Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin ...concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our study included 265 MM patients. Serum calretinin concentration was determined using ELISA. Patients were genotyped for seven polymorphisms in
,
,
,
, and
using competitive allele-specific PCR. Nonparametric tests, logistic regression, and survival analysis were used for statistical analysis. Higher serum calretinin concentration was associated with shorter progression-free (PFS) (HR = 1.18 (1.02-1.37),
= 0.023) and overall survival (OS) (HR = 1.20 (1.03-1.41),
= 0.023), but the association was not significant after adjusting for clinical factors (HR = 1.05 (0.85-1.31),
= 0.653 and HR = 1.06 (0.84-1.34),
= 0.613, respectively).
rs3801339 and
rs3807348 were associated with survival even after adjustment (HR = 1.76 (1.17-2.64),
= 0.007 and HR = 0.65 (0.45-0.95),
= 0.028, respectively). Calretinin concentration was higher in patients who progressed after treatment with cisplatin-based chemotherapy (1.68 vs. 0.45 ng/mL,
= 0.001). Calretinin concentration above 0.89 ng/mL was associated with shorter PFS and OS from the start of chemotherapy (HR = 1.88 (1.28-2.77),
= 0.001 and HR = 1.91 (1.22-2.97),
= 0.004, respectively), even after adjusting for clinical factors (
< 0.05).
rs3807348 was associated with a better response to chemotherapy (OR = 2.69 (1.17-6.18),
= 0.020). We showed that serum calretinin is associated with survival and chemotherapy treatment outcomes in MM and could serve as a predictive biomarker.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The malignant pleural mesothelioma (MPM) response rate to chemotherapy is low. The identification of imaging biomarkers that could help guide the most effective therapy approach for individual ...patients is highly desirable. Our aim was to investigate the dynamic contrast-enhanced (DCE) MR parameters as predictors for progression-free (PFS) and overall survival (OS) in patients with MPM treated with cisplatin-based chemotherapy.
Thirty-two consecutive patients with MPM were enrolled in this prospective study. Pretreatment and intratreatment DCE-MRI were scheduled in each patient. The DCE parameters were analyzed using the extended Tofts (ET) and the adiabatic approximation tissue homogeneity (AATH) model. Comparison analysis, logistic regression and ROC analysis were used to identify the predictors for the patient's outcome.
Patients with higher pretreatment ET and AATH-calculated K
and v
values had longer OS (P≤.006). Patients with a more prominent reduction in ET-calculated K
and k
values during the early phase of chemotherapy had longer PFS (P =.008). No parameter was identified to predict PFS. Pre-treatment ET-calculated K
was found to be an independent predictive marker for longer OS (P=.02) demonstrating the most favourable discrimination performance compared to other DCE parameters with an estimated sensitivity of 89% and specificity of 78% (AUC 0.9, 95% CI 0.74-0.98, cut off > 0.08 min
).
In the present study, higher pre-treatment ET-calculated K
values were associated with longer OS. The results suggest that DCE-MRI might provide additional information for identifying MPM patients that may respond to chemotherapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVESOsteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based ...on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients.
PATIENTS AND METHODSIn total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels.
RESULTSPolymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07–0.94; and P=0.034, HR=0.20, 95% CI=0.05–0.89, respectively. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10–0.72).
CONCLUSIONWe have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.
Malignant mesothelioma (MM) is characterized by poor prognosis and short survival. Extracellular vesicles (EVs) are membrane-bound particles released from cells into various body fluids, and their ...molecular composition reflects the characteristics of the origin cell. Blood EVs or their miRNA cargo might serve as new minimally invasive biomarkers that would enable earlier detection of MM or treatment outcome prediction. Our aim was to evaluate miRNAs enriched in serum EVs as potential prognostic biomarkers in MM patients in a pilot longitudinal study. EVs were isolated from serum samples obtained before and after treatment using ultracentrifugation on 20% sucrose cushion. Serum EV-enriched miR-103-3p, miR-126-3p and miR-625-3p were quantified using qPCR. After treatment, expression of miR-625-3p and miR-126-3p significantly increased in MM patients with poor treatment outcome (p = 0.012 and p = 0.036, respectively). A relative increase in miR-625-3p expression after treatment for more than 3.2% was associated with shorter progression-free survival (7.5 vs. 19.4 months, HR = 3.92, 95% CI = 1.20–12.80, p = 0.024) and overall survival (12.5 vs. 49.1 months, HR = 5.45, 95% CI = 1.06–28.11, p = 0.043) of MM patients. Bioinformatic analysis showed enrichment of 33 miR-625-3p targets in eight biological pathways. Serum EV-enriched miR-625-3p could therefore serve as a prognostic biomarker in MM and could contribute to a more personalized treatment.
Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic malignancy that is difficult to cure. Dynamic contrast-enhanced (DCE) MRI is a functional imaging technique used to analyze ...tumor microvascular properties and to monitor therapy response. Purpose of this study was to compare two tracer kinetic models, the extended Tofts (ET) and the adiabatic approximation tissue homogeneity model (AATH) for analysis of DCE-MRI and examine the value of the DCE parameters to predict response to chemotherapy in patients with MPM.
This prospective, longitudinal, single tertiary radiology center study was conducted between October 2013 and July 2015. Patient underwent DCE-MRI studies at three time points: prior to therapy, during and after cisplatin-based chemotherapy. The images were analyzed using ET and AATH models. In short-term follow-up, the patients were classified as having disease control or progressive disease according to modified response evaluation criteria in solid tumors (mRECIST) criteria. Receiver operating characteristic curve analysis was used to examine specificity and sensitivity of DCE parameters for predicting response to therapy. Comparison tests were used to analyze whether derived parameters are interchangeable between the two models.
Nineteen patients form the study population. The results indicate that the derived parameters are not interchangeable between the models. Significant correlation with response to therapy was found for AATH-calculated median pre-treatment efflux rate (k
) showing sensitivity of 83% and specificity of 100% (AUC 0.9). ET-calculated maximal pre-treatment k
showed 100% sensitivity and specificity for predicting treatment response during the early phase of the therapy and reached a favorable trend to significant prognostic value post-therapy.
Both models show potential in predicting response to therapy in MPM. High pre-treatment k
values suggest MPM disease control post-chemotherapy.
We evaluated the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment in malignant mesothelioma patients.
In total, 139 malignant ...mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome.
Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, p = 0.022 and p = 0.013, respectively).
Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy. Original submitted 7 October 2013; Revision submitted 15 January 2014.
The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including ...calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782–0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.
Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are ...affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin-based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p < 0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend<0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients.
DNA repair mechanisms are essential for maintaining genome stability, and genetic variability in DNA repair genes may contribute to cancer susceptibility. Our aim was to evaluate the influence of ...polymorphisms in the homologous recombination repair genes
,
, and
on the risk for osteosarcoma.
In total, 79 osteosarcoma cases and 373 controls were genotyped for eight single nucleotide polymorphisms (SNPs) in
,
, and
. Logistic regression was used to determine the association of these SNPs with risk for osteosarcoma.
None of the investigated SNPs was associated with risk for osteosarcoma in the whole cohort of patients, however, in patients diagnosed before the age of thirty years
rs861539 C>T and
rs1805794 G>C were associated with significantly decreased risk for osteosarcoma (
=0.047, OR=0.54, 95% CI=0.30-0.99 and
=0.036, OR=0.42, 95% CI=0.19-0.94, respectively). Moreover, in the carriers of a combination of polymorphic alleles in both SNPs risk for osteosarcoma was decreased even more significantly (
=0.007). The risk for developing osteosarcoma was the lowest in patients with no wild-type alleles for both SNPs (
=0.039, OR=0.31, 95% CI=0.10-0.94).
Our results suggest that polymorphisms in homologous recombination repair genes might contribute to risk for osteosarcoma in patients diagnosed below the age of thirty years.
Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member ...survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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