Socioeconomic differences in participation and diagnostic yield within the Dutch national colorectal cancer screening programme with faecal immunochemical testing.

BACKGROUND: CRC mortality rates are higher for individuals with a lower socioeconomic status (SES). Screening could influence health inequalities. We therefore aimed to investigate SES differences in participation and diagnostic yield of FIT screening. METHODS: All invitees in 2014 and 2015 in the Dutch national CRC screening programme were included in the analyses. We used area SES as a measure for SES and divided invitees into quintiles, with Quintile 1 being the highest SES. Logistic regression analysis was used to compare the participation rate, positivity rate, colonoscopy uptake, positive predictive value (PPV) and detection rate across the SES groups. RESULTS: Participation to FIT screening was significantly lower for Quintile 5 (67.0%) compared to the other Quintiles (73.0% to 75.1%; adjusted OR quintile 5 versus quintile 1: 0.73, 95%CI: 0.72-0.74), as well as colonoscopy uptake after a positive FIT (adjusted OR 0.73, 95%CI: 0.69-0.77). The detection rate per FIT participant for advanced neoplasia gradually increased from 3.3% in Quintile 1 to 4.0% in Quintile 5 (adjusted OR 1.20%, 95%CI 1.16-1.24). As a result of lower participation, the yield per invitee was similar for Quintile 5 (2.04%) and Quintile 1 (2.00%), both being lower than Quintiles 2 to 4 (2.20%-2.28%). CONCLUSIONS: Screening has the potential to reduce health inequalities in CRC mortality, because of a higher detection in participants with a lower SES. However, in the Dutch screening programme, this is currently offset by the lower participation in this group.

Quality Monitoring of a FIT-Based Colorectal Cancer Screening Program.

BACKGROUND: Quality assessment is crucial for consistent program performance of colorectal cancer (CRC) screening programs using fecal immunochemical test for hemoglobin (FIT). However, literature on the consistency of FIT performance in laboratory medicine was lacking. This study examined the consistency of FIT in testing positive or detecting advanced neoplasia (AN) for different specimen collection devices, lot reagents, and laboratories. METHODS: All participants with a FIT sample with a cutoff concentration of 47 µg Hb/g feces in the Dutch CRC screening program in 2014 and 2015 were included in the analyses. Multivariable logistic regression analyses were performed to estimate the odds ratios of collection devices, reagents, and laboratories on testing positive or detecting AN and positive predictive value (PPV). RESULTS: In total, 87519 (6.4%) of the 1371169 participants tested positive. Positivity rates and detection rates of AN differed between collection devices and reagents (all P < 0.01). In contrast, PPVs were not found to vary between collection devices, reagents, or laboratories (all P > 0.05). Positivity rates showed a small difference for laboratories (P = 0.004) but not for detection rates of AN. Size of the population affected by the deviating positivity rates was small (0.1% of the total tested population). CONCLUSIONS: Variations were observed in positivity and detection rates between collection devices and reagents, but there was no detected variation in PPV. Although the overall population effect of these variations on the screened population is expected to be modest, there is room for improvement.

Real-Time Monitoring of Results During First Year of Dutch Colorectal Cancer Screening Program and Optimization by Altering Fecal Immunochemical Test Cut-Off Levels.

BACKGROUND & AIMS: After careful pilot studies and planning, the national screening program for colorectal cancer (CRC), with biennial fecal immunochemical tests (FITs), was initiated in The Netherlands in 2014. A national information system for real-time monitoring was developed to allow for timely evaluation. Data were collected from the first year of this screening program to determine the importance of planning and monitoring for optimal screening program performance. METHODS: The national information system of the CRC screening program kept track of the number of invitations sent in 2014, FIT kits returned, and colonoscopies performed. Age-adjusted rates of participation, the number of positive test results, and positive predictive values (PPVs) for advanced neoplasia were determined weekly, quarterly, and yearly. RESULTS: In 2014, there were 741,914 persons invited for FIT; of these, 529,056 (71.3%; 95% CI, 71.2%-71.4%) participated. A few months into the program, real-time monitoring showed that rates of participation and positive test results (10.6%; 95% CI, 10.5%-10.8%) were higher than predicted and the PPV was lower (42.1%; 95% CI, 41.3%-42.9%) than predicted based on pilot studies. To reduce the burden of unnecessary colonoscopies and alleviate colonoscopy capacity, the cut-off level for a positive FIT result was increased from 15 to 47 µg Hb/g feces halfway through 2014. This adjustment decreased the percentage of positive test results to 6.7% (95% CI, 6.6%-6.8%) and increased the PPV to 49.1% (95% CI, 48.3%-49.9%). In total, the first year of the Dutch screening program resulted in the detection of 2483 cancers and 12,030 advanced adenomas. CONCLUSIONS: Close monitoring of the implementation of the Dutch national CRC screening program allowed for instant adjustment of the FIT cut-off levels to optimize program performance.

Clinical Use of Cancer Biomarkers in Epithelial Ovarian Cancer: Updated Guidelines From the European Group on Tumor Markers.

OBJECTIVE: To present an update of the European Group on Tumor Markers guidelines for serum markers in epithelial ovarian cancer. METHODS: Systematic literature survey from 2008 to 2013. The articles were evaluated by level of evidence and strength of recommendation. RESULTS: Because of its low sensitivity (50-62% for early stage epithelial ovarian cancer) and limited specificity (94-98.5%), cancer antigen (CA) 125 (CA125) is not recommended as a screening test in asymptomatic women. The Risk of Malignancy Index, which includes CA125, transvaginal ultrasound, and menopausal status, is recommended for the differential diagnosis of a pelvic mass. Because human epididymis protein 4 has been reported to have superior specificity to CA125, especially in premenopausal women, it may be considered either alone or as part of the risk of ovarian malignancy algorithm, in the differential diagnosis of pelvic masses, especially in such women. CA125 should be used to monitor response to first-line chemotherapy using the previously published criteria of the Gynecological Cancer Intergroup, that is, at least a 50% reduction of a pretreatment sample of 70 kU/L or greater. The value of CA125 in posttherapy surveillance is less clear. Although a prospective randomized trial concluded that early administration of chemotherapy based on increasing CA125 levels had no effect on survival, European Group on Tumor Markers state that monitoring with CA125 in this situation should occur, especially if the patient is a candidate for secondary cytoreductive surgery. CONCLUSIONS: At present, CA125 remains the most important biomarker for epithelial ovarian cancer, excluding tumors of mucinous origin.

Design of tumor biomarker-monitoring trials: a proposal by the European Group on Tumor Markers.

A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker-guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.

Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments.

BACKGROUND: Chromogranin A (CgA) is the most important tumour marker for well-differentiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differentiated neuroendocrine carcinoma (NEC). This study investigated whether the markers progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and CK19 (MonoTotal) can be of additional value to the histological classification and help predict survival in these patients. METHODS: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET (G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteristics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox regression analyses. RESULTS: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively) when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivariate survival analysis, only CKfr was associated with survival (P<0.0001) for patients with well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC, both CKfr and NSE were associated with survival (P<0.0001 and P=0.003, respectively). CONCLUSION: Within all histological groups a combination of tumour markers proved to be more informative as diagnostic and prognostic marker than each marker alone. In patients with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in patients with SCNEC, proGRP and CKfr are preferred.

Increase of angiogenic growth factors after hepatic artery embolization in patients with neuroendocrine tumours.

In the event of diffuse hepatic metastases, hepatic artery embolization (HAE) can be a successful treatment option in patients with well-differentiated neuroendocrine tumours (NET). However, embolization causes hypoxia which stimulates angiogenesis and therefore tumour growth. This study investigates angiogenesis activity following HAE by measuring vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and C-terminal proendothelin-1 (proET-1) in blood. Twelve patients with well-differentiated NET and liver metastases underwent HAE. VEGF, ET-1 and proET-1 were measured before embolization and the days following treatment during hospitalization. Mean levels during treatment were compared with those at baseline. From 12 patients, 90 blood samples were obtained before and daily for 8 days following HAE. Mean (± SE) VEGF level at baseline was 116 (± 33)ng/l which increased after HAE to 313 (± 46)ng/l at day 6, followed by a gradual decrease. ProET-1 showed a similar pattern, with a mean baseline level of 9.2 (± 2.0)pmol/l and the highest level of 40.8 (± 5.7)pmol/l at day 6. Some fluctuations were observed for ET-1, with maximum levels at day 3 compared to baseline levels. In patients with well-differentiated NET who underwent hepatic arterial embolization, angiogenic growth factors increase temporarily. This implies a need to investigate the effect of anti-angiogenic drugs as an adjuvant therapy to embolization.

Utility of FDG PET/CT and brain MRI in melanoma patients with increased serum S-100B level during follow-up.

BACKGROUND: The serum level of the S-100B protein is increasingly used as a tumor marker in melanoma patients. The aims of this study were to assess the clinical relevance of increased S-100B during follow up of high-risk melanoma patients and to determine the value of subsequent whole-body PET/CT and brain MRI. MATERIALS AND METHODS: A retrospective analysis was performed of all 46 melanoma patients with a normal history and physical examination who were found to have an elevated serum S-100B level (> or =0.10 microg/L) during follow-up between August 2006 and March 2009. Suspicious lesions on FDG PET/CT were biopsied for histological or cytological confirmation or were imaged further and followed if no pathology confirmation could be obtained. RESULTS: The positive predictive value of an elevated serum S-100B was 50%. PET/CT revealed hypermetabolic lesions in 27 of the 46 patients (59%). PET/CT was never false negative as confirmed by median follow-up of 1 year but was false positive in 4 patients. MRI revealed brain metastases in 1 patient (2%). Of the 23 patients with a true positive PET/CT scan, 6 (26%) received surgical treatment with curative intent; the other 17 (74%) received palliative treatment or supportive care. The survival of patients with a normal PET/CT was longer than patients with a positive PET/CT (P = .002). CONCLUSIONS: An elevated serum S-100B during follow-up of high-risk melanoma patients has a modest 50% positive predictive value for recurrent disease. Subsequent PET/CT and MRI can identify patients with recurrent disease.

Serum S100B in elderly patients with and without delirium.

OBJECTIVE: Elevation of S100B has been shown after various neurologic diseases with cognitive dysfunction. The aim of this study was to compare the serum level of S100B of patients with and without delirium and investigate the possible associations with different subtypes of delirium. METHODS: Acutely admitted medical patients aged 65 years or more were included from 2005 through 2008. Delirium was diagnosed by Confusion Assessment Method, delirium subtype by Delirium Symptom Interview and preexistent global cognitive function by the 'Informant Questionnaire on Cognitive Decline-short form'. S100B levels were determined in serum by electrochemiluminescence immunoassay. RESULTS: Samples of 412 patients were included, 91 during delirium, 35 after delirium and 286 of patients without delirium. Patients with delirium (31%) were significantly older, 81.5 versus 76.6 years (p < 0.001) and experienced significantly more often preexistent cognitive and functional impairment (p < 0.001). S100B level differed significantly (p = 0.004) between the three groups: median 0.07 microg/L (inter-quartile ranges: 0.05-0.14 microg/L) during delirium, 0.12 microg/L (0.05-0.29 microg/L) after delirium and 0.06 microg/L (0.03-0.10 microg/L) in patients without delirium. Combining the impact of cognitive impairment, infection and age on S100B, highest S100B was observed in the oldest patients after delirium with preexistent cognitive impaired and infection. Delirium subtype and S100B level were not significantly correlated. CONCLUSION: Higher S100B levels were found in patients with delirium than in patients without delirium, with highest levels of S100B in samples taken after delirium. Future studies are needed to elucidate the mechanism responsible for the increase of S100B and the possible association with long term cognitive impairment.

Chromogranin-A and N-terminal pro-brain natriuretic peptide: an excellent pair of biomarkers for diagnostics in patients with neuroendocrine tumor.

PURPOSE: For the last decade chromogranin-A (CgA) has been a well-established marker for neuroendocrine tumor (NET), and N-terminal pro-brain natriuretic peptide (NT-proBNP) has been a useful marker for left ventricular dysfunction. This study examined the diagnostic value of CgA and NT-proBNP for carcinoid heart disease (CHD), and their prognostic value for overall survival in NET patients. PATIENTS AND METHODS: Serum samples were obtained and cardiac ultrasound studies performed in 102 NET patients. The criterion for mild and severe CHD was tricuspid regurgitation stage I/II and III/IV, respectively. Proportional odds and Cox proportional hazards models were constructed respectively to identify the association between CHD and overall survival with patient characteristics and the two markers. RESULTS: Severe CHD was found in 15 (15%) of 102 patients, 13 of whom had elevated NT-proBNP levels. In the univariate proportional odds model CHD was correlated with age (P = .007), CgA (P = .002), and NT-proBNP (P < .001), whereas in the multivariate model NT-proBNP and CgA were significantly associated with CHD (P < .001 and P = .01). In the univariate Cox models, age (P = .04), sex (P = .03), CgA (P = .003), and NT-proBNP (P = .04) were related to overall survival, and in the multivariate model CgA and NT-proBNP remained significantly related to overall survival (P = .002 and P = .04, respectively). CONCLUSION: NT-proBNP and CgA are very important markers in the diagnosis of CHD in patients with NET. Furthermore, patients with elevated NT-proBNP in addition to elevated CgA levels showed worse overall survival than patients with elevated CgA alone.

Serum protein profiling for diagnosis of breast cancer using SELDI-TOF MS.

In search for novel markers for breast cancer, we aimed to identify and validate novel serum protein profiles specific for breast cancer, and assess the influence of clinical (subjects age) and pre-analytical (sample storage duration) variables on the constructed classifiers. To this end, sera of breast cancer patients (n=152) and healthy controls (n=129), randomly divided into a training and test set, were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS). In the training set, 14 peak clusters were found to differ significantly in expression between cases and controls. None of the peak clusters were influenced by subjects age and sample storage duration. Ten peak clusters were also found significantly discriminative in the test set. Peak clusters were structurally identified as C3a des-arginine anaphylatoxin, (tentative) inter-alpha-trypsin inhibitor heavy chain 4 fragments and a fibrinogen fragment. Logistic regression analyses on the training set yielded a classification model with a moderate performance on the test set, corresponding to those reported in previously performed validation studies. Most likely originating from the highly heterogeneous nature of breast cancer, selection of breast cancer subgroups for comparison with healthy controls is expected to improve results of future diagnostic SELDI-TOF MS studies.

Influence of sample storage duration on serum protein profiles assessed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS).

BACKGROUND: Issues have been raised concerning the robustness and validity of alleged serum markers discovered by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS). Pre-analytical variables have been shown to exert a profound effect on protein profiles, irrespective of true biological variation. However, little is known about the possible effects of sample storage duration on protein profiles. We, therefore, aimed to investigate the effects of extended storage duration on the serum protein profile. METHODS: Archival sera from 140 breast cancer patients, stored at -30 degrees C for 1-11 years, were profiled by SELDI-TOF MS using immobilised metal affinity capture (IMAC) arrays, a condition applied in the majority of breast cancer biomarker discovery studies. RESULTS: Fourteen peak clusters, structurally identified as C3a des-arginine anaphylatoxin and multiple fragments of albumin and fibrinogen, were found to be significantly associated with sample storage duration by five distinct patterns. These proteins have been described previously as potential cancer markers, rendering them specific to both disease and sample handling issues. CONCLUSIONS: To prevent experimental variation being interpreted erroneously as disease associated variation, assessment of potential confounding pre-analytical parameters is a pre-requisite in biomarker discovery and validation studies. In addition, with respect to the different (non-)linear patterns observed in the current study, simply performing linear corrections to account for sample storage duration will not necessarily suffice.

Markers of cerebral damage during delirium in elderly patients with hip fracture.

BACKGROUND: S100B protein and Neuron Specific Enolase (NSE) can increase due to brain cell damage and/or increased permeability of the blood-brain-barrier. Elevation of these proteins has been shown after various neurological diseases with cognitive dysfunction. Delirium is characterized by temporal cognitive deficits and is an important risk factor for dementia. The aim of this study was to compare the level of S100B and NSE of patients before, during and after delirium with patients without delirium and investigate the possible associations with different subtypes of delirium. METHODS: The study population were patients aged 65 years or more acutely admitted after hip fracture. Delirium was diagnosed by the Confusion Assessment Method and the subtype by Delirium Symptom interview. In maximal four serum samples per patient S100B and NSE levels were determined by electrochemiluminescence immunoassay. RESULTS: Of 120 included patients with mean age 83.9 years, 62 experienced delirium. Delirious patients had more frequently pre-existing cognitive impairment (67% vs. 18%, p < 0.001). Comparing the first samples during delirium to samples of non-delirious patients, a difference was observed in S100B (median 0.16 versus 0.10 microg/L, p = < 0.001), but not in NSE (median 11.7 versus 11.7 ng/L, p = 0.97). Delirious state (before, during, after) (p < 0.001), day of blood withdrawal (p < 0.001), pre- or postoperative status (p = 0.001) and type of fracture (p = 0.036) were all associated with S100B level. The highest S100B levels were found 'during' delirium. S100B levels 'before' and 'after' delirium were still higher than those from 'non-delirious' patients. No significant difference in S100B (p = 0.43) or NSE levels (p = 0.41) was seen between the hyperactive, hypoactive and mixed subtype of delirium. CONCLUSION: Delirium was associated with increased level of S100B which could indicate cerebral damage either due to delirium or leading to delirium. The possible association between higher levels of S100B during delirium and the higher risk of developing dementia after delirium is an interesting field for future research. More studies are needed to elucidate the role of S100B proteins in the pathophysiological pathway leading to delirium and to investigate its possibility as biomarker for delirium.

Estradiol and testosterone levels are lower after oophorectomy than after natural menopause.

OBJECTIVE: The aim of this study was to compare hormone levels between women who became postmenopausal after a prophylactic bilateral salpingo-oophorectomy, and women who became postmenopausal in a natural way. METHODS: In this cross-sectional study, we investigated estradiol, testosterone, SHBG, IGF-1 and IGFBP-3 levels in 35 surgically and 40 naturally postmenopausal women. RESULTS: Serum samples were drawn at a mean age of 45.9 years for women with surgical menopause and at 56.5 years for women with natural menopause. Mean estradiol levels declined 1.4 pmol/l per year in both menopausal groups, however, at an 11.1 pmol/l lower level for women with surgical menopause. Testosterone levels of naturally postmenopausal women remained stable at a level of 0.89 nmol/l, while testosterone levels of the surgically postmenopausal women declined 0.04 nmol/l per year. CONCLUSIONS: For IGF-1, IGFBP-3 and SHBG, no differences were found between surgically and naturally postmenopausal women. Lower estradiol levels of surgically as compared to naturally postmenopausal women seem to be fully explained by the earlier onset of menopause in combination with the same age-related decrease. However, a decrease in testosterone levels seems to occur in oophorectomized women only, suggesting postmenopausal activity of ovaries in situ.

Chromogranin A as an alternative to 5-hydroxyindoleacetic acid in the evaluation of symptoms during treatment of patients with neuroendocrine Tumors.

BACKGROUND: Urinary 5-HIAA excretion is a well-known marker in neuroendocrine tumors (NETs), but it has a low sensitivity and the 24-hour collection is inconvenient for patients. Chromogranin A (CgA) is a promising marker, but a thorough evaluation during follow-up is still lacking. METHODS: 39 patients with metastatic gastrointestinal NETs were monitored during treatment with the long-acting octreotide SandostatinLAR. A comparison was made between serum CgA and urinary 5-HIAA in relation to quality of life (HRQL) assessed by the EORTC QLQ-C30 questionnaire, supplemented with questions specific to carcinoid symptoms. Survival analyses were performed to examine the association between the markers and survival time. RESULTS: Correlations were found between CgA and physical functioning (p = 0.01) and quality of life (p = 0.03), while no significant correlations were observed between 5-HIAA levels and any of the self-reported health outcomes. Cox regression showed an association between CgA levels and survival time (p = 0.02), while no significant association was observed between 5-HIAA levels and survival time. CONCLUSION: Stronger correlations of CgA compared to 5-HIAA with physical functioning and wellbeing, the convenience of measuring in blood, as well as the prognostic value of CgA for survival, makes CgA the recommended marker in the management of patients with metastatic NETs.

No effect of red clover-derived isoflavone intervention on the insulin-like growth factor system in women at increased risk of colorectal cancer.

BACKGROUND: Increased insulin-like growth factor (IGF)-I and IGF-II concentrations are related to increased colorectal cancer risk. Isoflavones have been associated with reduced colorectal cancer risk, and may affect the IGF system because of their weak estrogenic activity. The aim of the study was to investigate the effect of isolated isoflavones on serum concentrations of IGF system components. MATERIALS AND METHODS: We conducted a randomized, placebo-controlled, double-blinded, crossover trial in four hospitals in the Netherlands to investigate the effect of an 8-week supplementation with red clover-derived isoflavones (84 mg/d) on serum IGF-I concentrations. In addition, serum concentrations of IGF-II and IGF binding proteins (IGFBP)-1, IGFBP-2, and IGFBP-3 were assessed. Normal colorectal tissue biopsies were obtained after the first intervention period and mRNA expression of IGF-I, IGF-II, IGFBP-3, and IGF-IR was evaluated. Our study population consisted of 34 postmenopausal women with a family history of colorectal cancer or a personal history of colorectal adenomas. RESULTS: Isoflavone supplementation did not significantly affect serum concentrations of total IGF-I (mean relative within-person difference; IGF-I, -2.0%; 95% confidence interval, -8.0% to 3.9%). IGF-II and IGFBPs were also not significantly altered after isoflavone supplementation. Colorectal tissue mRNA expression of IGF system components did not significantly differ between individuals on isoflavone supplementation and those who received placebo. CONCLUSIONS: The results of our trial, supported by a qualitative review of soy trials published to date, suggest that isoflavones do not significantly affect circulating levels of IGF system components. Increased levels of IGF-I, as observed in most of these trials, are likely due to simultaneous protein supplementation.

Effects of lycopene on the insulin-like growth factor (IGF) system in premenopausal breast cancer survivors and women at high familial breast cancer risk.

Insulin-like growth factor-I (IGF-I) is an important growth factor associated with increased risk of premenopausal breast cancer. We conducted a randomized, placebo-controlled, double-blind, crossover trial to evaluate whether tomato-derived lycopene supplementation (30 mg/day for 2 mo) decreases serum levels of total IGF-I in premenopausal women with 1) a history of breast cancer (n=24) or 2) a high familial breast cancer risk (n=36). Also, IGF binding protein (IGFBP) increasing effects were evaluated. Lycopene supplementation did not significantly alter serum total IGF-I and other IGF system components in the 2 study populations combined. However, statistically significant discordant results were observed between the 2 study populations (i.e., P<0.05 for total IGF-I, free IGF-I, and IGFBP-3). Total IGF-I and IGFBP-3 were increased in the breast cancer survivor population [total IGF-I=7.0%, 95% confidence interval (CI)= -0.2 to 14.3%; IGFBP-3=3.3%, 95% CI=0.7-6.0%), and free IGF-I was decreased in the family history population (-7.6%, 95% CI= -14.6 to -0.6%). This randomized controlled trial shows that 2 mo of lycopene supplementation has no effect on serum total IGF-I in the overall study population. However, lycopene effects were discordant between the 2 study populations showing beneficial effects in high-risk healthy women but not in breast cancer survivors.

Non-invasive diagnosis of pleural malignancies: the role of tumour markers.

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.

Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer.

BACKGROUND: Higher circulating insulin-like growth factor I (IGF-I) concentrations have been related to a greater risk of cancer. Lycopene intake is inversely associated with cancer risk, and experimental studies have shown that it may affect the IGF system, possibly through an effect on IGF-binding proteins (IGFBPs). OBJECTIVE: The objective of our study was to investigate the effect of an 8-wk supplementation with tomato-derived lycopene (30 mg/d) on serum concentrations of total IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3. DESIGN: We conducted a randomized, placebo-controlled, double-blinded crossover study in 40 men and 31 postmenopausal women with a family history of colorectal cancer, a personal history of colorectal adenoma, or both. RESULTS: Lycopene supplementation significantly (P = 0.01) increased serum IGFBP-1 concentrations in women (median relative difference between serum IGFBP-1 concentrations after lycopene supplementation and after placebo, 21.7%). Serum IGFBP-2 concentrations were higher in both men and women after lycopene supplementation than after placebo, but to a lesser extent (mean relative difference 8.2%; 95% CI: 0.7%, 15.6% in men and 7.8%; 95% CI: -5.0%, 20.6% in women). Total IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly altered by lycopene supplementation. CONCLUSIONS: This is the first study known to show that lycopene supplementation may increase circulating IGFBP-1 and IGFBP-2 concentrations. Because of high interindividual variations in IGFBP-1 and IGFBP-2 effects, these results should be confirmed in larger randomized intervention studies.