Katarzyna Szamotulska

Serum markers in early-stage and locally advanced melanoma

The identification of prognostic factors in cutaneous melanoma allows choosing the most effective treatment, especially in group of patients with locoregional disease. Markers related to carcinogenesis and angiogenesis in particular have effect on the course of the disease. The aim of this study was to evaluate clinical utility of vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase 1 (TIMP-1), and YKL-40 in serum of melanoma patients at pathological stages I–III. We included 148 adult patients with melanoma. The median follow-up was 40xa0months. Disease recurrence was observed in 43 patients; 3-year disease-free survival (DFS) rate was 71.7xa0%; 35 patients died; and the 3-year overall survival (OS) rate was 85xa0%. Concentrations of VEGF, MMP-2, MMP-9, TIMP-1, and YKL-40 were measured by ELISA kits. VEGF, MMP-9, TIMP-1, and YKL-40 were significantly higher in group of patients than in controls. Increased concentrations of TIMP-1 were related to patient survival, which in the group of lower and increased TIMP-1, disease-free survival amounted to 81 vs. 61xa0% (pu2009=u20090.014) and overall survival −88 vs. 82xa0% (pu2009=u20090.050), respectively. An increased concentration of YKL-40 was observed in 59xa0% of patients with ulceration and in 26xa0% of patients without ulceration (pu2009=u20090.012). We have found a clinically significant correlation between YKL-40 and MMP-9 (rhou2009=u20090.363; pu2009=u20090.004) as well as YKL-40 and VEGF (rhou2009=u20090.306; pu2009=u20090.018). In melanoma patients at stages I–III, the high concentrations of TIMP-1 in serum predicted adverse prognosis. YKL-40 was associated with ulceration of primary tumor, which is a very important prognostic factor.

Preoperative hypofractionated radiotherapy in the treatment of localized soft tissue sarcomas

BACKGROUNDnThe primary treatment of soft tissue sarcomas (STS) is a radical resection of the tumor with adjuvant radiotherapy. Conventional fractionation of preoperative radiotherapy is 50 Gy in fraction of 2 Gy a day. The purpose of the conducted study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in STS patients.nnnMETHODSn272 patients participated in this prospective study conducted from 2006 till 2011. Tumors were localized on the extremities or trunk wall. Median tumor size was 8.5 cm, 42% of the patients had tumor larger than 10 cm, whereas 170 patients (64.6%) had high grade (G3) tumors. 167 patients (61.4%) had primary tumors. Patients were treated with preoperative radiotherapy for five consecutive days in 5 Gy per fraction, with an immediate surgery. Median follow up is 35 months.nnnRESULTSn79 patients died at the time of the analysis, the 3-year overall survival was 72%. Local recurrences were observed in 19.1 % of the patients. Factors that had a significant adverse impact on local recurrence were tumor size of 10 cm or more and G3 grade. 114 patients (42%) had any kind of treatment toxicity, vast majority with tumors located on lower limbs. 7% (21) of the patients required surgery for treatment of the complications.nnnCONCLUSIONnIn this non-selected group of locally advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (81%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrant further evaluation.

Alterations in markers of bone metabolism and adipokines following a 3-month lifestyle intervention induced weight loss in obese prepubertal children.

BACKGROUNDnAdipokines may influence bone metabolism in children, but this phenomenon is not well understood. Therefore, we studied the relationships between bone markers and adipokines during weight loss in obese children.nnnMATERIALS AND METHODSnWe determined serum leptin, soluble leptin receptor (sOB-R), adiponectin, BALP (bone alkaline phosphatase), CTX-I (C-terminal telopeptide of type I collagen), body composition and bone mineral density (by dual-energy X-ray absorptiometry) in 100 obese prepubertal children before and after 3 months of lifestyle intervention (low-energy diet, physical activity). The control group consisted of 70 non-obese children.nnnRESULTSnObese children had higher BALP activity by about 20% (p<0.001) and similar value of CTX-I compared with non-obese children. After weight loss (-0.96 BMI-SDS mean change), the BALP value in obese patients decreased (p<0.001), whereas CTX-I concentration was unchanged. Changes in BALP were positively correlated with changes in BMI (Body Mass Index) (r=0.352, p<0.001), but not associated with adipokine levels. Trend analysis using SDS-BMI subgroups showed that greater reduction of body mass was associated with a greater decrease of BALP (p=0.035) and leptin values (p<0.001), as well as a greater increase of sOB-R (p<0.003).nnnCONCLUSIONSnObesity during the prepubertal period is associated with an alteration in the adipokines profile and greater whole-body bone mass as a result of increased bone formation rather than reduced bone resorption. Changes in bone metabolism during lifestyle intervention seem to be related to weight loss but not to changes in adipokines. Further studies should elucidate the influence of long-term therapy on bone mass in childhood.

The clinical significance of changes in ezrin expression in osteosarcoma of children and young adults

Ezrin is a protein that functions as a cross-linker between actin cytoskeleton and plasma membrane. Its clinical role in osteosarcoma is unclear. The aim of this study was to investigate, in osteosarcoma, the prognostic value of ezrin expression at biopsy and changes in expression levels after preoperative chemotherapy. Thirty-eight newly diagnosed osteosarcoma patients aged 6–23xa0years were included. At diagnosis, 20 patients had localized disease, the others had distant metastases. Median follow-up was 75xa0months (range 13–135). Ezrin expression was assessed immunohistochemically in biopsy tissue and primary tumour specimens resected after chemotherapy. The influence on survival of changes in ezrin expression after chemotherapy was analysed. Ezrin expression was significantly higher after preoperative chemotherapy and changes compared to biopsy tissue were significantly lower in patients with early progression than in patients with relapse or no further evidence of disease (pxa0=xa00.006 and pxa0=xa00.002, respectively). Similarly, ezrin expression was higher after preoperative chemotherapy and exhibited less change in expression in deceased patients compared to patients surviving more than 5xa0years (both pxa0=xa00.001). Ezrin expression at biopsy was significantly associated with both histopathological aggressiveness (pxa0<xa00.001) and tumour size (pxa0=xa00.037). The results of this study provide evidence that changes in overexpression of ezrin due to preoperative chemotherapy could be a useful predictive and prognostic marker in patients with osteosarcoma.

ADIPOQ -11377C>G Polymorphism Increases the Risk of Adipokine Abnormalities and Child Obesity Regardless of Dietary Intake.

Objective: The aim of the present study was to verify whether selected functional single nucleotide polymorphisms in LEP, LEPR, and ADIPOQ loci are associated with the development of obesity and serum levels of the respective adipokines in prepubertal white children with obesity. Methods: Frequencies of −2548G>A LEP (rs7799039), Q223R (rs1137101) and K656N (rs8129183) LEPR, and −11377C>G (rs266729) and −11426A>G (rs16861194) ADIPOQ polymorphisms were analyzed by restriction fragment length polymorphism in 101 obese (standard deviation score [SDS]-body mass index [BMI] >2) and 67 normal-weight (SDS-BMI <−1u200a+u200a1>) children. Serum adipokine concentrations were measured using the enzyme-linked immunosorbent assay method. Results: The GC/GG genotypes of −11377C>G ADIPOQ polymorphism were associated with a higher risk of obesity (Pu200a=u200a0.022, odds ratio 2.08 [95% confidence interval 1.11–3.90]). Individuals carrying the GG genotype had a higher leptin/total adiponectin ratio by 25% than CC homozygotes (Ptrendu200a=u200a0.05). In the multivariate linear regression model, we found differences among particular genotypes of this polymorphism in concentrations of high molecular weight (HMW) adiponectin (Ptrendu200a=u200a0.043) and HMW/total adiponectin ratio (Ptrendu200a=u200a0.048), with the lowest values in GG homozygotes. Positive correlations between SDS-BMI and dietary reference intake percentage were observed in individuals homozygous for allele C (ru200a=u200a0.403, Pu200a=u200a0.01) and CG heterozygotes (ru200a=u200a0.428, Pu200a=u200a0.004). No significant correlations between both parameters were found in the GG homozygotes. Conclusions: Among the analyzed polymorphisms, only −11377C>G ADIPOQ single nucleotide polymorphism was associated with obesity during the prepubertal period. Adipokine abnormalities coexisting with the lack of relations between SDS-BMI and dietary intake may predict a higher risk of future obesity-related disorders in obese children carrying the GG genotype than in those with other genotypes.

The effect of weight loss on body composition, serum bone markers, and adipokines in prepubertal obese children after 1-year intervention

ABSTRACT Purpose/Aim: The influence of weight loss on bone turnover and bone quality in childhood remains controversial, but it may implicate interactions between adiposity and bone metabolism. Therefore, we studied the relationships between bone markers and adipokines during weight loss in obese children. Materials and Methods: We determined serum leptin, soluble leptin receptor, adiponectin, bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteocalcin (OC), carboxylated-OC (Gla-OC), undercarboxylated-OC (Glu-OC), sclerostin, body composition, and bone mineral density (BMD) in 40 obese prepubertal children before and after therapy. The control group, matched for sex and age, consisted of 40 non-obese children. Results: We found that values of the total body less head-bone mineral content (TBLH-BMC) and TBLH-BMD were significantly increased, but TBLH-BMD Z-score was decreased by 25% (p = 0.002) in obese children with weight loss after therapy. We observed increases of CTX-I to OC ratio (p = 0.009), and Gla-OC concentrations (p = 0.049). Changes in TBLH-BMD Z-score in patients were positively correlated with changes in BMI Z-score (p = 0.001), percentage of fat mass (p = 0.004), and BALP activity (p = 0.01). Changes in BALP activity were negatively correlated (p < 0.001) with changes in adiponectin concentrations, while changes in sclerostin levels were positively correlated (p = 0.001) with leptin changes. Conclusions: We suggest that alterations in adipokines metabolism were associated with a lower rate of bone mineral accrual as a result of decreased bone formation rather than increased bone resorption. The lower rate of bone mass accrual in weight losing children may be an effect of reduced BALP levels related to increase in adiponectin levels.

Comparison of body composition and adipokine levels between thin and normal-weight prepubertal children ☆

OBJECTIVEnThinness can have substantial consequences for child development and health. Adipokines, including leptin and adiponectin, play a significant role in the regulation of important metabolic functions. The aim of this study was to investigate associations between body composition and serum leptin and adiponectin levels in thin and normal-weight children.nnnMETHODSnThe authors examined 100 healthy prepubertal children, who were divided into two subgroups: thin (n=50) and normal-weight children (n=50). Body composition was assessed by dual-energy X-ray absorptiometry. Serum concentrations of adipokines were determined by immunoenzymatic assays.nnnRESULTSnThin children had a similar body height but significantly lower (p<0.0001) body weight, body mass index, fat mass, lean mass, and bone mineral content compared with normal-weight children. Serum concentrations of leptin were about 2-fold lower (p<0.0001) in thin vs. normal-weight subjects. Serum levels of total adiponectin, adiponectin multimers, and soluble leptin receptor (sOB-R) were similar in both groups. The leptin/soluble leptin receptor ratio and leptin/adiponectin ratios were lower (p<0.0001) in thin vs. normal-weight children. In both groups of children, it was found that body composition parameters were positively related with leptin but not with adiponectin levels. Additionally, bone mineral content was positively related with body mass index, fat mass, lean mass, and leptin level in thin and normal-weight children.nnnCONCLUSIONSnPrepubertal thin children have disturbances in body composition and adipokine profile. Early recognition of thinness and determination of body composition parameters and adipokine levels can be useful in medical and nutritional care of thin children for the optimization of bone mineral accrual.

Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib

Introduction: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. Methods: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. Results: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio ≤2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 (p < .001); median PFS was 59.4 vs 32.7 (p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor (KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). Conclusions: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib.

The Assessment of Bone Regulatory Pathways, Bone Turnover, and Bone Mineral Density in Vegetarian and Omnivorous Children

Vegetarian diets contain many beneficial properties as well as carry a risk of inadequate intakes of several nutrients important to bone health. The aim of the study was to evaluate serum levels of bone metabolism markers and to analyze the relationships between biochemical bone markers and anthropometric parameters in children on vegetarian and omnivorous diets. The study included 70 prepubertal children on a lacto-ovo-vegetarian diet and 60 omnivorous children. Body composition, bone mineral content (BMC), and bone mineral density (BMD) were assessed by dual-energy X-ray absorptiometry. Biochemical markers—bone alkaline phosphatase (BALP), C-terminal telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), nuclear factor κB ligand (RANKL), sclerostin, and Dickkopf-related protein 1 (Dkk-1)—were measured using immunoenzymatic assays. In vegetarians, we observed a significantly higher level of BALP (p = 0.002) and CTX-I (p = 0.027), and slightly lower spine BMC (p = 0.067) and BMD (p = 0.060) than in omnivores. Concentrations of OPG, RANKL, sclerostin, and Dkk-1 were comparable in both groups of children. We found that CTX-I was positively correlated with BMC, total BMD, and lumbar spine BMD in vegetarians, but not in omnivores. A well-planned vegetarian diet with proper dairy and egg intake does not lead to significantly lower bone mass; however, children following a lacto-ovo-vegetarian diet had a higher rate of bone turnover and subtle changes in bone regulatory markers. CTX-I might be an important marker for the protection of vegetarians from bone abnormalities.

Changes in Oxidized Low-Density Lipoprotein Rather Than in Paraoxonase1 are Associated with Changes in the Leptin/Leptin Receptor Ratio in Obese Children During Weight-Loss Therapy

BACKGROUNDnOxidative stress and impaired production of adipokines in childhood obesity contribute to the development of obesity-related disorders. We assessed whether weight loss after lifestyle intervention alters biomarkers of oxidant/antioxidant status, and whether these alterations are associated with changes in anthropometric parameters and adipokines in obese children.nnnMATERIALS AND METHODSnWe determined oxidized low-density lipoprotein (ox-LDL), anti ox-LDL, paraoxonase1 (PON1), leptin, soluble leptin receptor (sOB-R), total adiponectin, high molecular weight adiponectin concentrations and body composition (by dual-energy X-ray absorptiometry) in 60 prepubertal obese children (Body Mass Index, BMI Z-score>2) before and after a 3-month intervention. The control group consisted of 44 non-obese children (BMI Z-score<-1+1>).nnnRESULTSnOx-LDL, ox-LDL/LDL, and anti ox-LDL concentrations as well as leptin to sOb-R ratio were reduced (p<0.001; p=0.018; p<0.001; p<0.001, respectively) in obese children with weight loss (BMI Z-score change≤-0.5) after a 3-month therapy. These parameters were stable in the obese group without weight loss (BMI Z-score change>-0.5). Changes in ox-LDL and PON1 levels in all obese children correlated positively with changes in the leptin to sOB-R ratio (r=0.400, p=0.002; r=0.304, p=0.028, respectively). After adjustment for changes in BMI Z-score in the multivariate regression model, the association between the changes in ox-LDL levels and changes in the leptin/sOb-R ratio remained statistically significant (β=0.184, p=0.014).nnnCONCLUSIONSnWe found out that a 3-month lifestyle intervention associated with weight loss improves the oxidant/antioxidant balance and promotes anti-atherogenic changes in prepubertal obese children in a way dependent on the alterations in the leptin to sOB-R ratio.