Findings were similar for HCC-specific and cirrhosis-specific mortality. Overall, engaging in average-pace walking for >3 hours/week could have prevented 25% of liver-related deaths (95% CI 0.12–0.38).
In 2 prospective, nationwide cohorts, both excess adiposity and reduced physical activity were significant predictors of liver-related mortality. Achieving higher physical activity levels counteracted the excess liver-related risks associated with obesity.
This is the first large, prospective cohort study to simultaneously evaluate the impact of obesity and physical activity on the long-term risk of liver-related mortality in 2 nationwide populations of American men and women. The study demonstrated that obesity predicted significantly increased risk of liver-related mortality, while physical activity predicted significantly lower risk of liver-related mortality. Importantly, the excess risk of liver-related mortality observed with obesity was no longer statistically significant among adults who engaged in the equivalent of average-pace walking for 3 hours or more, per week.
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•Low physical activity and obesity predicted an excess risk of liver-related death.•The excess risk conferred by obesity was markedly attenuated by physical activity.•Overall, walking for >3 hours/week could have prevented 25% of liver-related deaths.
Background & Aims Patients with colorectal cancer (CRC) have high circulating levels of macrophage inhibitory cytokine-1 (MIC1 or growth differentiation factor 15), a marker of inflammation that ...might be involved in carcinogenesis. We analyzed blood samples collected from individuals before they were diagnosed with CRC to determine whether levels of MIC1 were associated with mortality. Methods We collected data on survival of 618 participants diagnosed with CRC who provided prediagnosis blood specimens in 1990 (Nurses’ Health Study) and 1994 (Health Professionals’ Follow-up Study) and were followed through 2010. Levels of MIC1 were measured by enzyme-linked immunosorbent assay and then were categorized into quartiles based on the known distribution of MIC1 levels among previously matched individuals without CRC (controls) within each cohort. We then examined the association of MIC1 levels with overall and CRC-specific mortality using Cox proportional hazards models, with adjustments for mortality-associated risk factors and other plasma markers of inflammation. We also assessed the relationship between levels of MIC1 and levels of prostaglandin-endoperoxide synthase 2 expression (PTGS2 or cyclooxygenase-2), measured in 245 tumor samples by immunohistochemistry. Results Compared with participants in the lowest quartile for plasma level of MIC1, the multivariate hazard ratio for CRC-specific death for participants in the highest quartile of MIC1 level was 2.40 (95% confidence interval: 1.33−4.34; P for linear trend = .009). The association of MIC1 with survival varied with level of PTGS2 expression in tumor samples ( Pinteraction = .04). For individuals with PTGS2-positive tumors, the hazard ratio for CRC-specific death among those with high levels of MIC1 (equal to or greater than the median) was 2.13 (95% confidence interval: 0.99−4.58) compared with participants with low levels of MIC1 (below the median). In individuals with PTGS2-negative CRC, a high level of MIC1 was not associated with an increased risk of CRC-specific death (multivariate hazard ratio = 0.61; 95% confidence interval: 0.13−2.93). Conclusions Based on an analysis of blood and colorectal tumor samples from 2 large studies, high plasma levels of MIC1 (growth differentiation factor 15) before diagnosis of CRC are associated with greater CRC-specific mortality, particularly in individuals with PTGS2-positive tumors.
Background.
Conflicting data exist regarding the prognostic impact of the isocitrate dehydrogenase (IDH) mutation in intrahepatic cholangiocarcinoma (ICC), and limited data exist in patients with ...advanced‐stage disease. Similarly, the clinical phenotype of patients with advanced IDH mutant (IDHm) ICC has not been characterized. In this study, we report the correlation of IDH mutation status with prognosis and clinicopathologic features in patients with advanced ICC.
Methods.
Patients with histologically confirmed advanced ICC who underwent tumor mutational profiling as a routine part of their care between 2009 and 2014 were evaluated. Clinical and pathological data were collected by retrospective chart review for patients with IDHm versus IDH wild‐type (IDHwt) ICC. Pretreatment tumor volume was calculated on computed tomography or magnetic resonance imaging.
Results.
Of the 104 patients with ICC who were evaluated, 30 (28.8%) had an IDH mutation (25.0% IDH1, 3.8% IDH2). The median overall survival did not differ significantly between IDHm and IDHwt patients (15.0 vs. 20.1 months, respectively; p = .17). The pretreatment serum carbohydrate antigen 19‐9 (CA19‐9) level in IDHm and IDHwt patients was 34.5 and 118.0 U/mL, respectively (p = .04). Age at diagnosis, sex, histologic grade, and pattern of metastasis did not differ significantly by IDH mutation status.
Conclusion.
The IDH mutation was not associated with prognosis in patients with advanced ICC. The clinical phenotypes of advanced IDHm and IDHwt ICC were similar, but patients with IDHm ICC had a lower median serum CA19‐9 level at presentation.
Implications for Practice:
Previous studies assessing the prognostic impact of the isocitrate dehydrogenase (IDH) gene mutation in intrahepatic cholangiocarcinoma (ICC) mainly focused on patients with early‐stage disease who have undergone resection. These studies offer conflicting results. The target population for clinical trials of IDH inhibitors is patients with unresectable or metastatic disease, and the current study is the first to focus on the prognosis and clinical phenotype of this population and reports on the largest cohort of patients with advanced IDH mutant ICC to date. The finding that the IDH mutation lacks prognostic significance in advanced ICC is preliminary and needs to be confirmed prospectively in a larger study.
The correlation of isocitrate dehydrogenase (IDH) gene mutation status with overall survival and clinicopathologic features in patients with advanced intrahepatic cholangiocarcinoma (ICC) was evaluated. The mutation was not associated with prognosis in these patients. The clinical phenotype of patients with ICC who had the IDH mutation was similar to that of patients with IDH wild type, but the former had a lower median serum level of carbohydrate antigen 19‐9 at presentation.
Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating ...intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature.
For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017.
In the LCPP, obesity and diabetes were associated with a 62% Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12 and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I
= 0%. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I
= 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation.
These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.
Increased intake of whole grain and dietary fiber has been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for ...hepatocellular carcinoma (HCC). Therefore, we hypothesized that long-term intake of whole grains and dietary fiber may be associated with lower risk of HCC.
To assess the associations of whole grain and dietary fiber intake with the risk of HCC.
Cohort study of the intake of whole grains, their subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) in 125 455 participants from 2 cohorts from the Nurses' Health Study and the Health Professionals Follow-up Study.
Intake of whole grains, their subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) were collected and updated almost every 4 years using validated food frequency questionnaires.
Multivariable hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression model after adjusting for most known HCC risk factors.
After an average follow-up of 24.2 years, we identified 141 patients with HCC among 125 455 participants (77 241 women and 48 214 men (mean SD age, 63.4 10.7 years). Increased whole grain intake was significantly associated with lower risk of HCC (the highest vs lowest tertile intake: HR, 0.63; 95% CI, 0.41-0.96; P = .04 for trend). A nonsignificant inverse HCC association was observed for total bran (HR, 0.70; 95% CI, 0.46-1.07; P = .11 for trend), but not for germ. Increased intake of cereal fiber (HR, 0.68; 95% CI, 0.45-1.03; P = .07 for trend), but not fruit or vegetable fiber, was associated with a nonsignificant reduced risk of HCC.
Increased intake of whole grains and possibly cereal fiber and bran could be associated with reduced risk of HCC among adults in the United States. Future studies that carefully consider hepatitis B and C virus infections are needed to replicate our findings, to examine these associations in other racial/ethnic or high-risk populations, and to elucidate the underlying mechanisms.
The treatment of glioblastoma multiforme (GBM) is an unmet clinical need. The 5-year survival rate of patients with GBM is less than 3%. Temozolomide (TMZ) remains the standard first-line treatment ...regimen for gliomas despite the fact that more than 90% of recurrent gliomas do not respond to TMZ after repeated exposure. We have also independently shown that many of the Asian-derived glioma cell lines and primary cells derived from Singaporean high-grade glioma patients are indeed resistant to TMZ. This issue highlights the need to develop new effective anti-cancer treatment strategies. In a recent study, wild-type epidermal growth factor receptor (wtEGFR) has been shown to phosphorylate a truncated EGFR (known as EGFRvIII), leading to the phosphorylation of STAT proteins and progression in gliomagenesis. Despite the fact that combination of EGFR targeting drugs and rapamycin has been used before, the effect of mono-treatment of Nimotuzumab, rapamycin and combination therapy in human glioma expressing different types of EGFR is not well-studied. Herein, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an mTOR inhibitor (rapamycin) in Caucasian patient-derived human glioma cell lines, Asian patient-derived human glioma cell lines, primary glioma cells derived from the Mayo GBM xenografts, and primary short-term glioma culture derived from high-grade glioma patients.
The combination effect of Nimotuzumab and rapamycin was examined in a series of primary human glioma cell lines and glioma cell lines. The cell viability was compared to TMZ treatment alone. Endogenous expressions of EGFR in various GBM cells were determined by western blotting.
The results showed that combination of Nimotuzumab with rapamycin significantly enhanced the therapeutic efficacy of human glioma cells compared to single treatment. More importantly, many of the Asian patient-derived glioma cell lines and primary cells derived from Singaporean high-grade gliomas, which showed resistance to TMZ, were susceptible to the combined treatments.
In conclusion, our results strongly suggest that combination usage of Nimotuzumab and rapamycin exert higher cytotoxic activities than TMZ. Our data suggest that this combination may provide an alternative treatment for TMZ-resistant gliomas regardless of the EGFR status.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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