| 1. |
- Nisman, Benjamin, et al.
(author)
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Circulating Tumor M2 Pyruvate Kinase and Thymidine Kinase 1 Are Potential Predictors for Disease Recurrence in Renal Cell Carcinoma After Nephrectomy
- 2010
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In: Urology. - : Elsevier BV. - 0090-4295 .- 1527-9995. ; 76:2, s. 513.e1-
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Journal article (peer-reviewed)abstract
- OBJECTIVES Pyruvate kinase type M2 (TuM2-PK) and thymidine kinase 1 (TK1) are the key enzymes involved in tumor cells metabolism and proliferation. We explored the association of their preoperative circulating levels with disease recurrence in patients with renal cell carcinoma (RCC). METHODS We measured the plasma levels of TuM2-PK levels and serum TK1 activity preoperatively in patients with RCC, using a quantitative ELISA, and correlated the results with clinicopathological parameters. RESULTS Significantly higher levels of TuM2-PK and TK1 were found in 116 patients with RCC compared with 20 healthy participants (P < .001 and P = .03), but not compared with 27 patients with benign kidney tumors (P = .13 and P = .72). There was a significant association between the level of TuM2-PK and of TK1 activity with T stage (P = .01 and P = .04). Of 2 markers only TuM2-PK was significantly associated with tumor grade (P = .001). The presence of extensive tumor necrosis (> 50%) was associated with high TuM2-PK (P = .001) and low TK1 (P = .03). The 5-year recurrence-free survival for patients with elevated TuM2-PK or TK1 was significantly lower compared with those for patients with normal marker levels (55% vs 94%, P < .001 and 21% vs 90%, P = .002). Multivariate Cox Proportional Hazard analysis demonstrated that TuM2-PK and TK1, adjusted for stage, grade and tumor necrosis were retained as independent predictors of disease recurrence (HR = 7.3, P = .04 and HR = 3.8, P = .03). CONCLUSIONS The measurements of 2 circulating biomarkers, TuM2-PK and TK1, in RCC patients before nephrectomy can be useful for predicting recurrence and stratifying the patients into risk groups for possible adjuvant treatment.
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| 2. |
- Nisman, Benjamin, et al.
(author)
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Comparison of diagnostic and prognostic performance of two assays measuring thymidine kinase 1 activity in serum of breast cancer patients
- 2013
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In: Clinical Chemistry and Laboratory Medicine. - : Walter de Gruyter GmbH. - 1434-6621 .- 1437-4331. ; 51:2, s. 439-447
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Journal article (peer-reviewed)abstract
- Background: We compared two recently developed immuno assays for serum thymidine kinase 1 (TK1) activity: one manual assay (DiviTum, Biovica (R)) and one fully automated assay (Liaison, Diasorin (R)). Methods: The study included 368 women: 149 healthy blood donors (control), 59 patients with benign breast disease (BBD) and 160 patients with primary breast cancer (BC). Results: A regression analysis of the Liaison (y) and DiviTum (x) assays for all three groups yielded the equation y=3.93+0.03x (r=0.85, n=368). The r-value in BC was higher than in control and BBD (0.90 vs. 0.81 and 0.64). The correlation between the two assays for TK1 values above the cut-off was higher compared to that below (0.88 and 0.59). Breakdown of the BBD group into subgroups with proliferative and non-proliferative lesions was effective only with the measurement of TK1 with DiviTum assay (p=0.03). The TK1 activity determined preoperatively in BC patients with DiviTum and Liaison assays was significantly associated with T-stage (for both p=0.01), presence of vascular invasion (p=0.002 and p=0.02), lack of estrogen receptor (ER) (p=0.001 and p=0.01) and progesterone receptor (PR) (p=0.01 and p=0.03) expression. Only TK1 analyzed with the DiviTum assay was associated with tumor grade and molecular subtype of BC (p=0.02 and p=0.003). Multivariate Cox proportional hazards analyses demonstrated that T-stage, PR status and TK1 activity measured by both methods (DiviTum, RR=3.0, p=0.02 and Liaison, RR=3.1, p=0.01) were independent predictors of disease recurrence. Conclusions: In spite of differences observed between TK1 activity measured by the DiviTum and Liaison assays, both of them may be used for recurrence prediction in preoperative evaluation of BC patients.
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| 3. |
- Nisman, Benjamin, et al.
(author)
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Increased Proliferative Background in Healthy Women with BRCA1/2 Haploinsufficiency Is Associated with High Risk for Breast Cancer
- 2013
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In: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 22:11, s. 2110-2115
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Journal article (peer-reviewed)abstract
- Previous studies indicated that BRCA haploinsufficiency was associated with activation of the EGF receptor (EGFR) signaling pathway and increased proliferative activity in mammary epithelial cells of healthy women. We hypothesized that these processes might be reflected in the expression of serologic soluble EGFR (sEGFR) and thymidine kinase 1 (TK1) activity, which signal the initial and final steps of the proliferative pathway, respectively. We found that healthy carriers of BRCA1/2 mutations (n = 80) showed a significantly higher TK1 activity than age-matched controls (P = 0.0003), and TK1 activity was similar in women with BRCA1 and BRCA2 mutations (P = 0.74). The sEGFR concentration was significantly higher in women with BRCA1 than in controls and BRCA2 mutation (P = 0.013 and 0.002, respectively). During follow-up, four of 80 BRCA1/2 mutation carriers developed breast cancer. These women showed a significantly higher TK1 activity and somewhat higher sEGFR concentrations than the other 76 BRCA1/2 carriers (P = 0.04 and 0.09, respectively). All tumors were negative for ovarian hormone receptors, but showed a high EGFR expression. This study was limited by the short-term follow-up (mean, 27 months; range, 5-45), which resulted in a small sample size. Women with BRCA1 and BRCA2 mutations that had undergone risk-reducing bilateral salpingo-oophorectomy (BSO) showed significantly lower sEGFR compared with those without surgery (P = 0.007 and 0.038, respectively). Larger, prospective studies are warranted to investigate whether TK1 and sEGFR measurements may be useful for identifying healthy BRCA1/2 carriers with high risk of developing breast cancer; moreover, sEGFR measurements may serve as effective tools for assessing risk before and after BSO.
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| 4. |
- Nisman, Benjamin, et al.
(author)
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Serum thymidine kinase 1 activity in breast cancer
- 2010
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In: Cancer Biomarkers. - 1574-0153. ; 7:2, s. 65-72
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Journal article (peer-reviewed)abstract
- Aims: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis and an important proliferation marker. We explored the association of preoperative serum TK1 activity with clinicopathological parameters and prognosis in terms of recurrence-free survival (RFS) in breast cancer (BC) patients. Patients and methods: TK1 activity in serum of 120 healthy women and 161 BC patients was measured by quantitative ELISA. Results: Serum TK1 activity in BC patients was significantly higher than in healthy women (P < 0.0001). In BC patients elevated TK1 activity was significantly associated with advanced T stage (P = 0.015), higher grade (P = 0.013), presence of tumor necrosis (P = 0.006), vascular invasion (P = 0.002), and lack of estrogen receptor (ER) and progesterone receptor (PR) expression (P = 0.0004 and P = 0.003). Higher TK1 activity was found in patients with BRCA1/2 mutations compared to those without the mutation (P = 0.004). Multivariate Cox proportional hazards analyses demonstrated that TK1, adjusted for stage, grade, necrosis, ER and PR negativity was retained as an independent predictor of disease recurrence (Hazard Ratio = 3.9, 95%CI 1.3-11.6, P = 0.013). Conclusion: Elevated serum TK1 is an important risk factor indicating a high proliferation potential of tumors at the time of excision. In multivariate analysis TK1 activity was found to be an independent prognostic factor for RFS.
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| 5. |
- Nisman, Benjamin, et al.
(author)
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Serum Thymidine Kinase 1 Activity in the Prognosis and Monitoring of Chemotherapy in Lung Cancer Patients : A Brief Report
- 2014
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In: Journal of Thoracic Oncology. - 1556-0864 .- 1556-1380. ; 9:10, s. 1568-1572
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Journal article (peer-reviewed)abstract
- Introduction: Thymidine kinase 1 (TK1) is a metabolic enzyme involved in DNA synthesis. Most standard treatment protocols for lung cancer (LC) include cytotoxic agents, which are potential modulators of TK1. We aimed to assess the prognostic significance of serum TK1 activity and its role in monitoring chemotherapy in LC patients. Methods: TK1 activity was measured using the DiviTum (Biovica) assay in sera from 233 patients with non-small-cell lung cancer (NSCLC), 91 with small-cell lung cancer (SCLC), and 90 with benign lung disease. Results: TK1 activity was significantly associated with age, performance status, and stage in NSCLC and with stage and weight loss in SCLC. In multivariate analysis, pretreatment TK1 activity, adjusted for performance status, stage, and weight loss, independently affected survival in NSCLC (relative risk = 1.45, p = 0.031) and SCLC (relative risk = 2.49, p = 0.001). In NSCLC patients, adjusted elevated TK1 activity (>100 Du/L) at pretreatment was a significant predictor of treatment failure (odds ratio = 2.55, p = 0.01). A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was significantly associated with treatment failure and poor overall survival. Conclusions: Elevated pretreatment serum TK1 activity was an independent, adverse prognostic factor, based on survival, in the two main histological types of LC. A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was associated with treatment failure and poor overall survival.
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