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Background: Mutations in the genes encoding for IDH1 and IDH2 occur in ~20% of ICC patients (pts), and they lead to the production of the oncometabolite 2HG. We examined whether ...serum 2HG levels in IDHm ICC pts may 1) serve as a surrogate biomarker for IDH status, 2) correlate with tumor burden, and 3) correlate with circulating proangiogenic biomarkers. Methods: Blood samples from 33 ICC pts 11 IDHm, 22 IDH wild-type (IDHwt) of different AJCC stages from MGH and 39 surgically resected ICC patients (7 IDHm, 32 IDHwt) from HKU were analyzed for serum 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry. Eight circulating proangiogenic biomarkers were measured in plasma using multiplex ELISA. Results: In the MGH cohort, median serum 2HG levels were significantly elevated in IDHm (478 ng/ml interquartile range 174–643) versus IDHwt ICC pts (118ng/ml 68–160)(p<0.001). Similarly, in the HKU cohort, the pre-resection median serum 2HG levels were significantly elevated in IDHm (343ng/ml 192–596) versus IDHwt ICC pts (56ng/ml 42–81) (p<0.0001). The area under ROC curve for prediction of an IDH mutation using 2HG was 93%; with a threshold of 2HG≥170ng/ml, the sensitivity was 83% and specificity was 90%. IDH2 mutations were more frequent in the HKU cohort (3/7, 43%) compared with the MGH cohort (0/11, 0%) (p<0.05), but 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. 2HG levels correlated directly with tumor burden (Spearman’s rho=0.89; p<0.05) in the HKU cohort. Median plasma levels of PlGF—a growth factor from the VEGF-family—were higher in IDHm (35pg/ml 33–40) versus IDHwt ICC pts (median 26pg/ml 24–34) from the HKU cohort (p<0.05). No other associations were seen between proangiogenic biomarkers and IDH status. Conclusions: IDHm ICC pts had significantly higher serum 2HG levels compared to IDHwt ICC pts. High serum 2HG correlated with increased tumor burden. Pre-resection circulating PlGF levels were higher in IDHm ICC versus IDHwt pts. These data support further exploration of circulating 2HG as potential surrogate and response biomarker in IDHm ICC.
Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer ...metastasis is unclear. Here, we identified a subpopulation of CD26 super(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26 super(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26 super(+) cells, but not CD26 super(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26 super(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy.
In contrast to normal differentiated cells that depend on mitochondrial oxidative phosphorylation for energy production, cancer cells have evolved to utilize aerobic glycolysis (Warburg's effect), ...with benefit of providing intermediates for biomass production. MicroRNA-122 (miR-122) is highly expressed in normal liver tissue regulating a wide variety of biological processes including cellular metabolism, but is reduced in hepatocellular carcinoma (HCC). Overexpression of miR-122 was shown to inhibit cancer cell proliferation, metastasis, and increase chemosensitivity, but its functions in cancer metabolism remains unknown. The present study aims to identify the miR-122 targeted genes and to investigate the associated regulatory mechanisms in HCC metabolism. We found the ectopic overexpression of miR-122 affected metabolic activities of HCC cells, evidenced by the reduced lactate production and increased oxygen consumption. Integrated gene expression analysis in a cohort of 94 HCC tissues revealed miR-122 level tightly associated with a battery of glycolytic genes, in which pyruvate kinase (PK) gene showed the strongest anti-correlation coefficient (Pearson r = -0.6938, p = <0.0001). In addition, reduced PK level was significantly associated with poor clinical outcomes of HCC patients. We found isoform M2 (PKM2) is the dominant form highly expressed in HCC and is a direct target of miR-122, as overexpression of miR-122 reduced both the mRNA and protein levels of PKM2, whereas PKM2 re-expression abrogated the miR-122-mediated glycolytic activities. The present study demonstrated the regulatory role of miR-122 on PKM2 in HCC, having an implication of therapeutic intervention targeting cancer metabolic pathways.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Recurrent peptic ulcer after previous gastric operation is a difficult surgical problem and abdominal re‐operation is associated with significant morbidity, mortality and recurrence rate.
...Methods: The authors report on five patients with recurrent ulcers who, after previous gastric operation, were treated with thoracoscopic vagotomy.
Results: All patients tolerated the procedure well without complications, and the median hospital stay was 5 days. Endoscopy confirmed healing of the ulcers in all patients. Pre‐operative and postoperative gastric acid studies showed a significant postoperative reduction in both basal and maximal acid output (P < 0.05). In a follow‐up period of 18–33 months, one patient had a recurrent ulcer presenting with bleeding. Gastric biopsy revealed presence of Helicobacter pylori and repeated gastroscopy after a course of H. pylori eradication treatment showed a healed ulcer. The other four patients were asymptomatic.
Conclusions: We conclude that thoracoscopic vagotomy is a simple and safe procedure for the treatment of recurrent ulcers after previous gastric operation, but the long‐term results need further assessment.
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