[Faecal occult blood test for colorectal cancer screening: high quality for a good price]. / Ontlastingstest bevolkingsonderzoek darmkanker: goede kwaliteit tegen een goede prijs.

The Dutch National Institute for Public Health and the Environment (RIVM) awarded the immunochemical faecal occult blood test (IFOBT) to FOB Gold of Sentinel following a European call for tenders. The contract-awarding procedure included the application of quality knock-out criteria, which were met by two suppliers. The decisive factor was the best price/quality ratio. A recent review indicated that, at present, no single IFOBT is better than any other. The decision to opt for a test manufactured by a different supplier than was used in the previous screening pilots made it necessary to re-determine the cut-off value. This value has now been set (88 ng/ml) and is confirmed by a laboratory test. Colonoscopy-related capacity planning, as well as its diagnostic yield, depends on numerous factors; therefore, the RIVM is currently monitoring the referral percentage and number of adenomas detected and is collaborating on quality terms. Any necessary adjustments are to be made during the introduction of the screening test.

An elevated progastrin-releasing peptide level in patients with well-differentiated neuroendocrine tumours indicates a primary tumour in the lung and predicts a shorter survival.

BACKGROUND: Progastrin-releasing peptide (proGRP) is a recently identified biomarker of small-cell lung cancer. In well-differentiated neuroendocrine tumours (WDNETs), this study investigates the association between proGRP and tumour characteristics and the prognostic value of proGRP levels compared with chromogranin A (CgA) levels. PATIENTS AND METHODS: Serum samples were obtained in 282 patients with WDNET. The receiver operating characteristic (ROC) curve technique was used to assess specificity and sensitivity in the identification of a primary tumour location. Cox proportional hazards models and Kaplan-Meier curves were constructed to determine the association of patients' characteristics and tumour markers with survival. RESULTS: For proGRP, the ROC curve indicated a cut-off level of 90 ng/l (approximately twice the upper reference value), with a specificity of 99% and a sensitivity of 43% in distinguishing primary pulmonary tumours from other sites. In the multivariate Cox model, both proGRP and CgA were strongly associated with survival (P < 0.0001 for both variables). CONCLUSIONS: A high-risk proGRP level (more than twice the upper reference value) in patients with WDNETs is a strong indication for a primary tumour in the lung. Besides CgA, proGRP is a complementary tumour marker for prognosis and treatment monitoring in patients with neuroendocrine tumour.

Soluble epidermal growth factor receptor (sEGFR) and carcinoembryonic antigen (CEA) concentration in patients with non-small cell lung cancer: correlation with survival after erlotinib and gefitinib treatment.

BACKGROUND: In patients with non-small cell lung cancer (NSCLC), a higher response rate can be achieved with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) when selection for therapy is guided by mutation analysis or gene amplification. However, both tests are complex and require tumour tissue. Simple methods to identify responders prior to EGFR-TKI treatment are urgently needed. This study aimed to define the relation between serum sEGFR levels, carcinoembryonic antigen (CEA) and survival in NSCLC patients treated with EGFR-TKIs. METHODS: Patients with stage III/IV NSCLC treated with gefitinib or erlotinib between July 2002 and December 2005 were reviewed. Levels of serum soluble EGFR (sEGFR) were determined by a sandwich quantitative enzyme-linked immunosorbent assay. A chemiluminescence immunoassay was used for CEA. The relation between sEGFR and survival was investigated. RESULTS: One hundred and two NSCLC patients, mainly stage IV (80%), were identified. Mean sEGFR at baseline was 55.9 µg/l (range 35.3-74.5 µg/l). The median CEA level was 11.1 µg/l (range <1.0-2938.0 µg/l). Median overall survival was 5.2 months (range 1-52 months). Decreasing log CEA values (HR 1.51, 95% CI 1.11-2.04, multivariate analysis) and increasing sEGFR values (HR 0.96, 95% CI 0.93-0.99, multivariate analysis) were both independently associated with prolonged survival. Higher levels of pre-treatment sEGFR were associated with lower risk of progressive disease within three months (p=0.04). CONCLUSIONS: Both baseline sEGFR and CEA levels in NSCLC patients receiving EGFR-TKIs showed a significant correlation with survival. To distinguish whether these factors have a predictive or a prognostic value, validation is warranted in an independent patient series containing a control arm without EGFR-TKI treatment.

[Application of tumour markers in clinical practice]. / Toepassing van tumormarkers in de klinische praktijk.

Usefully requesting and applying serum tumour markers in diagnosis and treatment can be difficult. It should be noted that tumour markers are used for varying purposes: screening, diagnosis, staging and prognostic evaluation, detection of recurrence and treatment monitoring. Due to the poor sensitivity and specificity of current tumour markers, most are not suitable for screening an asymptomatic population. Further, the benefits of an improved prognosis by early detection should be weighed against a poorer quality of life and the cost of substantial over-diagnosis and over-treatment. Serum tumour markers are particularly applicable in treatment monitoring and detection of recurrence. Sometimes they can be used to support the diagnostic process and give useful prognostic information.

Value of serum S-100B for prediction of distant relapse and survival in stage III B/C melanoma.

BACKGROUND: The biochemical marker serum S-100B has been proven to reflect the stage of melanoma and to be useful for disease monitoring and prediction of survival, mainly in stage IV disease. For stage III melanoma, limited data are available and its predictive value for relapse is unknown. Serum S-100B was evaluated prospectively for monitoring response and its predictive value for relapse and overall survival in stage IIIB/C melanoma patients. PATIENTS AND METHODS: Treatment consisted of one cycle of neoadjuvant and adjuvant chemo(immuno)therapy, around surgery. S-100B was measured at enrollment and prior to and following surgery. The levels of S-100B in serum were compared to the pattern and intensity of the expression of S-100B in the melanoma tissue. RESULTS: Some patients with normal initial S-100B values (n=18) showed responses (3 complete remission and 2 partial remission), in contrast to patients with elevated S-100B values. Distant relapse within one year was found in 11/23 (48%) patients with increased S-100B versus 2/18 (11%) patients with a normal value (p=0.01). Overall survival was decreased in patients with increased S-100B compared to those with normal S-100B (p=0.02). Correlations between the pattern and intensity of S-100B expression in the tumor specimen and the value of serum the S-100B did not reach statistical significance. CONCLUSION: Serum S-100B is a valuable biomarker for the evaluation of response to treatment and prediction of early distant relapse and survival in stage IIIB/C melanoma. The marginal correlation between serum S-100B values and expression of S-100B in the tumor specimens needs further study.

S-100B protein and melanoma inhibitory activity protein in uveal melanoma screening. A comparison with liver function tests.

AIM: Our purpose was to determine whether S-100B or melanoma inhibitory activity (MIA) concentrations in the serum of patients with large uveal melanomas were better markers for the presentation of metastases than liver function tests. We also investigated whether increased marker levels were related to known clinical and histopathological prognostic parameters. METHODS: Total S-100B (A1B + BB) and MIA concentrations were measured in the sera from 104 patients with uveal melanoma prior to enucleation and in the sera from 50 healthy controls. Concentrations were also determined in the sera from 30 patients with known uveal melanoma metastases. Liaison Sangtec 100, an automated immunoluminometric assay measuring the total S-100B, and Roche MIA ELISA were used to quantify these proteins in serum. Results were compared with liver function tests [alkaline phosphatase, lactate dehydrogenase (LD), aspartate aminotransferase, alanine aminotransferase and gamma-glutamyl transpeptidase]. RESULTS: The mean S-100B and MIA concentrations were significantly higher in patients with metastases compared to melanoma patients without metastases. At the time of enucleation, S-100B and MIA were not prognostic for metastases in uveal melanoma, but S-100B and LD were the best tests to predict the occurrence of metastatic disease during the follow-up period. CONCLUSIONS: In our study, the S-100B and MIA serum concentrations were not correlated with any tested established prognostic parameter. S-100B and LD showed better performance in identifying melanoma metastases than gamma-glutamyl transpeptidase and MIA. A prospective follow-up study is needed to evaluate S-100B and MIA in identifying early micrometastasis in uveal melanoma.

Immunophenotypic markers to differentiate between benign and malignant melanocytic lesions.

BACKGROUND/AIMS: The authors investigated the expression of S100A1, S100A6, S100B, MelanA, and CEA in conjunctival naevi, primary acquired melanosis (PAM), conjunctival melanoma, and uveal melanoma in order to assess their potential usefulness in the pathological differential diagnosis of these entities. METHODS: Paraffin embedded sections of 18 conjunctival naevi, 14 PAM, 16 conjunctival melanomas, and 20 uveal melanomas were immunostained for S100A1, S100A6, S100B, MelanA, and CEA, and expression was scored semiquantitatively. RESULTS: Expression of S100A1 differed significantly between conjunctival naevi and conjunctival melanoma, with percentages of positive cells of 30.6% and 71.4%, respectively. Conjunctival melanomas had high average scores for S100A1 and S100B (71.4%, 62.9%, respectively), while uveal melanomas also had high S100A1 but low S100B scores (88.5%, 18.5%, respectively). MelanA was highly variable; naevi and uveal melanoma had higher average scores than conjunctival melanoma. CEA was hardly detectable in all four groups. CONCLUSION: S100A1 seems to be a possible candidate to differentiate conjunctival naevi from conjunctival melanoma. S100B seems to differentiate between uveal melanoma and conjunctival melanoma. However, the study size was small and therefore the data have to be confirmed by others.

SELDI-TOF MS serum protein profiles in breast cancer: assessment of robustness and validity.

There is an urgent need for new serum markers that can be applied in e.g. the early detection of breast cancer. Following detection of new, potential biomarkers, such as those reported by Vlahou et al. (Clin Breast Cancer 2003;4:230-239) and Laronga et al. (Dis Markers 2003;19:229-238), assessment of both their robustness and validity is essential to confirm their clinical applicability. We therefore aimed to determine robustness and validity of biomarkers reported by the authors mentioned, by analysis of an independent sample set (breast cancer: n=47, normal women: n=45) in our laboratory, according to the methods described by both authors. Although all markers for the differentiation between breast cancer patients and normal women, discovered in the study of Vlahou et al., were recovered in our validation data set, none had sufficient performance to be applied as a classifier. The markers discovered by Laronga et al. in the differentiation between lymph node positive and -negative breast cancer patients were in part recovered from our validation data set, but were also not applicable as a classifier. In conclusion, although (part of) the proteins discovered and designated as markers by either author could be detected, their validity as biomarkers could not be confirmed by the current study. This finding stresses that, when reporting on a potential biomarker, confirmation of both robustness and validity is essential in obtaining its true clinical applicability.

CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use.

CA125 is currently the most widely used tumor marker for ovarian epithelial cancer. The aim of this article is to provide guidelines for the routine clinical use of CA125 in patients with ovarian cancer. Due to lack of sensitivity for stage I disease and lack of specificity, CA125 is of little value in the detection of early ovarian cancer. At present, therefore, CA125, either alone or in combination with other modalities, cannot be recommended for screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial. Preoperative levels in postmenopausal women, however, may aid the differentiation of benign and malignant pelvic masses. Serial levels during chemotherapy for ovarian cancer are useful for assessing response to treatment. Although serial monitoring following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this lead-time is unclear. CA125 is the ovarian cancer marker against which new markers for this malignancy should be judged.

Comparison of four different assays for determination of serum S-100B.

BACKGROUND: S-100B determination has been shown to be clinically useful in the management of melanoma patients. After the development of a test for determination of the isoforms S100-A1B and S100-BB in serum (S-100B), several sensitive assays for the detection of serum S-100B have become available. We compared four S-100B assays, two automated (LIAISON Sangtec 100 and Elecsys S100) and two manual ones (Sangtec 100 ELISA and CanAg S100 EIA), with respect to clinical data, reference values and correlation. METHODS: In a total of 280 samples from 155 melanoma patients and 98 healthy individuals S-100B values were measured simultaneously with the different assays. RESULTS: The inter and intra coefficients of variation were best for the automated assays. The functional sensitivity of both manual assays was 0.15 microg/L. Method comparison revealed satisfactory correlation coefficients of 0.9 or higher, but the slopes ranged from 0.29 to 3.36. Except for the Sangtec 100 ELISA, the linearity between the assays was acceptable. The overall sensitivity for melanoma ranged from 37% (Elecsys S100) to 47% (LIAISON Sangtec 100) and the sensitivity increased with stage. ROC curves showed the best accuracy for the LIAISON Sangtec 100 assay. CONCLUSIONS: All assays gave satisfactory results, but it is advisable to improve the performance of the manual assays for better sensitivity. Agreement about an international reference standard is needed.

Role of natriuretic peptides in the diagnosis and treatment of patients with carcinoid heart disease.

Carcinoid heart disease (CHD) occurs in 20-70% of the patients with metastatic well-differentiated neuroendocrine tumours (NET). We evaluated whether natriuretic peptides (ANP or NT-proBNP) are useful in early detection of CHD. Blood samples from 32 patients with NET were compared with cardiac ultrasound follow-up. CHD was defined as thickening of the tricuspid valve in the presence of grade III-IV/IV tricuspid valve regurgitation. CHD was found in nine out of 32 patients (28%), all with symptoms of the carcinoid syndrome compared to 65% in the 23 patients without CHD (P=0.04). Median levels of NT-proBNP and 5-HIAA were significantly higher in patients with CHD (894 ng l(-1) and 815 micromol 24 h(-1)) compared to those without (89 and 206 ng l(-1), P<0.001 and P=0.007). No significant differences were detected in ANP levels (P=0.11). Dilatation of the right atrium and ventricle as well as thickening of the tricuspid valve and degree of regurgitation were statistically significant correlated with NT-proBNP levels. The accuracy of NT-proBNP in the diagnosis of CHD was higher than that of ANP. A significantly better survival was observed in case of normal NT-proBNP values. In conclusion, NT-proBNP is helpful as a simple marker in the diagnosis of CHD. Survival is better in patients with normal levels of NT-proBNP.

Reactivity to human papillomavirus type 16 L1 virus-like particles in sera from patients with genital cancer and patients with carcinomas at five different extragenital sites.

A retrospective seroepidemiologic study was performed to examine the association between human papillomaviruses (HPV) 16 infection and carcinomas of the oropharynx, the oesophagus, penis and vagina. Sera were selected from the serum bank from the Antoni van Leeuwenhoek Hospital (Netherlands Cancer Institute) and the Slotervaart Hospital in Amsterdam, the Netherlands. Presence of HPV 16 specific antibody was assessed using HPV 16 L1 capsids. Sera positive for HPV 16 capsid antibody were further tested for antibody against HPV 16 E7 peptides. Prevalence of antibody against HPV 16 L1 capsids among both the negative control group without cancer and the negative control group with gastric cancer was 18%, while seroprevalence among the control group of patients with HPV-associated cervical squamous cell carcinoma was 47% (P<0.001). Among the patients with penile squamous cell carcinoma seroprevalence was 38% (P<0.001), among patients with oropharyngeal carcinoma 33% (P=0.04) and among patients with oesophageal squamous cell carcinoma 14% (P=0.7). The serological evidence for association between HPV 16 infection and both oropharyngeal carcinoma and penile carcinoma was established. The conclusion that no association was found between the presence of antibody against HPV 16 L1 capsids and oesophageal squamous cell carcinoma was in accordance with results of other studies carried out in the Netherlands using HPV DNA technology. In the subjects with HPV 16 L1 capsid antibody, no association was found between the antibody against HPV 16 E7 and clinical outcome.

Serum S100B is suitable for prediction and monitoring of response to chemoimmunotherapy in metastatic malignant melanoma.

Serum S100B and lactate dehydrogenase (LDH) levels were evaluated for their ability to predict response in patients with metastatic malignant melanoma and to determine their usefulness in monitoring the results of chemoimmunotherapy. Levels were studied in 53 patients with metastatic malignant melanoma receiving chemoimmunotherapy and in 19 control patients with metastatic renal cell carcinoma receiving a similar immunotherapy regimen. The serum S100B level was elevated in 81% of the patients before treatment. Marker levels were significantly higher in patients who did not respond (n = 22). Patients with S100B levels >or= 1.0 microg/l were less likely to obtain remission or stable disease than the group with normal or moderately elevated serum concentrations (P < 0.01). After treatment, 17 of the 31 (55%) patients with stable or responsive disease had a S100B serum level below the cut-off point versus only one of the 22 (5%) patients in the group with progressive disease. For LDH the proportions of patients were 17 out of 31 (55%) and nine out of 22 (41%), respectively. In 15 melanoma patients there was a transient rise in the level of serum S100B at the beginning of systemic therapy. All 19 patients in the control group had an initial serum S100B level

Prognostic value of baseline and serial carcinoembryonic antigen and carbohydrate antigen 19.9 measurements in patients with pseudomyxoma peritonei treated with cytoreduction and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Tumor markers are useful for diagnosis and follow-up. We studied the prognostic value of baseline and serial carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) measurements in patients with pseudomyxoma peritonei treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Sixty-three patients with pseudomyxoma peritonei were treated with cytoreductive surgery and HIPEC. The tumor markers CEA and CA19.9 were collected before therapy and at 3-month intervals during follow-up. RESULTS: Preoperative CEA and CA19.9 levels were increased in, respectively, 75% and 58% of the patients. Baseline tumor marker values were related to the extent of tumor. Immediately after HIPEC, both tumor markers decreased markedly (P <.0001). CA19.9 was shown to be a more useful tumor marker than CEA for follow-up. During follow-up, a high absolute CA19.9 level (P =.0005) was predictive for imminent recurrence. Patients who never attained a normal CA19.9 level showed a higher recurrence rate at 1 year (53%; SE, 15%), in comparison to patients who did so (6%; SE 4%). The median lead time of increased CA19.9 to recurrence was 9 months. CONCLUSIONS: The measurement of the tumor marker CA19.9 is useful in evaluating therapy in patients with pseudomyxoma peritonei treated with cytoreductive surgery and HIPEC. CA19.9 is a prognostic factor for predicting recurrent disease.

Monitoring malignant melanoma with the S-100B tumour marker.

To assess the usefulness of the S-100B tumour marker in monitoring therapy and during follow-up we measured S-100B serum concentration in 31 patients participating in a phase I trial studying the effect of vaccination with GM-CSF gene-transduced autologous tumour cells. The S-100B serum concentration before treatment is a strong independent prognostic factor for survival, as in this study the 11 patients with low (< 0.16 microgram/l) S-100B levels were at considerably lower risk for death. All patients alive at the end of the study (n = 8) had a S-100B level within the reference range at the start of the study. At a level of 0.16 microgram/l the presence of disease could be predicted with 99% certainty for 63% of the patients. Nine patients became progressive after a stable disease. In four of them S-100 increased over 50% before clinical observation of progression, giving a lead time of more than a month in 44% of cases. In patients who acquired a status of no clinical evidence of disease after treatment, the S-100B concentration invariably decreased by more than 100%.

Serum insulin-like growth factor-I and breast cancer.

Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50.

Can initial serum cyfra 21-1, SCC antigen, and TPA levels in squamous cell cervical cancer predict lymph node metastases or prognosis?

OBJECTIVE: The aim of this study was to determine whether lymph node metastases or prognosis can be predicted by initial serum Cyfra 21-1, tissue polypeptide antigen (TPA), and squamous cell carcinoma antigen (SCC-Ag) levels in squamous cell cervical cancer. METHODS: Pretreatment serum levels of 92 patients were correlated with clinicopathologic parameters and prognostic data. The clinical performance of the tests was evaluated by their receiver operating characteristic curves. The prognostic power of the variables was assessed using Cox regression analysis. RESULTS: Serum levels of each marker were significantly related to tumor stage, size, and depth of infiltration. The clinical performance of each marker in predicting lymph node metastases or parametrial involvement was poor. In the stepwise Cox regression analysis, regarding patients with early stage cervical cancer (stage Ib/IIa, n = 63), tumor size (P = 0.0005) was the only independent prognostic factor for disease-free interval. Lymph node status (P = 0.0014), tumor size (P = 0.004), and parametrial involvement (P = 0.025) were independent risk factors for survival. Considering all patients with stages Ia through IVb disease, tumor size (P = 0.0001) and TPA level (P = 0. 026) were independent risk factors for disease-free interval, whereas tumor size (P = 0.0001) and parametrial involvement (P = 0. 0002) were risk factors for survival. CONCLUSIONS: Pretreatment Cyfra 21-1, TPA, and SCC-Ag levels were strongly related to tumor burden, but insufficiently reliable for identifying patients at risk of the presence of lymph node metastases or parametrial involvement. Serum levels of each marker showed no independent prognostic value in early stage cervical cancer.

Monitoring of impending myocardial damage after pleuropneumonectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma using biochemical markers.

In five patients who were treated for malignant pleural mesothelioma (MPM) with pleuropneumonectomy and intraoperative photodynamic therapy (IPDT), impending myocardial damage was monitored using ECG, the classical biochemical markers (creatine kinase [CK], total activity; CKMB, mass; and myoglobin), and the new cardiac markers troponin I (cTnI) and troponin T (cTnT). In the peroperative and postoperative period all classical markers were elevated, in contrast to cTnI and cTnT, because of the concomitant skeletal muscle damage. Sequential electrocardiogram monitoring showed no signs of myocardial damage. From this study in patients with MPM treated with pleuropneumonectomy and IPDT it can be concluded that measurement of cTnI and cTnT for the detection of myocardial damage is more suitable than measurement of the classical markers.

Prognostic value of the serum tumour markers Cyfra 21-1 and tissue polypeptide antigen in malignant mesothelioma.

In malignant mesothelioma, survival is claimed to be related to age, duration of symptoms, performance status, histological subtype, stage and platelet count. However the exact prognostic value of these factors is still a matter of debate. We studied the two cytokeratin markers, Cyfra 21-1 and Tissue polypeptide antigen (TPA) for their significance in predicting survival retrospectively in 52 patients. Cyfra 21-1 and TPA were elevated in 26 (50%) and 30 (58%) patients, respectively, and were highly correlated (r = 0.98). Univariate analysis of data from 51 patients, showed a relation with survival for performance status (P = 0.010), thoracic pain (P = 0.014), platelet count (P = 0.027), Cyfra 21-1 (P = 0.002) and TPA (P = 0.003). Multivariate analysis identified independent prognostic significance for performance status, platelet count and Cyfra 21-1. In addition to performance status ( < 80 vs. > 80) the cytokeratin markers identified patients with good prognosis in a log rank test. Values of Cyfra 21-1 and TPA are significantly correlated.