Serum Thymidine Kinase Levels Research Articles

Prediction of Overall Survival by Thymidine Kinase 1 Combined with Prostate-Specific Antigen in Men with Prostate Cancer.

Thymidine kinase 1 (TK1) is an intracellular enzyme involved in DNA-precursor synthesis. Increased serum TK1 levels are used as a biomarker in various malignancies. We combined serum TK1 with PSA and evaluated its capacity to predict overall survival (OS) in 175 men with prostate cancer (PCa), detected by screening in 1988-1989 (n = 52) and during follow-up (median 22.6 years) (n = 123). TK1 was measured in frozen serum, age was stratified into four groups, and dates of PCa diagnosis and dates of death were obtained from Swedish population-based registries. The median concentration of TK1 and PSA was 0.25 and 3.8 ng/ml. TK1 was an independent variable of OS. In the multivariate analysis, PSA was not statistically significant in combination with age whereas the significance remained for TK1 + PSA. Measured once, TK1 + PSA predicted a difference of up to 10 years (depending on patient subgroup) in OS at a median of 9 years before PCa diagnosis. The TK1 concentration in 193 controls without malignancies did not differ from that of the PCa patients, hence TK1 was likely not released from incidental PCa. Thus, TK1 in the blood circulation may indicate the release of TK1 from sources other than cancers, nonetheless associated with OS.

TK1 is an early screening marker for uterine corpus endometrial carcinoma and promotes its progression

BackgroundThe functional role of thymidine kinase 1(TK1) in uterine corpus endometrial carcinoma (UCEC) is unknown. MethodsThe expression of TK1 between UCEC and adjacent normal tissues was compared using different data sets. Clinical and survival data were used to determine the clinical and prognostic significance of TK1 in UCEC. Serum levels of TK1 were measured by ELISA. The role of TK1 in UCEC cells cultivated in vitro was investigated by loss-of-function tests. GO/KEGG analysis was performed using the TCGA-UCEC dataset to explore possible mechanisms for the role of TK1 in UCEC progression. ResultsWe found that the expression of TK1 increased with the malignancy of UCEC, and TK1 was highly expressed and significantly associated with UCEC prognosis. AUC of ROC curve (0.933) showed that serum TK1 levels may be a potential biomarker to identify UCEC patients. Serum levels of TK1 were higher before surgical treatment and significantly decreased after surgical treatment. Knockdown of TK1 inhibited the growth of UCEC cells. Mechanistically, the function of TK1 may be attributed to its effect on major pathways such as cell cycle. TK1 deletion significantly blocked the S phase in UCEC cells. ConclusionsOverall, TK1 may be a new marker for early screening and prognosis prediction of UCEC, as well as a potential therapeutic target of UCEC.

Endu combined with concurrent chemotherapy and radiotherapy for stage IIB-IVA cervical squamous cell carcinoma patients.

BACKGROUNDIn recent years, the incidence of cervical cancer has increased with increasing life pressures and changes in women's social roles, posing a serious threat to women's physical and mental health.AIMTo explore the clinical effect of Endo combined with concurrent radiotherapy and chemotherapy in the treatment of advanced cervical squamous cell carcinoma.METHODSA total of 120 patients admitted to the oncology department of our hospital were selected as the research subjects. They were equally divided into the test group and the control group (60 patients each) with a random number table. The test group was treated with Endo combined with concurrent radiotherapy and chemotherapy, and the control group was treated with concurrent radiotherapy and chemotherapy. We compared the serum thymidine kinase 1 (TK1), human epididymis protein 4 (HE4), vascular endothelial growth factor (VEGF), and squamous cell carcinoma-associated antigen (SCC-Ag) levels, the clinical effects and survival before and after radiotherapy and chemotherapy, the quality score, and the 3-year follow-up outcomes between the two groups.RESULTSAfter chemotherapy, the complete remission + partial remission rate was 85.00% in the test group and 68.33% in the control group; the difference was not statistically significant (P > 0.05). Before chemotherapy, the serum TK1, HE4, VEGF, and SCC-Ag levels of the two groups were not significantly different (P > 0.05). After chemotherapy, the levels of serum TK1 (1.27 ± 0.40 pmol/L), HE4 (81.4 ± 24.0 pmol/L), VEGF (235.1 ± 38.0 pg/mL), and SCC-Ag (1.76 ± 0.55 ng/mL) were lower than those in the control group [TK1 (1.58 ± 0.51 pmol/L), HE4 (98.0 ± 28.6) pmol/L, VEGF (284.2 ± 54.1 pg/mL), and SCC-Ag (2.34 ± 0.78 ng/mL)]. The difference was statistically significant (P < 0.05). Before chemotherapy, there were no significant differences in the physical, role, mood, cognition, social and symptom scale scores of the two groups (P > 0.05). After chemotherapy, the physical, role, mood, cognitive and social scores were higher in the test group than in the control group, and the difference was statistically significant (P < 0.05). The symptom scale scores of the test group were all lower than those of the control group, and the difference was statistically significant (P < 0.05). The 3-year progression-free survival (PFS) rate was 43.33% in the test group and 26.67% in the control group; the overall survival (OS) rate was 48.33% in the test group and 33.33% in the control group; the differences were not statistically significant (P > 0.05). The 3-year PFS time of the test group was 20.0 mo, which was longer than that of the control group (15.0 mo), and the difference was significant (P < 0.05). The OS time of the test group was 30.0 mo, which was longer than that of the control group (18.0 mo), and the difference was significant (P < 0.05).CONCLUSIONEndo combined with concurrent radiotherapy and chemotherapy for the treatment of advanced cervical squamous cell carcinoma has a positive effect on reducing the level of tumor markers in patients, prolonging the PFS and OS times of patients, and improving the quality of life.

Abstract 1902: Elevated thymidine kinase 1 (TK1) in cancer serum may suppress immune function

Abstract In this project, we wanted to investigate the role that TK1 may play in macrophage activation and immune suppression. The relationship between immune response and cancer development has been an enigma that researchers have sought to elucidate for decades. Recent and past studies have suggested that the presence and abundance of nucleotides can affect immune response. Thymidine Kinase 1 (TK1) is a salvage pathway enzyme that converts thymidine to thymidine monophosphate, a precursor to DNA synthesis. It is secreted into serum and as such has been suggested to be a tumor biomarker. TK1 has also shown to be present on the surface of many different cancer cell lines including breast, lung, and colorectal cancer. The reason for this upregulation of surface TK1 is unclear, but it has been suspected that the surface expression of TK1 may be beneficial to tumor growth and survival since high TK1 expression and secretion is an early event in tumorigenesis. Although the immunosuppressive properties of purines have been well established, pyrimidines such as thymidine have not been studied as potential immune suppressants. In our investigation, we first confirmed the increased surface expression levels of TK1 in cancerous cell lines. Flow cytometry showed that non-cancerous cells expressed surface TK1 at minimal levels (0.7%), MDA-MB-231 cells expressed TK1 at higher levels (45%), and PC3 cells expressed TK1 at elevated levels as well (64.6%). Bioinformatic analysis of nucleotide transport in relation to TK1 surface expression showed a strong positive correlation between the nucleotide transporter SLC29A2 and surface TK1 expression in colon adenocarcinoma (correlation value 0.455, p-value &amp;lt;0.001), head and neck squamous cell carcinoma (correlation value 0.416, p-value &amp;lt;0.001), rectum adenocarcinoma (correlation value 0.432, &amp;lt;0.001), stomach adenocarcinoma (correlation value 0.405, p-value &amp;lt;0.001), and uterine corpus endometrial carcinoma (correlation value 0.403, p-value &amp;lt;0.001) which further confirms the elevation of TK1 on the surface of cancer cells and suggests a mechanism whereby serum TK1 levels are elevated. Macrophage engulfment assays were then conducted in order to investigate the possibility that exposure to higher concentrations of TK1 leads to immune suppression. We found that macrophages differentiated from THP-1 monocytes that were exposed to varying concentrations of TK1 for 24 hours showed a decrease in macrophage engulfment (29%-37%) compared to controls that were not exposed to TK1(61.2%). These results suggest that TK1 may have some involvement in immune suppression during cancer development, and we intend to further investigate these findings. Citation Format: Kathryn R. Smith, Rachel M. Morris, Edwin J. Velazquez, David M. Bellini, Kim O'Neill. Elevated thymidine kinase 1 (TK1) in cancer serum may suppress immune function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1902.

Short Telomeres Are Independent Prognostic Factors Associated with Poor Outcome in Chronic Lymphocytic Leukemia (CLL) Treated with Chlorambucil with or without the Addition of Rituximab or Obinutuzumab: Results from CLL11 Trial of the Gcllsg

Abstract Telomeres are DNA repeats at the ends of the chromosomes that are important for maintaining genomic integrity by preventing erosion of the ends. Short telomeres in CLL have previously been shown to be associated with inferior prognosis however its prognostic relevance in chlorambucil based treatment has not been studied. Here, we evaluated associations and prognostic relevance of telomere length in CLL treated with chlorambucil (CLB), CLB+Rituximab(CLB+R) and CLB+Obinutuzumab (GA-101) (CLB+G) in the international, multicenter, randomized CLL11 trial. Telomere length was analyzed using a Q-PCR based method on a representative cohort of 700 patients (89.6%) with available DNA from CD19 enriched or unsorted PBMCs. The method was validated using terminal restriction fragment length analysis (TRF; R2=0.915). Telomere length in CLL11 patients was highly variable (2.2kb to 28.6kb) with a median telomere length of 4.2kb. Telomere length associations were studied by dichotomizing into short (≤median) and long (>median) telomere subgroups. Among the clinical parameters, telomere length showed no association with age, ECOG status, presence of B symptoms, CIRS score, and serum b2-microglobulin (b2-MG). However, short telomeres were significantly associated with male sex (P=0.010), Binet stage (P=0.001), serum thymidine kinase level (s-TK; P Regarding outcome, telomere length was associated with response to therapy in the CLB+R (P=0.001) and CLB+G (P=0.023) treatment arms, while no significant association was observed for the CLB group (P=0.275). Moreover, short telomeres were significantly associated with positive MRD in bone marrow (89.8% vs. 72.9%; P=0.018) and as a trend in peripheral blood (70.2% vs. 58.2%; P=0.068) for CLB+G treatment. At a median observation time of 41.6 months, there were 534 (76.3%) events for progression free survival (PFS) and 195 events (27.9%) for overall survival (OS). Telomere length showed a statistically significant association with PFS (P Multivariable analysis to identify independent prognostic factors was performed including variables significantly associated with PFS in univariate analysis such as treatment arms, Binet stage, b2-MG, s-TK, WBC count, presence of 17p- and/or TP53 mutation, 11q-, mutation status of IGHV and NOTCH1 and telomere length. Short telomeres (HR 1.307; 95%CI 1.054-1.622; P=0.015) along with the treatment arms CLB+R (P In summary, short telomere length in CLL was found to be associated with other adverse biological disease characteristics as well as treatment efficacy, as an independent prognostic factor for PFS and OS in the context of CLB based therapy. The study suggests the value to assess telomere length for risk stratification of CLL patients and to evaluate this marker in the context of novel treatment options targeting biological disease features. Download : Download high-res image (141KB) Download : Download full-size image Figure . Disclosures Bahlo: F. Hoffmann-LaRoche: Honoraria, Other: travel grants. Goede: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Ritgen: BMS: Consultancy, Other: travel support; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Other: travel support; Pfizer: Consultancy. Fingerle-Rowson: F. Hoffmann-La Roche: Employment. Kneba: AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding. Fischer: Roche: Other: Travel Grants. Hallek: AbbVie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Stilgenbauer: Pharmacyclics: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding.

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

Prognostic Impact of Immunohistochemistry and MRD Results in Bone Marrow after Frontline Chemoimmunotherapy of Chronic Lymphocytic Leukemia (CLL): Results of Central Laboratory Analyses of the CLL10 Trial of the German CLL Study Group (GCLLSG)

Elevated Serum Thymidine Kinase Levels Identify a Subgroup at High Risk of Disease Progression in Early, Nonsmoldering Chronic Lymphocytic Leukemia

AbstractChronic lymphocytic leukemia (CLL) shows a remarkably heterogeneous clinical outcome; survival ranges from several months in advanced stages to more than 10 years in early stages. The Binet and Rai staging systems distinguish three major prognostic subgroups, but do not accurately predict the individual risk of disease progression in early CLL (Binet stage A or Rai stage 0 to II). Because most newly diagnosed CLL patients present with early disease, it seems desirable to search for additional prognostic factors to identify early CLL patients at high risk of rapid progression. It has been shown that elevated serum thymidine kinase (s-TK) levels predict disease progression in CLL. Therefore, this study aimed to assess the prognostic value of s-TK in 122 previously untreated patients with Binet stage A CLL (mean age ± SD, 58.7 ± 8.5 years). In univariate analyses, 18 of the 22 parameters investigated predicted progression-free survival (PFS). In a stepwise multiple regression analysis, only three parameters provided independent prognostic information on PFS: s-TK greater than 7.1 U/L; presence of lymphadenopathy; and white blood cell (WBC) count greater than 75,000/μL. When added to the classification of smoldering versus nonsmoldering CLL, s-TK levels separated two groups within the group of nonsmoldering stage A patients: patients with s-TK values greater than 7.1 U/L had a median PFS of 8 months, whereas patients with s-TK values ≤ 7.1 U/L expected a much longer PFS (49 months; P < .001), similar to smoldering CLL (42 months). The results demonstrate that s-TK is a prognostic parameter that adds independent prognostic information to the definitions of smoldering and nonsmoldering CLL in Binet stage A.

Clinical Significance and Role of TK1, CEA, CA 19-9 and CA 72-4 levels in Diagnosis of Colorectal Cancers.

To explore the diagnostic value, pre-operative serum thymidine kinase 1(TK1), CEA, CA 19-9 and CA 72-4 levels were measured in 106 patients with colorectal carcinoma (53 colon and 53 rectal carcinoma patients) and 53 healthy controls. Sandwich Elisa, biotin-labeled antibody kit was used for TK1, and other tumor markers were measured using electro-chemiluminescence. Serum TK1 levels were significantly higher in CRC than in healthy controls (p<0.05) and showed significant associations with tumor stage, histopathological grade, lymph node status and metastasis (p<0.01). TK1 showed the highest (0.824-0.862) area under receiver operating characteristics curve (AUC) in comparison to other markers, and the AUC of the panel of combination tests performed even better (0.935-0.952). Significant variation was observed between the single biomarker test and their combination (Z test, p<0.01) and the Hosmer-Lemeshow test showed an adequate model of calibration. The algorithm based on combination of TK1, CEA, CA19-9 and CA72-4 can improve the diagnostic efficiency in CRC patients.

Abstract LB-149: Serum thymidine kinase 1 levels predict prostate cancer-specific survival

Abstract Background: Thymidine kinase 1 (TK1) is an enzyme involved in DNA synthesis. Thymidine kinases phosphorylate thymidine as part of the DNA synthetic pathway. TK1 expression is a marker of active cellular proliferation; intracellular concentrations are low during the G0/G1 phases of the cell cycle, increasing during the S/G2 phases. Previous studies have suggested that serum TK1 levels could be used as marker for presence of prostate cancer (PCa). Here, we evaluated whether serum TK1 levels could predict risk of PCa prognosis. Materials and Methods: The study population included 40 men with clinically defined T1/T2NxM0 PCa and 43 men with de novo metastatic cancer (M1) at diagnosis confirmed by bone scan imaging. All men were diagnosed and treated at the Tampere University Hospital between 2000-2010. All men provided a serum sample at the time of diagnosis. Information on deaths and causes of death were obtained from national causes of death registry. Serum TK1 concentrations were determined using the AroCell TK210 ELISA kit. Cox regression and Kaplan-Meier Curves with adjustment for tumor risk group (Gleason-grade, TNM stage and PSA level) were used to evaluate the risk of PCa death in relation to TK1 levels (median or below vs. above median). ROC analyses were used to evaluate the predictive accuracy of PSA, TK1 and their combination. Results: M1 cases were older than M0 cases; median age 72 vs 62 years, respectively. M1 cases were mainly managed with androgen deprivation therapy, whereas M0 cases were most often managed with radical prostatectomy. Median serum TK1 levels were significantly higher among M1 cases compared to M0 cases (p for difference 0.001). In the combined study population, serum TK1 levels were a significant predictor of PCa-specific (HR 8.33, 95% CI 2.05-33.88) and overall mortality (HR 5.53, 95% CI 1.93-15.85) after adjustment for established prognostic factors including tumor risk group. Kaplan-Meier survival curves defined by TK1 level started to differ within 24 months from PCa diagnosis. In ROC analyses TK1 alone or in combination with PSA was no more accurate than PSA alone in predicting PCa death. Conclusion: The proliferation biomarker TK1 in serum predicted survival after PCa diagnosis, demonstrating independent predictive value over established clinical risk factors. If confirmed in further and larger studies, this biomarker could be incorporated in PCa risk stratification when selecting optimal treatment and surveillance schedule. Citation Format: Teemu J. Murtola, Paavo Raittinen, Teuvo Tammela. Serum thymidine kinase 1 levels predict prostate cancer-specific survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-149.

Serum AFU, GGT and TK1 levels in PHC patients and their correlation with clinicopathology and diagnostic value

To investigate the expression level and clinical significance of fucosidase (AFU), glutamyltranspeptidase (GGT), and thymidine kinase 1 (TK1) in the serum of patients with primary liver cancer (PHC). A total of 135 PHC patients in Baoji Central Hospital from September 2014 to February 2018 were selected as a research group (RG), while 127 healthy subjects were collected as a control group (CG). Enzyme-linked immunosorbent assay (ELISA) was used to detect the AFU, GGT, and TK1 concentrations in serum of the two groups, and the diagnostic value of combined detection of the three for PHC was analyzed. AFU, GGT, and TK1 concentrations in serum of the RG were dramatically higher than those of the CG (P&lt; 0.050). ROC curve analysis showed that the sensitivity of AFU, GGT, and TK1 in the single diagnosis of PHC was 88.00, 94.00, and 66.00% respectively, and the specificity was 68.00, 54.00, and 66.00% respectively. The sensitivity and specificity of the combined diagnosis of PHC were 76.00 and 90.00%, respectively. AFU, GGT, and TK1 concentrations were different in the presence or absence of liver cirrhosis, TNM stage, and tissue type (P&lt; 0.050). AFU, GGT, and TK1 concentrations in PHC patients were dramatically higher than those in healthy people. Combined detection of the three has good diagnostic value for PHC.

Relationship between thymidine kinase 1 before radiotherapy and prognosis in breast cancer patients with diabetes.

In a retrospective study design, we explored the relationship between serum thymidine kinase 1 (TK1) concentration before radiotherapy and clinical parameters and evaluated the prognostic value of serum TK1 concentration before radiotherapy in breast cancer patients with type 2 diabetes mellitus. The present study finally consisted of 428 breast cancer patients with a mean age of 53.0 years. Compared with low TK1 group, the high TK1 group tended to have larger tumor size (P=0.011) and had more lymph node number (P=0.021). Significant differences were also observed in clinical stages I, II and III (P=0.000). There was no significant difference between TK1 and other clinical parameters. For disease-free survival (DFS), the univariate analysis indicated that the high TK1 increased the risk of poor prognosis (HR = 2.38, 95% CI: 1.64–4.23, P=0.000). The Kaplan–Meier curve indicated the high TK1 group was poorer than that in the low TK1 group (P=0.002). For the overall survival (OS), similar results were found that the high TK1 was related to poor OS (HR = 1.89, 95% CI: 1.34–3.67, P=0.000). The multivariate Cox regression indicated that the TK1 was still associated with DFS (HR = 1.83, 95% CI: 1.22–3.17, P=0.001) and OS (HR = 1.63, 95% CI: 1.19–2.08, P=0.006). The high pretreatment serum TK1 levels in breast cancer patients were associated with poor OS and DFS. TK1 could be a potential predictive factor in differential diagnosis of poor prognosis from all patients.

Knockdown of Thymidine Kinase 1 Suppresses Cell Proliferation, Invasion, Migration, and Epithelial-Mesenchymal Transition in Thyroid Carcinoma Cells.

Patients with advanced thyroid carcinoma have poor prognosis with low overall survival. Unfortunately, the underlying mechanisms of thyroid carcinoma progression remain unclear. The elevated expression of thymidine kinase 1 (TK1) has been implicated in the progression of thyroid carcinoma, while the role of TK1 in thyroid carcinoma progression has not been explored. The present study aimed to determine the role TK1 in the progression of thyroid cancer and to explore the underlying molecular mechanisms. In this study, it was found that serum TK1 levels were markedly increased in the patients with thyroid nodules. Further online data mining showed that TK1 expression was upregulated in thyroid carcinoma tissues, and higher expression of TK1 was correlated with shorter disease-free survival of patients with thyroid carcinoma. Silencing of TK1 suppressed cell proliferation, invasion, migration, and epithelial–mesenchymal transition, and also induced cell apoptosis in the thyroid carcinoma cell lines. Animal studies showed that TK1 knockdown inhibited in vivo tumor growth of thyroid carcinoma cells. Importantly, miR-34a-5p was found to be downregulated in the thyroid carcinoma cells. Furthermore, miR-34a-5p targeted the 3′ untranslated region of TK1 and suppressed the expression of TK1 in thyroid carcinoma cell lines. In summary, first, these results demonstrated the upregulation of TK1 in thyroid nodules and thyroid carcinoma tissues; second, TK1 promoted thyroid carcinoma cell proliferation, invasion, and migration; lastly, TK1 was negatively regulated by miR-34a-5p. Our study may provide novel insights into the role of TK1 in regulating thyroid carcinoma progression.

Clinical significance and diagnostic capacity of serum TK1, CEA, CA 19-9 and CA 72-4 levels in gastric and colorectal cancer patients.

Despite extensive progress in treatment for cancer in recent decades, the early diagnosis for gastric cancer (GC) and colorectal cancer (CRC) remains poor. In this study, we explore the diagnostic value of joint detection of thymidine kinase 1 (TK1), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 72-4 (CA 72-4) in the diagnosis of GC and CRC, and to evaluated the relationship between TK1 expression and clinical pathological characteristics in the patients. Serum TK1, CA 19-9, CA 72-4 and CEA levels were measured in 169 patients with GC, 344 patients with CRC and 75 healthy controls using electro-chemiluminescence. The TK1 concentration was significantly higher in patients with cancer than in healthy controls and patients with clinical stage Ⅲ+Ⅳ had higher TK1 levels than clinical stage Ⅰ+Ⅱ (P<0.05). The levels of TK1 is significantly associated with tumor stage, lymph node metastasis, distant metastasis, tumor differentiation and age (P<0.05). When the tumor markers (TK1, CA 19-9 and CA 72-4) were detected respectively, the area under receiver operating characteristics curve (AUC) of TK1 for three cancers was the highest (0.823-0.895). However, the combination of AUC was higher than that for each tumor marker detected respectively (0.934-0.953), and the Hosmer-Lemeshow test showed an adequate model of calibration (P>0.05). Moreover, the AUCs varied significantly between the combination tests and single biomarker tests (Z test, P<0.01). In conclusion, serum TK1 may be an independent tumor marker for GC and CRC patients, and the combination of TK1, CA 19-9 and CA 72-4 and CEA performed even better. This study suggests that combination detection of four tumor markers may prove to be useful for the diagnosis of GC and CRC.

Standardized Centile Curves and Reference Intervals of Serum Thymidine Kinase 1 Levels in a Normal Chinese Population Using the LMS Method.

The aim of the present study was to re-establish a set of normative data for serum thymidine kinase 1 (STK1) for the Chinese population. The study included 14,960 Chinese subjects (9586 males and 5374 females) from 20 to 79 years old. Subjects suffering from diseases that could affect STK1 levels were excluded. STK1 was measured by a sensitive chemiluminescence dot blot assay. The reference intervals were calculated using the LMS method. Peak thymidine kinase 1 (TK1) serum levels were observed at 20 years of age for both genders. After the age of 20 years, serum TK1 levels decreased slowly from 0.51 to 0.36 pM, reaching a plateau to a mean of 0.35 pM in late adulthood. The mean pretreatment STK1 Z-scores in patients with solid malignant tumors obtained from related studies for cancers were 0.01 ± 0.99 (males, -0.07 ± 0.97; females, 0.09 ± 1.02). The present study established age- and gender-specific normative STK1 data for the Chinese population and showed the utility of these references for screening patients with solid malignant tumors.

Thymidine Kinase: A Biomarker for Recently Diagnosed Acute Leukemia in Pediatric Patients According to the Cell Line Involved

Acute leukemia (AL) is a heterogeneous group of diseases characterized by a disorganized clone proliferation of hematopoietic cells. Thymidine kinase (TK) is a cell enzyme involved in DNA synthesis and is considered a cellular proliferation marker in some solid tumors. A cross-sectional prospective and comparative study was performed in the Federico Gomez Children's Hospital in Mexico (HIMFG, in Spanish) in 125 samples of patients of the HIMFG with AL and 138 samples of children without leukemia. Serum TK levels were determined for both groups. Of the children with AL, 90 presented B-cell acute lymphoblastic leukemia (B-ALL); 13, T-cell acute lymphoblastic leukemia (T-ALL); and 22, acute myeloid leukemia (AML). A median (m) TK level of 23.7 IU (IQR 17-35.7) was observed in the group without AL and 91 IU (IQR 98-392) in the AL group. This difference was statistically significant (p <0.0001). When analyzing TK levels according to the type of leukemia, the m was as follows: 68 IU (IQR 35-118) for B-ALL, 470 IU (IQR 88-750) for AML, and 1678 IU (IQR 288-2108) for T- ALL. TK is an enzyme showing heterogeneous levels in B-ALL although it is significantly increased in 90% of patients with T-ALL and AML.

Expression of thymidine kinase 1 in serum of patients with breast carcinoma and its clinical significance

Objective To investigate the influence of surgery on the level of thymidine kinase 1(TK1) in the serum of patients with breast carcinoma detecting its serum level.Methods Sensitive chemiluminescence dot-blot assay was used to detect the serum TK1 levels of 33 healthy women and 65patients with breast carcinoma.The clinical implications were also analyzed.The serum TK1 levels of 38 patients with breast carcinoma were compared between before and after the operatiou.Results The serum TK1 level was higher in the patients with breast carcinoma than in the healthy women,with a statistical difference(P ＜ 0.01).Serum TK1 level didn' t correlated with age and pathologic types but correlated with clinical stage; the serum TK1 level was higher in stage Ⅳ patients than in stage Ⅲ,in stage Ⅲ than in stage Ⅱ,and in stage Ⅱ than in stage Ⅰ (P ＜ 0.01,P ＜ 0.05).The level of serum TK1 was obviously reduced in patients with breast carcinoma after the operation(P ＜ 0.01).Conclusions The serum TK1 levels in patients with breast carcinoma are higher; it could be an indicator assessing the disease status,therapeutic effect,and the prognosis of breast carcinoma. Key words: Thymidine kinase 1; Breast carcinoma; Operation

Thymidine Kinase Levels Correlate With Prognosis In High Grade Lymphoma, and Can Discriminate Patients With a Clinical Suspicion Of Low Grade To High Grade Transformation

IntroductionHematologic malignancies accounts for about 10% of all cancers. Of these, the lymphoid tumors are most prevalent, cells transforming at various stages of the lymphoid lineage differentiation. The lymphoid tumors can further be divided into low grade, slow growing diseases, and rapidly growing high grade diseases.Measurement of total cell division activity using serum thymidine kinase 1 (TK1) has been evaluated previously for these diseases. It correlates with disease progression, stage and grade. The prognostic utility of pretreatment TK1 activity has been only partially investigated. In addition, its ability to differentiate the subset of patients where a transformation from low grade to high grade is suspected, has never been investigated. Study AimsIn this study, the new TK chemiluminescence immunoassay was used to assess serum TK1 levels in patients with various hematologic neoplasms. Serum TK1 levels were correlated with baseline clinical and laboratory parameters and overall survival. In addition, we hypothesized that serum TK1 levels may discriminate the transformation from low grade to high grade lymphoma in the context of a clinical suspicion. Patients and MethodsAt the first phase of the study, we analyzed a total of 194 patients using DiaSorin TK1 elisa kit (Stillwate, MN, USA). All levels were taken during the initiation of treatment at diagnosis or relapse, except for TK kinetics along time. Most had lymphoid neoplasms of various origins. Most patients had DLBCL (60 including transformation) and low grade NHL (46). We analyzed in addition patients with HL, MM and CLL, as well as patients with very aggressive tumors such as Burkitt's Ly/Leukemia, ALL and AML (the latter for control purposes). At the second phase we collected, assessed and compared a cohort of patients with transformation of low to high grade lymphoma, and patients with low grade lymphoma with suspected transformation, whom eventually had other diagnoses (i.e. infections, low grade related symptoms, large low grade-related masses etc.). ResultsMeasurements of TK and B2M in Normal samples: Considering the relatively new use of the TK levels,measurement method by ELISA, we first verified its values in normal subjects.38 subjects, male and female adults were tested. The average reading revealed normal levels to be 4.06 u/L +/- 1.83. We therefore set the upper limits of normal to be 7.7 u/L (average + 2 standard deviations). Low grade lymphomas had significantly (p<0.03) lower readings mean 12.8 u/L (± 21.5) as compared with 32.8 (± 36.6) u/L for high grade diseases. In low grade diseases TK levels did not correlate with survival. However, in high grade diseases normal TK levels correlated with a significantly better long term survival (p=0.04). Of note were six patients with transformations who had a TK level of 48.8 u/L (± 29.73). We thus further analyzed another cohort of 60 patients with a base line low grade lymphoma and suspected transformation. Of these, 36 patients had a suspicion eventually proving to be low grade disease or infection related (i.e.-no evidence of transformation), and 24 with biopsy proven transformations. The TK level differed significantly (p<0.01) between the two groups. After censoring for 3 CLL patients with very high WBC count in the non-transforming group, and 5 patients with stage 1 in-situ transformations in the transformation group, these differences became striking (P<0.0001) with a median level of 7.6 versus 48.6 u/L, respectively (figure). Having a TK level of > 14.1 u/L had a sensitivity of 95% and a specificity of 76% for having a low to a high grade lymphoma transformation, with a negative predictive value of 96% and a positive predictive value of 69%, respectively. [Display omitted] ConclusionsTK levels are useful in assessing prognosis, especially in high grade lymphomas. Moreover, TK levels were able to discriminate low grade patients suspected of a high grade transformation, but eventually having none, and patients with proven transformations. Disclosures:No relevant conflicts of interest to declare.

Analysis of correlation between serum thymidine kinase 1 and acute myeloid leukemia

This study was purposed to investigate the clinical significance of serum thymidine kinase 1 (STK1) level change in acute myeloid leukemia (AML). Peripheral blood samples of 60 newly diagnosed AML patients were collected and the STK1 levels were determined by enhanced chemiluminescent dot-blot method before and at two weeks after start of inductive treatment and in consolidatory treatment. Using non-parametric test, the differences between groups were analyzed. Then the correlation between STK1 level and clinical characteristics was explored by a way of chi-square test. The results indicated that the serum TK1 level in complete remission (CR) or partial remission (PR) AML patients decreased in varying degree as compared to pretreatment (P < 0.05), while there was no significant difference of TK1 level in non-remission (NR) ones (P > 0.05). The serum TK1 level in CR patients remained low level but increased noticeably after relapse into progressive disease (P < 0.05). A significant correlation was found between STK1 level and chromosomal abnormalities, serum LDH level as well as whether had fever in de novo AML patients (P < 0.05). It is concluded that the serum TK1 level change may be applied for reflecting the aggressiveness of disease, monitoring the clinical response to chemotherapy, evaluating the prognosis and predicating the relapse risk. The decrease of TK1 level suggests effective treatment and tumor burden reduction, while its increase indicate poor prognosis and relapse risk.

Elevation of serum thymidine kinase 1 in a bacterial infection: Canine pyometra

Pyometra is a bacterial infection of the uterus that is common in dogs and is potentially life-threatening if delayed in diagnosis and/or treatment. Thymidine kinase 1 (TK1) is a cytosolic enzyme involved in DNA precursor synthesis, and it is also present in serum from patients with malignant diseases. TK1 has been used as a cell proliferation biomarker for many years in human medicine and recently in dogs. However, little is known regarding serum TK1 levels in individuals with bacterial infection. The objective of this study was to determine the activity of serum TK1 in dogs with pyometra and compare it with hematologic and biochemical parameters, e.g., acute phase proteins and inflammatory mediators such as C-reactive protein and Prostaglandin F2α. Serum and plasma TK1 activity of 40 healthy female dogs and 54 dogs with pyometra were analyzed using an optimized [3H]-thymidine phosphorylation assay.TK1 activities in serum or plasma were significantly higher in dogs with pyometra as compared with healthy female dogs (mean ± SD: 4.0 ± 7.3 pmol/min/mL in the pyometra group and 1.07 ± 0.34 pmol/min/mL in healthy control group). However, there was no difference in TK1 activity between systemic inflammatory response syndrome (SIRS) positive (n = 38) and SIRS negative (n = 16) pyometra cases. Furthermore, the plasma TK1 activity decreased in six and increased in one pyometra patients (n = 10), 24 h after ovariohysterectomy. No significant correlations (P > 0.05) were found between TK1 activity and hematological or other biochemical parameters.In conclusion, the TK1 activity was significantly elevated in dogs with pyometra. Further studies are needed to evaluate the mechanism and role of serum TK1 activity in bacterial infections and its possible diagnostic or prognostic value.

A sensitive and kinetically defined radiochemical assay for canine and human serum thymidine kinase 1 (TK1) to monitor canine malignant lymphoma

Thymidine kinase 1 (TK1) is a cell cycle regulated enzyme with maximum expression during the S phase. Serum TK1 (S-TK1) is a unique biomarker for cell proliferation. Here, an optimized [(3)H]-thymidine (dThd) phosphorylation assay is described, which is as sensitive as the commercially available TK-REA and TK-Liaison assays for measurement of S-TK1 activity in dogs and humans. Serum samples from dogs (35 healthy, 32 with lymphoma, 2 with leukemia, and 35 with solid tumors) and humans (18 healthy, 9 with chronic lymphocytic leukemia, 10 with myelodysplastic syndrome) were analyzed using the [(3)H]-dThd assay. Mean S-TK1 activities were 1.11 ± 0.46 pmol/min/mL in healthy dogs and 1.15 ± 0.32 pmol/min/mL in healthy humans. S-TK1 activities in dogs with hematological malignancies were 24.2 ± 47.9 pmol/min/mL, and the receiver operating characteristic curve showed an area under the curve of 0.88. With a cut-off value of 1.9 pmol/min/mL (mean value ± 2 SD), the sensitivity was 0.94 and the specificity was 0.68. Very similar results were obtained with human samples (healthy and lymphoma cases). S-TK1 activities measured during chemotherapy of six dogs with lymphoma were drastically reduced. In one case, S-TK1 activity increased prior to relapse. S-TK1 levels in dogs with solid tumors did not differ from the healthy group. S-TK1 activities correlated with those determined with the TK-REA and TK-Liaison assays (r=0.92 and r=0.96, respectively). In conclusion, this optimized [(3)H]-dThd assay is fast, sensitive and economical for measuring S-TK1 activity and should increase its clinical use as biomarker.