Tumor location determines midkine level and its association with the disease progression in colorectal cancer patients: a pilot study

Purpose

The purpose of this study was to evaluate midkine, multipotential cytokine, and growth factor in colorectal cancer (CRC) stratified by tumor location.

Methods

Midkine was assessed immunoenzymatically in paired cancerous and noncancerous tissues from 53 CRCs and referred to CRC stage, tumor location, and size, and circulating cytokine levels.

Results

Midkine was higher in cancerous versus noncancerous tissue in 98?% cases (424.2 vs. 31.1?pg/mg, p?p?=?0.005) due to higher midkine level in noncancerous rectal than colonic tissue (45.5 vs. 26.2?pg/mg, p?=?0.074). Tumor location affected midkine association with CRC stage. Midkine fold change was higher in advanced stages of rectal cancers (16.8 vs. 5.3, respectively in III/IV vs. I/II, p?=?0.013), while it tended to be lower in colonic ones (25.3 vs. 47.8, p?=?0.134). In addition, fold change in midkine level was higher in rectal N1 than N0 cancers (17.3 vs. 16.5, p?=?0.032), while it tended to be lower in colonic cancers (23.6 vs. 50.1, p?=?0.085). Midkine negatively correlated with tumor size (r?=?0.40, p?=?0.017), while it tended to positively correlate with its serum levels (r?=?0.45, p?=?0.081).

Conclusions

Midkine is differently expressed in tumors arising from colonic and rectal mucosa, where it may play diverse roles in carcinogenesis. High midkine expression in noncancerous rectal mucosa might contribute to, a characteristic for rectal cancers, higher incidence of local recurrence. Divergent expression of midkine and its association pattern ought to be taken into account while designing midkine-directed therapies for CRC.     

FGF23 contributes to insulin sensitivity in obese adolescents - preliminary results

Fibroblast growth factor‐23 (FGF23) is a hormonal regulator of circulating phosphate and vitamin D levels. Recent investigations revealed that besides a key role in the pathogenesis of calcium–phosphorus disorders, in some patients FGF23 may be an indicator of cardiovascular complications. As a ‘hormone‐like’ factor, it may also be involved in some metabolic processes, especially in the metabolism of glucose and fat. Its potential contribution to metabolic syndrome (MS) development has not been confirmed yet. Objective The study was to examine the possible correlations between FGF23 serum levels and body composition, blood pressure and selected parameters of glucose, insulin and fat metabolism in adolescents with simple obesity. Patients and design In 68 (35 female) adolescents (mean age 13·9 years) with simple obesity [mean BMI SDS 4·9 (95% CI 4·4–5·4)], the levels of FGF23, total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol and triglycerides were measured. Standard oral glucose tolerance tests were performed with the assessment of fasting and after 120′ postload glucose and insulin levels; the insulin resistance index HOMA‐IR was calculated. Results Regardless of gender, there was a significant inverse correlation between FGF23 and fasting insulin level (r = ?0·3), as well as HOMA‐IR (r = ?0·29). Multiple regression model showed the independent association between FGF23 and HOMA‐IR. Conclusion FGF23 seems to be a novel factor contributing to insulin sensitivity. Further investigations are needed to define its role in the development of MS.     

Prognostic impact of high ABC transporter activity in 111 adult acute myeloid leukemia patients with normal cytogenetics when compared to FLT3, NPM1, CEBPA and BAALC

ATP-binding cassette transporter (and specially P-glycoprotein) activity is a well known prognostic factor in acute myeloid leukemia, but when compared to other molecular markers its prognostic value has not been well studied. Here we study relationships between this activity, fms-like tyro-sine kinase 3(FLT3/ITD), nucleophosmin(NPM1), CAAT-enhancer binding protein alpha(CEBPα), and brain and acute leukemia cytoplasmic protein (BAALC), in 111 patients with normal cytogenetics who underwent the same treatment, and evaluate its prognostic impact. Independent factors for survival were age (P=0.0126), ATP-binding cassette transporter activity (P=0.018) and duplications in the fms-like tyrosine kinase 3 (P=0.0273). In the 66 patients without fms-like tyrosine kinase 3 duplication and without nucleophosmin mutation, independent prognostic factors for complete remission achievement and survival were age and ATP-binding cassette transporter activity. In conclusion, ATP-binding cassette transporter activity remains an independent prognostic factor, and could assist treatment decisions in patients with no nucleophosmin mutation and no fms-like tyrosine kinase 3 duplication.     

Treatment of undifferentiated embryonal sarcoma of the liver in children—single center experience

Background

Undifferentiated embryonal sarcoma of the liver (UESL) represents less than 5% of all malignant hepatic tumors in childhood. It is considered an aggressive neoplasm with an unfavorable prognosis. The aim of this paper is to present a single center experience in the treatment of children with UESL.

Materials and methods

Ten children with UESL were treated between 1981 and 2012. Age at diagnosis ranged from 4 months to 17 years (median age, 6 years and 9 months). Surgery after neoadjuvant chemotherapy (CHT) was performed in 7 patients, and in 3 patients primary surgery was done. Adjuvant chemotherapy was administered in all 10 patients (CYVADIC, CAV, CAV/ETIF/IF + ADM, CDDP/PLADO). Right hemihepatectomy was performed in 1 patient, extended right hemihepatectomy in 6, and partial resection of the right lobe (segments V-VI, segment V) in 2 patients. One patient with unresectable tumor affecting both lobes was listed for liver transplantation (LTx).

Results

Follow-up from diagnosis ranged from 50 to 222 months (mean 138 months). Among 9 patients treated with partial liver resection, distant metastases/local recurrence was not observed in any, and disease-free survival in this group is 100% (9 patients alive). The patient that underwent liver transplantation died of multiorgan failure 4 months postoperatively.However, this patient was misdiagnosed as having hepatoblastoma (HBL) and received PLADO chemotherapy. The overall survival rate is 90%.

Conclusion

Excellent results with long-term survival can be achieved in children with UESL with conventional therapy, including a combination of neoadjuvant and adjuvant chemotherapy and surgery, even in large extensively growing tumors.     

Downregulation of CPPED1 Expression Improves Glucose Metabolism In Vitro in Adipocytes

We have previously demonstrated that the expression of calcineurin-like phosphoesterase domain containing 1 (CPPED1) decreases in adipose tissue (AT) after weight reduction. However, the function of CPPED1 in AT is unknown. Therefore, we investigated whether the change in CPPED1 expression is connected to changes in adipocyte glucose metabolism. First, we confirmed that the expression of CPPED1 decreased after weight loss in subcutaneous AT. Second, the expression of CPPED1 did not change during adipocyte differentiation. Third, CPPED1 knockdown with small interfering RNA increased expression of genes involved in glucose metabolism (adiponectin, adiponectin receptor 1, and GLUT4) and improved insulin-stimulated glucose uptake. To conclude, CPPED1 is a novel molecule involved in AT biology, and CPPED1 is involved in glucose uptake in adipocytes.Lifestyle modification improves glucose metabolism and results in a substantial reduction in the risk of type 2 diabetes in the long-term (1). In searching new putative genes related to obesity and type 2 diabetes, we have previously demonstrated a multitude of changes in adipose tissue (AT) gene expression in response to weight reduction in individuals with metabolic syndrome (2,3). Among the downregulated genes was calcineurin-like phosphoesterase domain containing 1 (CPPED1) (2); its function in AT is completely unknown.Therefore, we continued to study the role of CPPED1 in AT in more detail. Interestingly, the experiment using a Simpson-Golabi-Behmel syndrome (SGBS) cell strain demonstrated an impact of CPPED1 small interfering RNA (siRNA) on insulin-stimulated glucose uptake in mature adipocytes. Overall, the results demonstrate that CPPED1 is a novel molecule expressed in AT and is related to adipocyte function.     

The use of calcium phosphate cement in vertebroplasty of the base of odontoid process

The authors describe the use of bone cement containing calcium phosphate for vertebroplasty of the cavity in the base of odontoid process. A 23-year-old female patient was operated on by incision in lateral cervical area (anterior open access). After a blunt dissection, the working cannula (Kyphon) was introduced under fluoroscopic guidance through the C2 vertebral body to the cavity in the base of the odontoid process. Intraoperatively biopsy of the lesion was taken and histopathological examination excluded the presence of neoplasm. The cavity, presumably haemangioma, was successfully filled with calcium phosphate bone cement KyphOs? FS (Kyphon). The proper filling without paravertebral cement leak was confirmed by postoperative computed tomography (CT). The CT and magnetic resonance imaging performed 9 months after the procedure showed that cement was still present in the cavity. This is the first use of calcium phosphate cement to conduct the vertebroplasty of C2 vertebra.     

GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis

High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.     

Impact of genetic variants of selected cytochrome P450 isoenzymes on pharmacokinetics and pharmacodynamics of clopidogrel in patients co-treated with atorvastatin or rosuvastatin

Impaired antiplatelet effect of clopidogrel (CLP) can result from drug-drug interactions and genetic polymorphisms of drug-metabolizing enzymes. The aim of the study was to evaluate the effect of genetic polymorphisms of ABCB1 and the selected cytochrome P450 isoenzymes on the pharmacodynamics and pharmacokinetics of CLP and its metabolites in patients co-treated with atorvastatin or rosuvastatin. The study involved 50 patients after coronary angiography/angioplasty treated with CLP and atorvastatin (n = 25) or rosuvastatin (n = 25) for at least 6 months. Plasma concentrations of CLP, diastereoisomers of thiol metabolite (inactive H3 and active H4), and inactive CLP carboxylic acid metabolite were measured by UPLC-MS/MS method. Identification of the CYP2C19*2, CYP2C19*17, CYP3A4*1G, CYP1A2*1F, and ABCB1 C3435T genetic polymorphisms was performed by PCR-RFLP, while platelet reactivity units (PRU) were tested using the VerifyNow P2Y12 assay. There were significant differences in the pharmacokinetic parameters of the H4 active metabolite of CLP in the atorvastatin and rosuvastatin group divided according to their CYP2C19 genotype. There were no significant associations between CYP3A4, CYP1A2, and ABCB1 genotypes and pharmacokinetic parameters in either statin groups. In the multivariate analysis, CYP2C19*2 genotype and non-genetic factors including BMI, age, and diabetes significantly affected platelet reactivity in the studied groups of patients (P < 0.01). In the atorvastatin group, CYP2C19*2, CYP3A4*1G, and ABCB1 C3435T TT genotypes were independent determinants of PRU values (P < 0.01). The CYP2C19*2 allele is the primary determinant of the exposition to the H4 active metabolite of clopidogrel and platelet reactivity in patients co-treated with atorvastatin or rosuvastatin.