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BACKGROUND: For lung cancer, circulating tumor markers (TM) are available to guide clinical treatment decisions. To ensure adequate accuracy, pre-analytical instabilities need to be known and addressed in the pre-analytical laboratory protocols. OBJECTIVE: This study investigates the pre-analytical stability of CA125, CEA, CYFRA 21.1, HE4 and NSE for the following pre-analytical variables and procedures; i) whole blood stability, ii) serum freeze-thaw cycles, iii) electric vibration mixing and iv) serum storage at different temperatures. METHODS: Left-over patient samples were used and for every investigated variable six patient samples were used and analysed in duplicate. Acceptance criteria were based on analytical performance specifications based on biological variation and significant differences with baseline. RESULTS: Whole blood was stable for at least 6 hours for all TM except for NSE. Two freeze-thaw cycles were acceptable for all TM except CYFRA 21.1. Electric vibration mixing was allowed for all TM except for CYFRA 21.1. Serum stability at 4°C was 7 days for CEA, CA125, CYFRA 21.1 and HE4 and 4 hours for NSE. CONCLUSIONS: Critical pre-analytical processing step conditions were identified that, if not taken into account, will result in reporting of erroneous TM results. [ABSTRACT FROM AUTHOR]

Background: Colorectal carcinoma is rising worldwide, representing a major cause of cancer-related mortality and morbidity. Carcinoembryonic antigen (CEA) is an established tumor marker for colorectal cancer, with uses in screening, pre-treatment staging, post-therapeutic monitoring, and recurrence detection. However, multiple factors affect CEA, including smoking and benign gastrointestinal diseases. Hence, there is a need to investigate alternative tumor markers like cytokeratin fragment 21.1 (CYFRA 21.1). Methods: This cross-sectional study aimed to determine if the combination of CYFRA 21.1 and CEA is superior to CEA alone as a diagnostic marker in colonic cancer. From June 2016 to December 2019, 69 consecutive patients with a histologically-confirmed diagnosis of colonic adenocarcinoma were studied. The serum levels of both tumor markers were analyzed before starting any definite treatment. The sensitivity and positive predictive values for both tumor markers were calculated. The correlation between tumor markers was tested using Pearson's correlation. The correlation between the TNM stage and tumor markers was tested using Spearman's Rho test. Results: Forty-one patients had elevated CEA, while 33 patients had elevated CYFRA 21.1. CEA and CYFRA 21.1 mildly positively correlated with each other, with an R-value of 0.2598 (P=0.031). Spearman's correlation with the clinical stage of cancer was found to be 0.50834 for CEA (P<0.005) and 0.59828 for CYFRA 21.1 (P<0.005). The sensitivity of CEA was 59.42%, while that of CYFRA 21.1 was 47.83%. The combination of both had a sensitivity of 75.36%. Conclusion: The combination of CYFRA 21.1 and CEA was more effective in picking up cases of colonic cancer than CEA alone. Both CYFRA 21.1 and CEA correlated well with the stage of the disease. Combining these biomarkers has great potential to evolve as a diagnostic aid in colonic cancer. [ABSTRACT FROM AUTHOR]

Background: For lung cancer, circulating tumor markers (TM) are available to guide clinical treatment decisions. To ensure adequate accuracy, pre-analytical instabilities need to be known and addressed in the pre-analytical laboratory protocols., Objective: This study investigates the pre-analytical stability of CA125, CEA, CYFRA 21.1, HE4 and NSE for the following pre-analytical variables and procedures; i) whole blood stability, ii) serum freeze-thaw cycles, iii) electric vibration mixing and iv) serum storage at different temperatures., Methods: Left-over patient samples were used and for every investigated variable six patient samples were used and analysed in duplicate. Acceptance criteria were based on analytical performance specifications based on biological variation and significant differences with baseline., Results: Whole blood was stable for at least 6 hours for all TM except for NSE. Two freeze-thaw cycles were acceptable for all TM except CYFRA 21.1. Electric vibration mixing was allowed for all TM except for CYFRA 21.1. Serum stability at 4°C was 7 days for CEA, CA125, CYFRA 21.1 and HE4 and 4 hours for NSE., Conclusions: Critical pre-analytical processing step conditions were identified that, if not taken into account, will result in reporting of erroneous TM results.

OBJETIVO: Dosar os marcadores tumorais antígeno carcinoembrionário (CEA), fragmento da citoqueratina 19 (CYFRA21-1) e antígeno glicosídico associado a tumor 15-3 (CA 15-3) em sangue e líquido pleural de portadores de derrames pleurais benignos e malignos, avaliando a sensibilidade de cada um deles nesses fluidos. MÉTODOS: Avaliamos prospectivamente 85 pacientes com derrame pleural. O estudo do líquido pleural obedeceu a critérios determinados pela literatura. A dosagem dos marcadores foi realizada por eletroquimioluminescência. A sensibilidade foi determinada sob a condição de que a especificidade fosse > 90%. RESULTADOS: Foram diagnosticados 36 casos malignos (42,4%), 30 benignos (35,3%); em 19 pacientes (22,3%), o diagnóstico foi inconclusivo. Nos casos malignos, os valores de CEA e CYFRA21-1 foram maiores no líquido pleural do que no sangue, fato não observado para o CA 15-3. Nos casos benignos, os valores do CYFRA21-1 foram maiores no líquido pleural do que no soro, enquanto que para o CEA e o CA 15-3, ocorreu o oposto. Todos os marcadores apresentaram diferença significativa entre os casos malignos e benignos, em líquido pleural e soro. Foi encontrada sensibilidade para CEA, CYFRA21-1 e CA 15-3 no líquido pleural de 69,4%, 69,4% e 66,7%, respectivamente e quando associados, foi 80,6%. No soro, a sensibilidade foi 57,1, 71,4 e 48,6% para CEA, CYFRA21-1 e CA 15-3, respectivamente, e quando associados, foi 77%. CONCLUSÃO: Os resultados sugerem que a utilização desses marcadores pode ser útil na diferenciação entre derrames pleurais malignos e benignos.OBJECTIVE: To determine the levels of the tumor markers carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1) and carbohydrate antigen 15-3 (CA 15-3) in the blood and pleural fluid of patients with benign or malignant pleural effusion, evaluating the sensitivity of each marker in these fluids. METHODS: We prospectively evaluated 85 patients with pleural effusion. The study of the pleural fluid observed the criteria established in the literature. Levels of the markers were determined using electrochemiluminescence. The sensitivity was determined on the condition that the specificity was > 90%. RESULTS: Of the 85 cases, 36 (42.4%) were malignant, 30 (35.3%) were benign, and the results were inconclusive in 19 (22.3%). In the malignant cases, the CEA and CYFRA21-1 levels were higher in the pleural fluid than in the blood, which was not observed for CA 15-3. In the benign cases, the CYFRA21-1 levels were higher in the pleural fluid than in the blood, whereas the opposite was found for CEA and CA 15-3. There were significant differences between malignant and benign cases for all markers, in pleural fluid and blood. In the pleural fluid, the sensitivity of CEA, CYFRA21-1 and CA 15-3 was 69.4, 69.4 and 66.7%, respectively, and the combined sensitivity was 80.6%. In the blood, the sensitivity was 57.1%, 71.4% and 48.6% for CEA, CYFRA21-1 and CA 15-3, respectively, and the combined sensitivity was 77%. CONCLUSION: The results suggest that these markers might be useful in the differentiation between malignant and benign pleural effusion.

The aim of this study is to determine the prognostic value of tumor markers, as squamous cell carcinoma antigen (SCCAg) and cytokeratin-19 fragment (CYFRA 21.1) and interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), soluble tumor necrosis factor receptor I (sTNF RI), and sTNF RII in patients with squamous cell carcinoma of the cervix. The subjects of analysis were 138 patients with stage I-IVA according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The collected research material comes from one oncology center. During the 10 years of follow-up, 56 relapses and 53 deaths were observed, and recurrent disease in early stage was confirmed in 45 % of patients. The pretreatment serum levels of SCCAg and CYFRA 21.1, and cytokines IL-6, VEGF, sTNF RI, and sTNF RII were determined in all patients. The probability of disease-free survival (DFS) and overall survival (OS) was evaluated using the log-rank test and the Cox regression model. Based on the ROC curve analysis for patients with recurrence, the largest area under the curve was demonstrated for SCCAg and IL-6 and for patients who died, for SCCAg and VEGF. Cox analysis demonstrated that independent prognostic factor for DFS was only SCCAg and for OS cytokine IL-6 and SCCAg, but in patients with early stage the prognostic value for DFS was VEGF, whereas IL-6 and CYFRA 21.1 for OS. Serum level of VEGF, CYFRA 21.1 and IL-6 before treatment in patients with early stage cervical cancer appears to be an important prognostic factor. [ABSTRACT FROM AUTHOR]

Aim: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of interstitial lung diseases, however, clinically relevant biomarkers of diagnosis or prognosis are lacking. In this study, we investigated the levels of a fragment of Cytokeratin 19 (CYFRA 21.1) in bronchoalveolar lavage (BAL) of IPF patients at time of diagnosis. We further evaluated associations between CYFRA 21.1, pulmonary function evolution, mortality, and BAL cell count.Materials and Methods: Using the Lumipulse® G1200, CYFRA 21.1 was measured in BAL samples of 81 IPF patients and 9 controls. Based upon the median detected level (1.2 ng/mL) of CYFRA 21.1 in IPF patients, they were subdivided into an IPF CYFRA 21.1 low group (≤ 1.2 ng/mL) and IPF CYFRA 21.1 high group (> 1.2 ng/mL).Results: The CYFRA 21.1 levels were significantly higher in BAL of IPF patients compared to controls (P= .0015).Worse survival was observed, but no changes in pulmonary function, for IPF patients with high CYFRA 21.1 levels versus patients with low CYFRA 21.1 levels [P= .030, HR: 0.41, (0.18-0.92)[. The CYFRA 21.1 level correlated with both neutrophils (%:R= 0.60,P< .0001; #:R= 0.47,P< .0001) and eosinophils (%:R= 0.38,P= .0005; #:R= 0.30,P< .0072).Conclusions: CYFRA 21.1 is increased in BAL of IPF patients. IPF patients with a high CYFRA 21.1 concentration have a worse survival. CYFRA 21.1 levels correlate with eosinophils and neutrophils. Further studies are warranted in using CYFRA 21.1 as a biomarker for IPF prognosis. [ABSTRACT FROM PUBLISHER]

Objective: No investigation has been conducted on the association between PET findings and serum Cyfra 21.1 and CEA levels in nonsmall cell lung cancers (NSCLC). The purpose of this study is to find out if the serum levels of Cyfra 21.1 and CEA are related to metabolic parameters by FDG PET in patients with NSCLC who had not received treatment. Methods: Seventy-six NSCLC patients, who were admitted for initial staging by FDG PET/CT, were included in the study. Serum Cyfra 21.1 and CEA levels were assayed by enzyme-linked immunosorbent assay. FDG-PET images were analyzed with visual and quantitative methods. Standard uptake values (SUV), metabolic tumor volumes (MTV) and total lesion glycolysis were calculated for primary lesion (T) and whole-body lesions (primary and metastatic) (WB). Results: Serum Cyfra 21.1 and CEA level was significantly higher in patients with locoregionally advanced disease ( p < 0.05, p < 0.05, respectively) and metastatic disease ( p < 0.01, p < 0.05, respectively) compared to those with localized disease. The serum ln-Cyfra-21.1 was significantly correlated with all volumetric tumor parameters ( p < 0.001) and slightly with ln-SUVmean.WB ( p < 0.05). There was no relationship between CEA levels and any PET metabolic parameters ( p > 0.05). In multiple linear regression analysis incorporating ln-MTV.WB and ln-SUVmean.WB as independents, ln-MTV.WB correlated significantly and positively with ln-Cyfra-21.1 ( β = 0.744, p < 0.001), whereas ln-SUVmean.WB did not significantly predict ln-Cyfra-21.1 ( β = 0.019, p > 0.05). Conclusion: This study demonstrates the existence of a significant relationship between total tumor burden and the serum Cyfra 21.1 level in NSCLC patients who had not received treatment. However, it requires further confirmation in operated NSCLC patients. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to assess the clinical utility of circulating preoperative Cyfra 21.1 [soluble fragment of cytokeratin (CK) 19] and galectin-3 (gal-3) in patients with thyroid tumors, to compare their serum values with tissue expression and to analyze the prognostic significance of these markers in relation to the clinical status of postsurgical differentiated thyroid carcinoma (DTC) patients. Patients: Concentrations of Cyfra 21.1 and gal-3 were evaluated by immunoassays in sera of 9 healthy subjects, 97 preoperative patients with diverse thyroid tumors (10 FTA, 63 PTC, 11 FTC, 5 PDTC, 4 ATC, 4 LNM) and 25 postoperative DTC patients (14 remissions and 11 metastases). Results: Low Cyfra 21.1 values were found in all subgroups, but with a tendency toward higher values in poorly differentiated DTC patients. Compared to the control (0.23 ng/mL), serum levels of gal-3 were significantly elevated in patients with thyroid tumors but with overlapping between adenoma (4.16 ng/mL) and carcinoma (3.85, 4.37, 4.64, 6.07 ng/mL for PTC, PDTC, ATC and LNM, respectively). The tissue expression of CK19 and gal-3 was immunohistochemically determined on 45 matched paraffin-embedded sections. Most thyroid carcinomas showed positive CK19 (27/35) and gal-3 immunostaining (31/35), while adenomas were mostly immunonegative (8/10 and 7/10, respectively). However, there was no significant correlation between their serum and tissue levels. Clinical status of postoperative DTC patients had no influence on serum concentrations of the tested markers. Conclusions: While CK19 and gal-3 are accurate as tissue markers, their serum levels could not be used as reliable markers for identification of thyroid malignancy or in thyroid cancer follow-up. On the other hand, a tendency toward higher serum levels of Cyfra 21.1 in the small number of PDTC patients examined adds weight to previous reports postulating a role for cytokeratins in predicting a high degree of malignancy. [ABSTRACT FROM AUTHOR]

Summary: Background: Serum markers have been tested in patients with malignant effusions for their ability to differentiate malignant pleural mesothelioma from other causes. We have assessed three different serum markers and report our findings in a series of patients with different thoracic malignancies and a group of healthy controls. Methods: A retrospective analysis of 179 patients and 50 healthy controls was performed. Seventy-four patients had a confirmed mesothelioma, and 106 patients had non-small cell lung cancer (NSCLC), 55 had adenocarcinoma. Soluble mesothelin-related protein (SMRP), Cyfra 21.1, and carcino-embrionic antigen (CEA) were tested in serum at time of presentation. Results: Cyfra 21.1 was the best single marker discriminating healthy from any malignant disease (area under receiver operating characteristics curve (AUC): 0.92; 95% confidence interval (CI): 0.89–0.96). By combining all three markers the discriminatory power improved marginally (AUC: 0.95; CI: 0.93–0.98; p =0.015). The combination of CEA and SMRP was most accurate in differentiating mesothelioma from NSCLC (AUC: 0.94; 95% CI: 0.90–0.97) and could correctly identify 152 of 179 (85%) cases. Conclusions: By using two serum markers (CEA and SMRP) we were able to discriminate mesothelioma from NSCLC with high sensitivity, while Cyfra 21.1 is useful in the discrimination of normal versus malignancy. [Copyright &y& Elsevier]

Abstract: Objectives: The objective of this prospective study is to establish an appropriate cutoff value of urinary CYFRA 21.1 assay and to assess its utility combined with voided cytology and/or haemoglobin dipstick in the follow-up of patients with superficial bladder cancer. Methods: From December 2000 to November 2003, 446 patients in follow-up for superficial bladder cancer (Ta–T1) after transurethral resection of the bladder (TURB) were included in a prospective study. Voided urine specimens were collected 7–14 d before cystoscopy and/or TURB for CYFRA 21.1 (one sample), haemoglobin dipstick (one sample), and cytology (three samples). All samples were processed for CYFRA 21.1 and haemoglobin dipstick according to manufacturer instructions. A control group (n =185) was obtained from patients in follow-up after transurethral resection of superficial disease (without recurrences within the following 6 mo). There were 125 recurrent transitional tumours detected by cystoscopy (34 TaG1; 53 TaG2/T1G1–2; 23 Ta–1G3/Tis, and 15 T2–4). Receiver operator characteristic (ROC) curves were constructed and cutoff values were chosen. Sensitivity, specificity, PPV (positive predictive value), NPV (negative predictive value), and their 95% confidence intervals were calculated. Results: ROC curve analysis based on the previously reported cutoff value of 4ng/ml for CYFRA 21.1 demonstrated a sensitivity and specificity of 43% and 68%, respectively. At a cutoff value of 1.5ng/ml, sensitivity was 73.8% with a low specificity (41%). Further lowering of the cutoff point below 1.5ng/ml did not demonstrate a significant increase in sensitivity. Therefore, this value was chosen as the most sensitive CYFRA 21.1 cutoff point during the rest of the study. Specificity increased when all the patients treated with pelvic radiotherapy or with UTI, urethral catheterisation, and intravesical instillations within 3 previous months were not included in our analysis. CYFRA 21.1 plus cytology and the combination of CYFRA 21.1, cytology, and haemoglobin dipstick demonstrated the highest overall sensitivities, and detected 91.3% of Ta–1G3 tumours and 93.3% of T2–4 tumours. However, there were one muscle-invasive tumour, two T1G3/Tis, three T1G2, and nine T1G1 neoplasms with negative combination of cytology and CYFRA 21.1 (1,5ng/ml). All these tumours were smaller than 2cm in size; most were single tumours. Nevertheless, there were 16 tumours larger than 0.5cm (0.5–2cm), and multiple neoplasms were endoscopically detected in 14 patients. Similar results were obtained through the combination of CYFRA 21.1 (cutoff: 1.5ng/ml), cytology, and haemoglobin dipstick. Conclusions: In our experience the low sensitivity of urinary CYFRA 21.1, even using lower cutoff values and/or a combination with cytology and/or haemoglobin dipstick, makes its application not very useful as a surveillance tool for superficial bladder carcinoma. [Copyright &y& Elsevier]

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Simple Summary: The role of serum Cyfra 21.1 as a biomarker in thyroid cancer has yet to be validated. This study investigated the diagnostic or prognostic role of serum Cyfra 21.1 in thyroid cancer. In the present analysis, we found that serum Cyfra 21.1 was increased in thyroid cancer with distant metastasis compared with thyroid cancer without metastasis. Furthermore, in progressive disease when thyroglobulin was undetectable or thyroglobulin monitoring was useless because of thyroglobulin antibody, serial follow-up based on serum Cyfra 21.1 levels might be used as an alternative biomarker for disease monitoring. Background: Serum Cyfra 21.1, the soluble fragment of CK19, has been used as a prognostic tumor marker in various cancers, indicating poor tumor differentiation and increased metastasis. Methods: We analyzed the serum Cyfra 21.1 level in 51 consecutive patients with thyroid cancer manifesting distant metastasis treated with prior total thyroidectomy. Serum Cyfra 21.1 levels of 26 thyroid cancer patients without metastasis and 50 healthy individuals were used for comparison. Results: Higher serum Cyfra 21.1 levels were detected in thyroid cancer patients with distant metastasis compared with healthy subjects and thyroid cancer patients without metastasis (p = 0.012). Serum Cyfra 21.1 levels were significantly increased in patients with positive BRAF V600E mutation (p = 0.019), undergoing Tyrosine Kinase Inhibitor (TKI) therapy (p = 0.008), with radioiodine-refractory status (p = 0.047), and in disease progression compared with those manifesting stable disease (p = 0.007). In progressive disease with undetectable or unmonitored thyroglobulin because of thyroglobulin antibody, serum Cyfra 21.1 was useful as a biomarker for follow-up of disease course. Conclusion: Serum Cyfra 21.1 in thyroid cancer patients might represent an alternative biomarker predicting tumor progression, especially in cases not associated with serum Tg levels. [ABSTRACT FROM AUTHOR]

Fine needle aspiration cytology (FNAC) and washout thyroglobulin (Tg) measurements are the standard for evaluating a metastatic lymph node (LN) in thyroid cancer. However, patients rarely benefit from these procedures due to false results. This study aims to identify a reliable biomarker that significantly improves the diagnosis of metastatic LNs, in addition to FNAC and washout Tg. This study analyzed 130 LNs that were suspected to have metastases on thyroid ultrasonography, from June 2016 to December 2017. All subjects underwent FNAC, washout Tg measurements and a new biomarker, washout Cytokeratin fragment 21-1 (CYFRA 21-1) measurement. The final LN outcomes were confirmed by surgical histology, repeat FNAC, or follow-up image. The diagnostic values of the presence of washout CYFRA 21-1 for diagnosing metastatic LNs were evaluated according to final LN outcomes. Among the 130 LNs, 42 were metastatic lesions and 88 were benign. The washout CYFRA 21-1 levels were significantly higher in metastatic LNs than in benign LNs. In contrast to the findings of washout Tg, washout CYFRA 21-1 showed little overlap between benign and malignant LNs, and its diagnostic cutoff values were not affected by surgery. The combinations of FNAC and washout CYFRA 21-1 showed higher sensitivity (91.9%), specificity (96.5%), negative predictive value (98.8%), and diagnostic accuracy (94.2%) than FNAC with washout Tg. The combination of FNAC, washout Tg, and washout CYFRA 21-1 showed the best sensitivity (98.8%). When washout CYFRA 21-1 was applied to the discordant results that were observed between FNAC and washout Tg, 20 of 22 LNs were correctly diagnosed. Washout CYFRA 21-1 measurements in thyroid LNs provide a diagnostic modality. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine the prognostic value of tumor markers, as squamous cell carcinoma antigen (SCCAg) and cytokeratin-19 fragment (CYFRA 21.1) and interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), soluble tumor necrosis factor receptor I (sTNF RI), and sTNF RII in patients with squamous cell carcinoma of the cervix. The subjects of analysis were 138 patients with stage I-IVA according to the International Federation of Gynecology and Obstetrics (FIGO) classification. The collected research material comes from one oncology center. During the 10 years of follow-up, 56 relapses and 53 deaths were observed, and recurrent disease in early stage was confirmed in 45 % of patients. The pretreatment serum levels of SCCAg and CYFRA 21.1, and cytokines IL-6, VEGF, sTNF RI, and sTNF RII were determined in all patients. The probability of disease-free survival (DFS) and overall survival (OS) was evaluated using the log-rank test and the Cox regression model. Based on the ROC curve analysis for patients with recurrence, the largest area under the curve was demonstrated for SCCAg and IL-6 and for patients who died, for SCCAg and VEGF. Cox analysis demonstrated that independent prognostic factor for DFS was only SCCAg and for OS cytokine IL-6 and SCCAg, but in patients with early stage the prognostic value for DFS was VEGF, whereas IL-6 and CYFRA 21.1 for OS. Serum level of VEGF, CYFRA 21.1 and IL-6 before treatment in patients with early stage cervical cancer appears to be an important prognostic factor.