Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under ...chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8
T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
Background
Nutritional factors are suggested to influence the incidence and severity of glandular gastric disease (GGD) in horses.
Objectives
To retrospectively assess whether dietary fermentable ...carbohydrates increase the severity of GGD and to prospectively evaluate whether the partial substitution of concentrates by dehydrated alfalfa would decrease GGD severity scores.
Animals
In total, 82 trotters from 4 training centers exercised ≥5 days/week.
Methods
Multicenter retrospective observational study, and prospective 2‐arm randomized trial. Glandular mucosae were observed by gastroscopy and scored (0‐4 severity scale) at day 0 (D0). Biochemical composition of the diet fed was compared between ulcerated and nonulcerated groups. After D0, horses either received the same diet (control, n = 41) or pelleted dehydrated alfalfa substituting 50% concentrates (alfalfa, n = 41). Glandular scores were recorded in both groups after 21 (D21) and 42 days (D42). The first end point was a successful outcome, defined as a horse with a glandular score of 2 to 4 on D0, decreasing to a score of 0 to 1 on days 21 or 42.
Results
Horses scored 0 to 1 at D0 ingested more (P = .01) soluble sugars from concentrates than those scored 2 to 4 before D0 (77.5 g/kg BW; 95% confidence interval CI: 71.1‐84.0, vs 59.1 g/kg BW; 95% CI: 48.0‐70.3), whereas starch intake did not differ between groups (P = .24). Among horses scored 2 to 4 at D0, fewer were scored 2 to 4 in the alfalfa group (1 out of 6) compared with the control group (6 out of 6) at D42 (P = .02). Clinical success was 47.7 times more likely in horses fed alfalfa compared with horses in the control group (95% CI: 1.6‐1422.8).
Conclusion and Clinical Importance
Relationships were found between diet composition and integrity of the glandular mucosa. Feeding pelleted dehydrated alfalfa could help to reduce the incidence and severity of GGD.
Background. An increased incidence of alveolar echinococcosis (AE) in patients with immunosuppression (IS) has been observed; our aim was to study this association and its characteristics. Methods. ...Fifty AE cases with IS-associated conditions (ISCs) before or at AE diagnosis were collected from the French AE registry (1982–2012, 509 cases). There were 30 cancers, 9 malignant hematological disorders, 14 chronic inflammatory diseases, 5 transplants, and 1 case of AIDS; 9 patients had ≥2 ISCs. Characteristics of the 42 IS/AE cases and the 187 non-IS/AE cases diagnosed during the period 2002–2012 were statistically compared. Results. There was a significant increase in IS/AE cases over time. Risk factors did not differ between IS/AE and non-IS/AE patients. However, AE was more frequently an incidental finding (78% vs 42%) and was diagnosed at earlier stages (41% vs 23%) in IS/AE than in non-IS/AE patients. Serology was more often negative (14% vs 1%) and treatment efficacy was better (51% regression after 1-year treatment vs 27%) in IS/AE patients. All IS/AE patients but 7 took IS drugs; 7 received biotherapeutic agents. When not concomitant, AE occurred in IS patients within a 48-month median time period. Atypical presentation and abscess-, hemangioma-, and metastasis-like images delayed AE diagnosis in 50% of IS/AE patients, resulting in inappropriate treatment. Liver images obtained for 15 patients 1–5 years before diagnosis showed no AE lesions. Albendazole efficacy was good, but 19 of 48 treated patients experienced side effects. Conclusions. Patients with immunosuppression are at increased risk for occurrence, delayed diagnosis, and progression of AE.
To validate a triple-echo gradient-echo sequence for measuring the fat content of the liver, by using hydrogen 1((1)H) magnetic resonance (MR) spectroscopy as the reference standard.
This prospective ...study was approved by the appropriate ethics committee, and written informed consent was obtained from all patients. In 37 patients with type 2 diabetes (31 men, six women; mean age, 56 years), 3.0-T single-voxel point-resolved (1)H MR spectroscopy of the liver (Couinaud segment VII) was performed to calculate the liver fat fraction from the water (4.7 ppm) and methylene (1.3 ppm) peaks, corrected for T1 and T2 decay. Liver fat fraction was also computed from triple-echo (consecutive in-phase, opposed-phase, and in-phase echo times) breath-hold spoiled gradient-echo sequence (flip angle, 20 degrees), by estimating T2* and relative signal intensity loss between in- and opposed-phase values, corrected for T2* decay. Pearson correlation coefficient, Bland-Altman 95% limit of agreement, and Lin concordance coefficient were calculated.
Mean fat fractions calculated from the triple-echo sequence and (1)H MR spectroscopy were 10% (range, 0.7%-35.6%) and 9.7% (range, 0.2%-34.1%), respectively. Mean T2* time was 14.7 msec (range, 5.4-25.4 msec). Pearson correlation coefficient was 0.989 (P < .0001) and Lin concordance coefficient was 0.988 (P < .0001). With the Bland-Altman method, all data points were within the limits of agreement.
A breath-hold triple-echo gradient-echo sequence with a low flip angle and correction for T2* decay is accurate for quantifying fat in segment VII of the liver. Given its excellent correlation and concordance with (1)H MR spectroscopy, this triple-echo sequence could replace (1)H MR spectroscopy in longitudinal studies.
Little is known about the impact of changes in the management of hepatocellular carcinoma (HCC) over time. We assessed trends in the pattern of care and in prognosis at a population level.
Data on ...diagnostic conditions, treatment, and prognosis from 1976-2005 were collected by the population-based digestive cancer registry of Burgundy (France). A nonconditional logistic regression was used to identify factors associated with treatment for cure. A multivariate relative survival analysis was also performed.
The context of HCC diagnosis has changed; the proportion of asymptomatic patients increased from 5.6% (1976-1985) to 37.2% (1996-2005). The proportion of cases diagnosed on the basis of morphologic criteria increased from 14% during 1976-1985 to 35.6% during 1996-2005, whereas histologically verified cases decreased from 62.2% to 41.2% between the same time periods. The proportion of patients who were treated with intent to cure increased from 2.7% (1976-1985) to 19.6% (1996-2005). This increase was associated with improvements in relative survival from 4.7% (1976-1985) to 32.8% (1996-2005) at 1 year and from 1.4% to 10.0% at 5 years. The 5-year relative survival of patients treated with curative intent increased, reaching 46.6% for the 1996-2005 period. In the multivariate relative survival analysis, age, period of diagnosis, clinical presentation, alpha-fetoprotein level, and treatment were independent prognostic factors.
During a 30-year period, there was an increase in the number of HCCs diagnosed in asymptomatic subjects that was associated with the development of new effective therapies; this association might account for improvements in prognosis of patients with HCC.
Objectives: The mechanisms underlying steatosis during hepatitis C virus (HCV) infection are complex and multifactorial. Obesity is a well-recognized risk factor for the development of steatosis in ...chronic hepatitis C infection. The aim of our study was to investigate the role of adipocytokines in HCV-related steatosis. Therefore, we hypothesized that the endocrine function of adipose tissue could be, in part, responsible for HCV-related steatosis.
Seventy-one consecutive untreated chronic hepatitis C patients were studied to assess the effects of adipocytokines, body mass index (BMI), age, and HCV genotype on steatosis. We used ELISA to determine serum adiponectin, leptin, and soluble TNF receptors I and II concentrations.
Results: Steatosis was observed in 42 (59.1%) patients. BMI was significantly associated with leptin (r = 0.64; P = 0.0001) and was border significantly associated with adiponectin concentrations (r = −0.22; P = 0.06). In univariate analyses, age, HCV genotype 3, BMI, increased leptin level, increased insulin level, and decreased adiponectin concentration were associated with steatosis. In multivariate analysis, steatosis was significantly associated with low adiponectin concentration, age, HCV genotype 3, and aspartate aminotransferase (ASAT) level, whereas steatosis was not associated with leptin, insulin, and BMI.
Conclusion: In chronic HCV patients, hypoadiponectinemia is significantly associated with the development of liver steatosis. The fact that the plasma levels of adiponectin inversely correlate with steatosis in HCV-infected subjects suggests that hypoadiponectinemia may contribute to hepatic steatosis progression and liver injury in this population. One practical implication is that therapy to increase circulating adiponectin concentration, such as overweight reduction or thiazolidinediones, provides the potential to improve steatosis in chronic hepatitis C infection.
Objective
To assess the heterogeneity of liver fat deposition with MR of the liver in type-2 diabetic (T2D) patients.
Methods
We enrolled 121 consecutive T2D patients. The reference standard was ...3.0-T
1
H-MR spectroscopy. Hepatic steatosis was defined as liver fat content (LFC) ≥5.56 %. A triple-echo gradient-echo sequence corrected for T1 recovery and T2* decay was used to calculate LFC in left and right livers and hepatic segments. Analyses were performed using a linear mixed model.
Results
Fifty-nine (48.8 %) patients had liver steatosis, whereas 62 (51.2 %) did not. Steatosis was greater in the right than in the left liver (
P
< 0.0001) mean difference: 1.32 % (range: 0.01–8.75 %). In seven patients (5.8 %), LFC was <5.56 % in one side of the liver, whereas it was ≥5.56 % in the other.
Steatosis of the left and right liver was heterogeneous at the segmental level in both non-steatotic (
P
< 0.001 and
P
< 0.0001 respectively) and steatotic (
P
< 0.0001 and
P
= 0.0002 respectively) patients mean maximum difference: 3.98 % (range: 0.74–19.32 %). In 23 patients (19 %), LFC was <5.56 % in one segment, whereas it was ≥5.56 % in at least one other.
Conclusion
Overall, the mean segmental/lobar variability of steatosis is low. However, segmental variability can sometimes lead to a misdiagnosis.
Key Points
There is a need for methods quantifying steatosis over a large region.
Steatosis is usually greater in the right than left lobe of the liver.
Steatosis within both left and right hepatic lobes is segmentally heterogeneous.
Segmental variability of steatosis can result in misdiagnosis.
Purpose
An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to ...validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use.
Methods
In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications).
Results
Median follow-up lasted 373 days, and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was ≥165 U/L (281 days vs. 850 days;
P
< 0.001). GGT ≥165 U/L (hazard ratio (HR) = 2.06;
P
= 0.02), WHO PS of 2 (HR = 5.4;
P
= 0.002), and tumor size (HR = 1.12;
P
= 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was ≥165 U/L (508 days vs. not reached;
P
< 0.001). GGT ≥ 165 U/L (HR = 3.05;
P
= 0.029), WHO PS of 2 (HR = 12.95;
P
< 0.001), alfa-fetoprotein (HR = 2.9;
P
= 0.01), and tumor size (HR = 1.096;
P
= 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping.
Conclusions
Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT ≥ 165 U/L is independently associated with both shorter TTTF and OS.
The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic ...susceptibility. However, to date, only a few single‐nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409G allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta‐analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio OR per G allele, additive model = 1.77; 95% confidence interval CI: 1.42‐2.19; P = 2.78 × 10−7). This association was more pronounced in ALD (OR = 2.20; 95% CI: 1.80‐2.67; P = 4.71 × 10−15) than in CHC patients (OR = 1.55; 95% CI: 1.03‐2.34; P = 3.52 × 10−2). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development. (Hepatology 2014;59:2170–2177)
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