Common Variants in Osteopontin and CD44 Genes as Predictors of Treatment Outcome in Radiotherapy and Chemoradiotherapy for Non-Small Cell Lung Cancer.

Osteopontin (OPN)-CD44 signaling plays an important role in promoting tumor progression and metastasis. In cancer, OPN and CD44 overexpression is a marker of aggressive disease and poor prognosis, and correlates with therapy resistance. In this study, we aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in the OPN and CD44 genes with clinical outcomes in 307 non-small cell lung cancer (NSCLC) patients treated with radiotherapy or chemoradiotherapy. The potential impact of the variants on plasma OPN levels was also investigated. Multivariate analysis showed that OPN rs11730582 CC carriers had a significantly increased risk of death (p = 0.029), while the CD44 rs187116 A allele correlated with a reduced risk of locoregional recurrence (p = 0.016) in the curative treatment subset. The rs11730582/rs187116 combination was associated with an elevated risk of metastasis in these patients (p = 0.016). Furthermore, the OPN rs1126772 G variant alone (p = 0.018) and in combination with rs11730582 CC (p = 7 × 10-5) was associated with poor overall survival (OS) in the squamous cell carcinoma subgroup. The rs11730582 CC, rs187116 GG, and rs1126772 G, as well as their respective combinations, were independent risk factors for unfavorable treatment outcomes. The impact of rs11730582-rs1126772 haplotypes on OS was also observed. These data suggest that OPN and CD44 germline variants may predict treatment effects in NSCLC.

Blood serum proteins as biomarkers for prediction of survival, locoregional control and distant metastasis rate in radiotherapy and radio-chemotherapy for non-small cell lung cancer.

BACKGROUND: Several studies have documented that blood biomarkers can improve basic prognostic models in radiotherapy and radio-chemotherapy for non-small cell lung cancer. The current study evaluated the prognostic impact of six markers focusing on their utility in homogenous subsets, compared to the significance in a large heterogeneous group. METHODS: Blood samples of 337 patients who were referred for curative or palliative external beam thoracic radiotherapy for non-small cell lung cancer were collected. The concentration of osteopontin (OPN), vascular endothelial growth factor (VEGF), erythropoetin (EPO), high mobility group box 1 protein (HMGB1), insulin-like growth factor 1 (IGF-1) and platelet-derived growth factor (PDGF) in serum were measured by ELISA assay and the prognostic potential was assessed using univariable and multivariable survival models. RESULTS: Multivariable analysis revealed that out of several variables studied six dichotomized features: namely: cigarette smoking, lack of chemotherapy, palliative doses of radiotherapy, high OPN concentration, advanced T stage and high VEGF concentration had a highly significant (p < 0.005) and independent influence on overall survival in the group of 337 patients. In a subset of patients treated with curative radio-chemotherapy or radiotherapy (N = 148) tumor pathology, EPO concentration and VEGF concentration, significantly and independently influenced overall survival. In a subset of patients with squamous cell cancer (N = 206) OPN had a highly significant impact on overall survival. In contrast, in a subset of patients with nonsquamous histology (N = 131) only VEGF had a significant influence on survival. CONCLUSIONS: Blood serum proteins appear to be clinically useful prognosticators of overall survival in radio-chemotherapy and radiotherapy for non-small cell lung cancer. In unselected heterogeneous groups, dichotomized concentrations of OPN and VEGF emerged among the strongest independent prognosticators of overall survival. VEGF and EPO concentration (dichotomized) were found to be independent prognostic factors among the patients treated with curative doses of radiotherapy. The utility of OPN as a prognostic marker appeared restricted to the patients with squamous histology.

Therapy-Related Changes in the Serum Proteome Patterns of Early Stage Breast Cancer Patients with Different Outcomes.

Adjuvant chemo- and/or radiotherapy is applied in a majority of patients treated for early stage breast cancer, although only a small percentage of these individuals are at high risk of metastasis or recurrence. Hence, knowledge of the biomarkers associated with the risk of disease progression might facilitate the planning of an optimal therapy and protect many patients from the toxicity of unnecessary treatment. In this study, we characterized the serum proteome of patients diagnosed with early-stage breast cancer, exhibiting either no evidence of disease five years after the end of therapy or suffering from metastasis, relapse or a second cancer during the corresponding follow-up. Samples collected before treatment and one year after the end of therapy, when no clinical symptoms of a treatment failure was evidenced, were analyzed using two classical proteomics approaches: LC-MS/MS and 2D-PAGE. A total of 42 proteins with relative quantities that were significantly different between pre- and post-treatment samples were identified in either group of patients; however, the observed changes were more frequent in the treatment-failure group. Among the posttreatment samples, 30 proteins were upregulated, and 10 proteins were downregulated, while 11 proteins were upregulated, and eight proteins were downregulated in the control group. Moreover, several proteins exhibited different patterns of changes in both groups of patients. For example, haptoglobin expression increased in the treatment-failure group but decreased in the control group (this pattern of changes was confirmed using an immunoassay). Notably, proteins affected in posttreatment samples in either group of patients could be associated with different molecular and cellular functions, including angiogenesis, blood coagulation and wound healing in the treatment-failure group and cell adhesion and cell death in the control group.

Radiation-induced injury of the exocrine pancreas after chemoradiotherapy for gastric cancer.

BACKGROUND AND PURPOSE: The pancreas is located almost entirely within the treatment area for radiotherapy of gastric cancer. The aim of this study was to analyze radiation-induced injury of the exocrine pancreas. MATERIAL AND METHODS: The study included 127 gastric cancer patients, who underwent preoperative or postoperative chemoradiotherapy. A total dose of 45 Gy was given in 25 fractions. Concurrent chemotherapy was 5-fluorouracil-based. Lipase and α-amylase were assayed before, during and after treatment. RESULTS: Lipase and α-amylase deficiencies were found in 48.2% and 19.7% of patients, respectively. In the univariant analysis, age and pretreatment α-amylase and lipase activities influenced on risk of injury of the exocrine pancreas (p<0.05). Younger patients (<65 years) had a lower risk of hypoamylasemia than older patients. The probability of insufficiency was lower than 0.2 for patients with pretreatment α-amylase and lipase activities above 50 U/L and 55 U/L, respectively. The multivariate analyses of the time to hypolipasemia showed that only pretreatment lipase activity was significant. CONCLUSIONS: Gastric cancer patients have an increased risk of exocrine pancreatic insufficiency after chemoradiotherapy. Thus, the pancreas should be regarded as an OAR. Measuring lipase activity should be the standard for assessing radiation-induced pancreatic injury.

The VEGFR2, COX-2 and MMP-2 polymorphisms are associated with clinical outcome of patients with inoperable non-small cell lung cancer.

Certain common inherited variations in genes involved in tumor angiogenesis, progression and metastasis may contribute to cancer therapy outcome and prognosis by altering the gene expression and protein activity. In this report, we examined the effect of functional polymorphisms in MMP-1, MMP-2, MMP-3, VEGF, VEGFR2, FGFR4 and COX-2 genes on overall (OS) and progression-free survival (PFS) of 350 Caucasian patients with inoperable non-small cell lung cancer (NSCLC). The results of multivariate analysis indicated that VEGFR2 -906C and COX-2 -1195G alleles were strongly associated with poor OS and PFS (p = 0.002 and 0.015, respectively, for OS; p = 0.009 and 0.015, respectively, for PFS), while MMP-2 -1306 T allele carriers had significantly reduced PFS (p = 0.010). Moreover, an increased risk of death and progression was significantly associated with the number of adverse alleles for VEGFR2/COX-2 (p = 0.0005 for OS and 0.0006 for PFS in >1 adverse allele carriers) and VEGFR2/COX-2/MMP-2 combinations (p = 0.0003 for OS and 0.0001 for PFS in patients with >2 adverse alleles). Finally, VEGFR2 TC/CC, COX-2 AG/GG and MMP-2 CT/TT genotypes as well as "at risk" allele combinations were identified as independent predictors of unfavorable OS and PFS in the group. In conclusion, the data suggest that selected VEGFR2, COX-2 and MMP-2 polymorphisms may be potential prognostic markers in unresectable NSCLC treated with radiotherapy with or without chemotherapy, although further validation studies are warranted to confirm our observations.

[Usefulness of osteopontin (OPN) determinations in ovarian cancer patients who underwent first-line chemotherapy]. / Przydatnosc oznaczen stzenia osteopontyny (OPN) u chorych na raka jajnika poddanych chemioterapii I rzutu.

INTRODUCTION: Currently CA 125 is a marker of choice for monitoring ovarian cancer Nonetheless, scientists are still searching for new markers, which could provide additional information for the evaluation of treatment, especially in patients with normal CA 125 levels, despite the progression of the disease. According to the latest reports, OPN can be a potential new marker: AIM: Estimation of usefulness of OPN determinations in the monitoring of ovarian cancer patients. MATERIAL AND METHODS: The study included 54 ovarian cancer patients, undergoing chemotherapy Markers were measured before, during and after treatment. The dynamics of the change of OPN levels was shown on line graphs, using Microsoft Excel programme. Statistical analysis was performed by Kaplan-Meier method and log-rank test. RESULTS: 44% of patients from the study group were found to have low CA 125 levels. In these cases only the increase of OPN concentration indicated recurrence of the disease. In 43% of patients the high initial CA 125 and OPN levels decreased during chemotherapy and complete regression was stated in these patients. Nevertheless, in 13/17 patients a repeated increase of OPN concentration signalling the recurrence, earlier than CA 125 and clinical recurrence manifestation, was observed. In 13% of patients high initial levels of markers did not decrease during chemotherapy which correlated with the progression of the disease. Our study showed that only the CA 125 levels had a significant influence (p=0.00063) on the disease-free survival time. CONCLUSIONS: Our data suggest a potential usefulness of the OPN determinations in estimating ovarian cancer recurrence. Nonetheless, there was no correlation between the initial OPN concentration and the disease-free survival time.

[Usefulness of the SCC, CEA, CYFRA 21.1, and CRP markers for the diagnosis and monitoring of cervical squamous cell carcinoma]. / Przydatnosc oznaczania markerów: SCC, CEA, CYFRA 21.1 oraz CRP w diagnostyce i monitorowaniu plaskonablonkowego raka szyjki macicy.

OBJECTIVE: To determine the usefulness of the SCC, CEA, CYFRA 21.1, and CRP markers for the diagnosis and early monitoring after treatment completion in women diagnosed with cervical squamous cell carcinoma. MATERIAL AND METHODS: Serum of 140 patients with diagnosed cervical squamous cell carcinoma was investigated. The women with the advanced stage of cervical carcinoma (FIGO IIIB) were divided into two subgroups: with positive and negative outcomes of the treatment. Levels of SCC, CEA, CYFRA 21.1, and CRP were measured before the treatment and immediately after the completion of radiotherapy. Immunochemical methods were used to measure proteins in both serum and plasma samples. RESULTS: 75% of the markers measured were within the reference range for FIGO stage I. The marker levels rose with the clinical progression of the disease. The median levels of all markers and the CRP levels in both groups were compared before the treatment. Only in case of CEA a considerable variation between these groups was observed. Elevated levels of CRP were observed twice more often in patients with negative outcome of the treatment. After the treatment, a significant decrease in all marker levels was observed in patients with positive outcome when compared to the levels at the moment of the diagnosis. CONCLUSIONS: SCC, CEA and CYFRA 21.1 markers show low diagnostic sensitivity in early stages of the disease in women diagnosed with cervical squamous cell carcinoma. The concentration of markers measured before the treatment, particularly CEA, may prove to be of prognostic value for women diagnosed with advanced cervical cancer. Certain markers may prove useful in the assessment of the therapy used. Measuring the CRP before the treatment may aid the prognosis of response to treatment in these patients.

[Evaluation of selected serum protein markers as early detectors of ovarian cancer]. / Ocena mozliwosci wczesnej diagnostyki raka jajnika na podstawie oznaczen wybranych bialek surowicy.

OBJECTIVE: an attempt to determine the value of the simultaneous quantization of osteopontin (OPN), insulin-growth factor II (IGF II), leptin, prolactin and CA 125 for early detection of ovarian cancer. MATERIALS AND METHODS: Prospective study of 69 women including: 15 females with ovarian cancer; 33 females with benign ovarian neoplasm; 21 disease-free females; The levels of IGF II, prolactin, leptin and CA 125 were determined in serum, while the level of OPN was checked in plasma. RESULTS: The concentrations of IGF II, leptin and prolactin do not let us distinguish among disease-free females, females with ovarian cancer and those with benign ovarian neoplasms on the basis of biochemical markers. The comparison of OPN and CA 125 levels showed significant differences in the concentrations of the biomarkers between disease-free females and females with ovarian cancer, as well as between females with benign ovarian neoplasms and females with ovarian cancer. The ROC curves for two groups: disease-free females and females with ovarian cancer, proved the diagnostic value of OPN and CA 125. CONCLUSIONS: The simultaneous quantization of OPN, IGF II leptin and prolactin has not been proved useful for the early detection of ovarian cancer. Statistically significant increase of OPN & CA 125 levels was noted in case of women with ovarian cancer diagnosed through microscopic examination. The analysis of ROC curves showed comparable diagnostic usefulness of both markers. Quantization of OPN may have an additional value for treatment monitoring of women diagnosed with ovarian cancer but with concentration of CA 125 within the reference value.

[Risk of distant metastases after postoperative radiation therapy for locally advanced laryngeal cancer]. / Ocena ryzyka przerzutów odleglych u chorych na raka krtani napromienianych pooperacyjnie.

PURPOSE: To evaluate the prognostic factors for the risk of distant metastases after postoperative radiotherapy for laryngeal cancer. MATERIAL AND METHODS: Medical records of 267 patients cancer treated between 1997 and 2003 were analyzed. All pts had locally advanced squamous cell laryngeal cancer treated with surgery and postoperative radiotherapy. Metastasis Free Survival was analyzed using Kaplan-Meier method. A multivariate Cox proportional hazard model and logistic regression model was used to evaluated influence of the following variables on MFS and the ultimate risk of metastases: age, sex, localization, TN stage, HGB before and at the end radiotherapy, total radiation dose, dose per fraction, overall treatment time, interval surgery-radiation time, pathological margins and positive nodes in surgical specimen. RESULTS: The crude incidence of distant metastases was 12% (33/267 pts). One year, 3-year, 5-year actuarial metastases free survival were 95%, 85% and 84% respectively. The lungs and bones were the most common sites of metastases (58% and 33% respectively), whereas metastases to liver (6%) and brain (3%) were rare. Localization of cancer (glottic vs. supraglottic) and number of positive lymph nodes at pathological staging significantly and independently affected MFS. CONCLUSIONS: Number of positive lymph nodes in pathological specimen and site of primary cancer (glottic vs. supraglottic) significantly and independently predict a risk of distant metastases in combined modality treatment for laryngeal cancer.