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PURPOSE : Circulating tumour DNA (ctDNA) is a promising biomarker for detection of non-invasive epidermal growth factor receptor ( EGFR ) mutations in patients with non-small-cell lung cancer (NSCLC). However, the existing methods have limitations in sensitivity or in availability. The aim was to evaluate the accuracy of capture target sequencing for detecting EGFR mutations in ctDNA. METHODS : A total of 79 patients with NSCLC and available plasma and matched tissue specimens were enrolled. Through capture target sequencing, mutations were searched in over 20 000 reads obtained from each exon region. Parameters corresponding to the limit of detection and limit of quantification were used as the thresholds for mutation detection. To evaluate the accuracy, detection of EGFR mutations in matched tissue samples was performed by target capture sequencing and the amplification refractory mutation system (ARMS). RESULTS:   : EGFR mutations were discovered in 32.9 % (26/79) of the patients with NSCLC, the overall rate of consistency for the 79 paired plasma and tissue samples was 86.1 % (68/79). The sensitivity and specificity of detecting EGFR mutations in the plasma were 72.7 % and 95.7 %. In terms of the EGFR mutations identified by ARMS, the overall consistency was 78.5 % (62/79) in three groups. Of 21 patients with EGFR sensitive mutation defined by next generation sequencing in ctDNA, 20 (95.2%) showed long-term disease control with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) treatment; the median progression-free survival was 10.8 months (95% CI 9.1 to 16.8). CONCLUSIONS: Target capture sequencing of ctDNA can be used for genotyping of EGFR in patients with NSCLC, which may enable a direct recommendation for EGFR TKI on the basis of positive results with plasma DNA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Primary adenosquamous carcinoma (ASC) of the lung is rare. The current study was a retrospective two-institutional analysis of surgical therapy with respect to the clinicopathological characteristics and prognostic factors associated with ASC of the lung., Methods: The clinical records of patients with pathologically confirmed ASC of the lung treated surgically in two centres between January 2008 and December 2014 were retrospectively reviewed., Results: One hundred and four patients with ASC of the lung after surgical intervention, including 68 males and 36 females were identified. The 5-year overall survival (OS) and disease-free survival (DFS) of all ASC stages were 38.3 and 16.9%, respectively. Patients with N0, N1 and N2 ASC [N0 vs N1 (P = 0.047) and N1 vs N2 (P = 0.028), respectively], or Stage I, II and IIIA ASC [Stage I vs Stage II (P = 0.005) and Stage II vs Stage IIIA (P = 0.016), respectively] had significant differences with respect to OS. Multivariate analysis using a Cox proportional hazards model indicated that the level of serum carbohydrate antigen 12-5 (CA 12-5) (normal vs high level, P = 0.029), TNM stage [Stage I vs Stage IIIA (P < 0.001), Stage II vs Stage IIIA (P = 0.001)] and adjuvant chemotherapy (P = 0.027) were significant factors associated with OS in ASC patients, and TNM stage [Stage I vs Stage IIIA (P < 0.001), Stage II vs Stage IIIA (P = 0.003)] and adjuvant chemotherapy (P < 0.001) were the significant prognostic variables for DFS., Conclusions: Serum CA 12-5 level and TNM status predict the long-term prognosis of resected primary ASC of the lung. Postoperative platinum-based chemotherapy improved survival in patients with ASC., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We hypothesized that plasma-based EGFR mutation analysis for NSCLC may be feasible for monitoring treatment response to EGFR TKIs and also predict drug resistance.Clinically relevant mutations including exon 19 deletion (ex19del), L858R and T790M were analyzed using droplet digital PCR (ddPCR) in longitudinally collected plasma samples (n = 367) from 81 NSCLC patients treated with EGFR TKI. Of a total 58 baseline cell-free DNA (cfDNA) samples available for ddPCR analysis, 43 (74.1%) had the same mutation in the matched tumors (clinical sensitivity: 70.8% [17/24] for L858R and 76.5% [26/34] for ex19del). The concordance rates of plasma with tissue-based results of EGFR mutations were 87.9% for L858R and 86.2% for ex19del. All 40 patients who were detected EGFR mutations at baseline showed a dramatic decrease of mutant copies (>50%) in plasma during the first two months after treatment. Median progression-free survival (PFS) was 10.1 months for patients with undetectable EGFR v 6.3 months for detectable EGFR mutations in blood after two-month treatment (HR 3.88, 95% CI 1.48-10.19, P = 0.006). We observed emerging resistance with early detection of T790M as a secondary mutation in 14 (28.6%) of 49 patients. Plasma-based EGFR mutation analysis using ddPCR can monitor treatment response to EGFR TKIs and can lead to early detection of EGFR TKIs resistance. Further studies confirming clinical implications of EGFR mutation in plasma are warranted to guide optimal therapeutic strategies upon knowledge of treatment response and resistance.

Background: Several prognostic factors have been studied in NSCLC, although it is unknown which is most useful. In this study, we aimed to investigate whether pre-treatment serum albumin level has prognostic value in patients with Stage IIIB NSCLC., Materials and Methods: This cross-sectional study included a total of 204 patients with Stage IIIB NSCLC who met the inclusion criteria. Pre-treatment serum albumin levels and demographic, clinical, and histological characteristics, as well as laboratory variables were recorded. A cut-off value was defined for serum albumin level and the patients were stratified into four groups on thios basis., Results: The majority of the patients was males and smokers, with a history of weight loss, and squamous histological type of lung cancer. The mean serum albumin level was 3.2±1.7 g/dL (range, 2.11-4.36 g/dL). A cut-off value 3.11 g/dL was set and among the patients with a lower level, 68% had adenocarcinoma and 82% were smokers. The patients with low serum albumin levels had a lower response rate to e first-line chemotherapy with a shorter progression-free survival and overall survival. Multivariate analysis showed that low serum albumin level was an independent poor prognostic factor for NSCLC., Conclusions: This study results suggest that low serum albumin level is an independent poor prognostic factor in patients with Stage IIIB NSCLC, associated with reduction in the response rate to first-line therapy and survival rates.

Background: We evaluated the prognostic value of pretreatment serum biomarkers in predicting outcomes in cervical cancer patients subjected to treatment., Methods: Serum samples collected from 60 cervical cancer patients and 60 age-matched healthy individuals were used for the detection of 22 biomarkers, prior to therapy. Cox multivariate analysis and classification and regression tree analysis (CART) were performed to evaluate the prognostic factors., Results: Cox multivariate analysis disclosed that carbohydrate antigen 153 (CA153), squamous cell carcinoma antigen (SCC) and tumor necrosis factor-α (TNF-α) are associated with prognosis in cervical cancer. CART analysis led to the stratification of patients into 3 groups: (1) serum concentrations of CA153 ≥17.60 μg/l, (2) serum concentrations of CA153 <17.60 μg/l and TNF-α ≥10.60 pg/ml, and (3) serum concentrations of CA153 <17.60 μg/l and TNF-α <10.60 pg/ml. The 2-y overall survival rates for Groups 1, 2 and 3 were 33.3%, 60.0% and 93.9%, respectively., Conclusions: Higher serum concentrations of TNF-α, SCC and CA153 before therapy are independently associated with poor prognosis in patients with stage I and II disease. Combined usage of these three biomarkers allows efficient evaluation of outcomes in cervical cancer patients., (© 2013 Elsevier B.V. All rights reserved.)

Gastric cancer (GC) is 1 of the most common human cancers. Early detection remains the most promising approach to improving long-term survival of patients with GC. We previously performed Serial Analysis of Gene Expression (SAGE) on 4 primary GCs and identified several GC-specific genes including Reg IV. Of these genes, olfactomedin 4 (OLFM4, also known as GW112 or hGC-1) is a candidate gene for cancer-specific expression. In this study, we examined the expression of olfactomedin 4 in human GC by immunohistochemistry. We also assessed serum olfactomedin 4 levels in GC patients by enzyme-linked immunosorbent assay. 94 (56%) of 167 GC cases were positive for olfactomedin 4 by immunostaining. Olfactomedin 4 staining was observed more frequently in stage I/II cases than in stage III/IV cases. The serum olfactomedin 4 concentration in presurgical GC patients (n = 123, mean +/- SE, 36.3 +/- 3.5 ng/mL) was significantly higher than that in healthy individuals (n = 76, 16.6 +/- 1.6 ng/mL). In patients with stage I GC, the sensitivity of serum olfactomedin 4 (25%) and Reg IV (35%) was superior to that of CA19-9 (5%) or CEA (3%). Furthermore, in patients with stage I GC, the combination of olfactomedin 4 and Reg IV elevated the diagnostic sensitivity to 52%. These results suggest that serum olfactomedin 4 is a useful marker for GC and its measurement alone or in combination with Reg IV has utility in the early detection of GC.

Background: The propensity of malignant tumors to increase in size, to invade locally and to metastasize is dependent on angiogenesis, which is induced by a variety of proteins including the family of fibroblast growth factors, vascular endothelial growth factor and angiogenin (ANG). The aim of the present study was to measure the serum levels of ANG in patients with CIN and invasive cervical cancer and to evaluate a possible correlation between ANG and various clinicopathologic parameters., Materials and Methods: Blood was collected from 62 patients with invasive cervical cancer and 47 patients with CIN. Serum samples of 30 age-matched healthy women acting as a control group were obtained. Determination of serum levels of ANG was performed using a quantitative human ANG immunoassay., Results: The overall median ANG serum level was 272.0 pg/ml (range 101.6-869.2). The median serum levels of ANG were 248.9 (range 101.6-307.2) for healthy female controls, 246.8 (range 169.7-468.1) for patients with CIN and 308.1 pg/ml (range 180.1-869.2) for patients with invasive cervical cancer. Serum levels of ANG were significantly elevated in patients with invasive cervical cancer compared with patients with CIN (p < 0.05) as well as healthy female controls (p < 0.05). No difference was found between ANG serum levels in women with CIN, and healthy controls (p < 0.05). No correlations were found between serum levels of ANG and clinico-pathologic parameters (p > 0.05)., Conclusions: Our data indicate the important role of ANG in tumor angiogenesis in invasive cervical cancer as ANG serum levels were significantly elevated in these patients. However, elevated ANG serum levels seem to occur only after the transformation from pre-invasive to invasive lesions.

Objective: The clinical value of tumor markers for early detection of recurrence was investigated in 32 patients with cervical adenocarcinoma or adenosquamous carcinoma who had recurrent tumors., Methods: Serum levels of CA 125, CA 19-9, carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCC), in addition to clinical status at the time of recurrence were investigated., Results: Among the 32 patients, 26 had no symptoms at the time of recurrence. In 20 patients, elevated serum levels of tumor markers were the first sign of recurrence. In 21 patients with recurrent adenocarcinoma, the positive rates were 14% (CA 125), 62% (CA 19-9), 29% (CEA), and 5% (SCC). There were 71% of cases positive for CA 19-9 and/or CEA. In 11 patients with recurrent adenosquamous carcinoma, the corresponding positive rates were 37% (CA 125), 46% (CA 19-9), 64% (CEA), and 55% (SCC), with 100% positive for CA 19-9, CEA, and/or SCC., Conclusions: The combination of CA 19-9 and CEA is probably the most promising for detection of recurrent cervical adenocarcinoma. For adenosquamous carcinoma, the additional use of SCC is recommended., (Copyright 2000 S. Karger AG, Basel.)

The relationship between preoperative serum carcinoembryonic antigen (CEA) level and treatment outcome for 39 clinical-stage I patients with surgically resected non-small-cell lung cancer (NSCLC) was retrospectively studied. Serum CEA levels were measured with an enzyme-linked immunosorbent assay kit, with the upper limit of normal defined as 6.7 ng/mL based on the 95% specificity level for benign lung disease in our hospital. Patients with serum CEA > or = 6.7 ng/mL (n = 9) were more likely to have advanced disease at surgery than those with serum CEA < 6.7 ng/mL (n = 30) (77.8% vs 16.7%, p = 0.0049). This increase in disease stage at surgery was mainly due to mediastinal lymph node metastasis. The sensitivity and specificity of serum CEA in the detection of pathological N2 disease were 62.5% and 87.1%, respectively. Survival for the high CEA group was significantly worse than that for the low CEA group (median survival time, 40.2 vs 75.8 months, p = 0.0125). Relapse-free survival for the high CEA group was also poorer than that of the low CEA group (p = 0.0032). In a multivariate analysis, serum CEA level was the most dominant factor affecting relapse-free survival (hazard ratio = 6.68, p = 0.0053). These findings suggest that preoperative serum CEA level is useful not only in detection of mediastinal lymph node metastasis, but also in prediction of survival for clinical-stage I patients with NSCLC.

We examined the expression of cytokeratin 20 (CK20) mRNA in the peripheral blood of oral squamous cell carcinoma (SCC) patients by reverse transcriptase polymerase chain reaction (RT-PCR). Eleven out of 12 oral SCC patients showed positive RT-PCR results. However, there is no clear relationship between the haematogenous CK20 mRNA and the metastasis. After initial treatment, all of the tumour-free survivors tested showed negative RT-PCR results. CK20 mRNA in peripheral blood can be used as a marker for tumour recurrence but not not for metastasis in oral SCC patients.

Preoperative evaluation of squamous cell carcinoma antigen (SCCa) was performed in 220 patients with surgically treated early-stage carcinoma of the cervix. The median duration of follow-up was 1.9 years. SCCa was significantly higher in tumors with a squamous element (P < 0.001). There was a squamous element in 171 tumors. SCCa was elevated (>2 ng/ml) in 21.6%. Significantly higher levels were associated with stage II disease (P < 0.001), tumors >4-cm size (P < 0.001), and lymph node metastases (P < 0.001). The positive predictive value for lymph node metastases at >2, >4, and >8.6 ng/ml SCCa is 51.4, 70.0, and 100% and the sensitivity is 58.1, 45.2, and 22.6%, respectively. Low SCCa is a poor predictor of absence of lymph node metastasis. The median SCCa for patients who developed tumor recurrence was greater than those who remained disease free (1.7 and 1.0 ng/ml, respectively, P = 0.009); however, in a multivariate analysis only lymph node metastasis and tumor size were of independent prognostic significance (P = 0.002 and P = 0.004, respectively). SCCa level >8.6 ng/ml is highly predictive of lymph nodal disease. There is no independent prognostic significance in patients with early-stage surgically treated cervical carcinoma.

Tissue polypeptide specific antigen (TPS) was measured by TPS ELISA in the sera of 88 patients with FIGO stage II and III cervical cancer and 93 healthy Thai women as the control group. The mean serum TPS levels were 63.1 U/L in the control group, and 166.4 and 363.2 U/L in stage II and III cervical cancer respectively. The mean of the control group and stage II patients were not significantly different while the mean of stage III patients was significantly different from those two groups (p < 0.0005). With the cut-off value of 90 U/L, the rates of TPS elevation were 22/35 (65.7%) in stage II and 42/53 (79.2%) in stage III patients. As for the pathology, squamous cell carcinoma showed a statistical difference from adenocarcinoma and adenosquamous carcinoma of P = 0.001. For squamous cell carcinoma, there was no difference between the keratinized and non-keratinized type (P = 0.451). TPS is not sensitive in stage II. However, it might be useful for predicting prognosis if the elevation is significantly high, and distant metastases or local recurrence should be investigated.