Factors influencing blood tumor marker concentrations in the absence of neoplasia.

BACKGROUND: Tumor markers (TMs) are a heterogeneous group of molecules used in the diagnosis, prognosis and follow-up of cancer patients. During neoplastic differentiation, cells can either directly synthesize or induce the synthesis of TMs, and the release of these molecules into the bloodstream allows their quantification in biological fluids. Although very small concentrations of TMs are usually present in the serum or plasma of healthy subjects, increased concentrations may also be found in the presence of benign diseases or due to technical interference, producing false positive results. MATERIAL AND METHODS AND RESULTS: Our review analyses the causes of false positives described between January 1970 to February 2023 for the TMs most frequently used in clinical practice: α-fetoprotein (AFP), ß2-microglobulin (ß2-M), cancer antigen 15-3 (CA 15-3), cancer antigen CA 19-9 (CA 19-9), cancer antigen CA 72-4 (CA 72-4), cancer antigen 125 (CA 125), carcinoembryonic antigen (CEA), chromogranin A (CgA), choriogonadotropin (hCG), cytokeratin 19 fragment (CYFRA 21-1), neuron-specific enolase (NSE), human epididymis protein 4 (HE4), serum HER2 (sHER2), squamous cell carcinoma antigen (SCCA), protein induced by vitamin K absence-II (PIVKA-II), Pro-gastrin-releasing peptide (Pro-GRP), prostate-specific antigen (PSA), Protein S-100 (S-100) and thyroglobulin (Tg). A total of 247 references were included. CONCLUSIONS: A better understanding of pathophysiological processes and other conditions that affect the concentration of TMs might improve the interpretation of results and their clinical application.

Analytical and clinical evaluation of DiaSorin Liaison® Calprotectin fecal assay adapted for serum samples.

BACKGROUND: Calprotectin is a calcium-binding protein that can be measured in serum, plasma, and feces. Increased serum and plasma calprotectin concentrations have been found in chronic inflammatory rheumatic disorders. An analytical and clinical evaluation of the DiaSorin Liaison® fecal Calprotectin assay using LIAISON® XL was performed. METHODS: The protocol included an analytical and clinical evaluation in which imprecision, the linearity of dilution, differences between serum and plasma samples and method comparison with CalproLab™ ELISA kit were assessed. Serum calprotectin concentrations in active (n = 26) and remission (n = 23) rheumatoid arthritis (RA) patients were compared. RESULTS: The intra-day and inter-day analytical imprecision CVs ranged from 2.9% to 4.0% and 2.7% to 10.4%, respectively. Correlation between measured and expected values was high (R > 0.99), indicating good linearity. The Wilcoxon signed-rank test showed that serum and plasma matched samples presented statistically significant differences (p < 0.001) being the highest concentrations of calprotectin observed in serum samples. Deming regression equation was as follows: Diasorin calprotectin (µg/ml) = -0.32 (95% CI: -0.65 - -0.05) +1.58 (95% CI: 1.42-1.79).* Calprolab calprotectin (µg/ml). Significantly higher serum calprotectin levels were found in RA patients with active disease when compared to patients with low disease activity or in clinical remission (mean ± SD) [(3.35 µg/ml ± 1.55) vs. (1.63 µg/ml ± 0.52), p < 0.001] and these levels correlated well with all disease activity indices. CONCLUSIONS: The DiaSorin Liaison® fecal Calprotectin assay adapted for serum samples showed adequate technical performances and the clinical performances were similar to other assays.

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures.

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aß42], total-tau protein [T-tau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF-biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aß and 14-3-3; whereas NfL and 14-3-3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.

Reassessment colonoscopy to diagnose serrated polyposis syndrome in a colorectal cancer screening population.

Background and study aims Serrated polyposis syndrome (SPS) is a high risk condition for colorectal cancer (CRC). Surveillance strategies for patients with serrated lesions remain controversial. We aimed to evaluate a diagnostic strategy to detect SPS consistently during reassessment colonoscopy in patients with proximal serrated lesions. Methods This was a retrospective study of all individuals from a fecal immunochemical test (FIT)-based CRC screening program (2010 - 2013) with one or more serrated lesions of ≥ 5 mm proximal to the sigmoid colon on baseline colonoscopy. We analyzed all individuals empirically scheduled for a reassessment colonoscopy aimed at diagnosing SPS within 1 year. Reassessment colonoscopy was performed with standard white-light or chromoendoscopy ±â€Šhigh definition endoscopy depending on availability. SPS diagnosis was based on the cumulative number of polyps in both the baseline and reassessment colonoscopies. Factors associated with SPS diagnosis were analyzed. Results From 3444 screening colonoscopies, 196 patients met the study entry criteria, of whom 11 patients (0.32 %) met the criteria for SPS on baseline colonoscopy. Reassessment colonoscopies were performed in 71 patients at 11.9 ±â€Š1.7 months and detected 20 additional patients with SPS, a tripling of the rate of SPS up to 0.90 %. Independent factors associated with SPS diagnosis were: having five or more proximal serrated lesions (odds ratio [OR] 4.01 [95 % confidence interval 1.20 - 13.45]; P = 0.02) or two or more sessile serrated polyps ≥ 10 mm (OR 6.35 [1.40 - 28.81]; P = 0.02) on baseline colonoscopy and the use of chromoendoscopy ±â€Šhigh definition endoscopy during reassessment colonoscopy (OR 4.99 [1.11 - 22.36]; P = 0.04). Conclusions A 1-year reassessment colonoscopy using chromoendoscopy and high definition endoscopes substantially improves SPS detection in individuals from a FIT-based screening program with proximal serrated lesions. Five or more proximal serrated lesions or two or more sessile serrated polyps ≥ 10 mm could be thresholds for requiring a reassessment colonoscopy. Prospective studies are required to validate these results and adjust surveillance recommendations in patients with serrated lesions.

Utility of proGRP as a tumor marker in the medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor caused by a malignant transformation in the parafollicular C-cells of the thyroid, where calcitonin (CT) is released. Nowadays the main tumor markers (TM) used in the diagnosis and follow-up of MTC patients are CT and carcinoembryonic antigen (CEA). Nonetheless, progastrin releasing peptide (proGRP) has been recently proposed as a TM useful in the MTC. Our aims were to investigate the release of proGRP in thyroid tumors, its role in the assessment of advanced MTC and its utility in the differential diagnosis between MTC and non-MTC thyroid tumors. METHODS: Serum samples from 22 patients with MTC and 16 with non-MTC were collected. Patients were classified into advanced cancer or no evidence of disease (NED). ProGRP was performed by Architect (Abbot Diagnostics), CT by Liaison (Diasorin) and CEA by Cobas E601(Roche Diagnostics). RESULTS: ProGRP median concentration in advanced MTC was significantly higher (1398.4 pg/mL) when compared with non-MTC, either in advanced disease (24.9 pg/mL) or NED (14.6 pg/mL). In non-MTC patients, proGRP median concentration was below its cutoff level (50 pg/mL). Similar to CT, proGRP was able to detect 88.9% of MTC patients, but with a slightly lower specificity of 76.9%. Using proGRP together with CT the sensitivity increased to 100%. CONCLUSIONS: The low prevalence of this malignancy strongly recommends further collaborative studies, mainly focused on monitoring proGRP during tyrosine kinase inhibitors treatment for early detection of resistance and assessing its usefulness to avoid the observed false positive fluctuations that occur with CT and CEA.

Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer.

RATIONALE: We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC). OBJECTIVES: To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence. METHODS: We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC. MEASUREMENTS AND MAIN RESULTS: LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC. CONCLUSIONS: The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.

Clinical utility of one versus two faecal immunochemical test samples in the detection of advanced colorectal neoplasia in symptomatic patients.

BACKGROUND: The utility of faecal immunochemical tests (FIT) in assessment of symptomatic patients with lower gastrointestinal symptoms has not been well explored. The aims of this study were to evaluate the diagnostic yield for advanced colorectal neoplasia (ACRN) in symptomatic patients using the first of two FIT samples (FIT/1) and the higher concentration of two FIT samples (FIT/max). METHODS: Samples from two consecutive bowel motions from 208 symptomatic patients who required colonoscopy were analysed using the HM-JACKarc analyser (Kyowa Medex Co., Ltd., Tokyo, Japan). Patients were categorised into two groups: patients with any ACRN and individuals with other diagnoses or normal colonoscopy. RESULTS: Colonoscopy detected ACRN in 29 patients. In these patients, FIT/1 and FIT/max were significantly higher than in patients with low-risk adenoma (p=0.006 and p=0.024), other findings (p=0.002 and p=0.002) and normal colonoscopy (p<0.001 and p<0.001). The areas under the curves (AUC) of FIT/1 and FIT/max were 0.71 and 0.69, respectively. Undetectable FIT/1 rules out 96.6% of ACRN and the specificity was 10.6%. Increasing the FIT/1 cut-off to 10 µg Hb/g faeces, sensitivity and specificity were 34.5% and 87.2%, respectively. Similar results were obtained using FIT/max with 20 µg Hb/g faeces cut-off, providing a sensitivity and specificity of 34.5% and 85.6%, respectively. CONCLUSIONS: Undetectable FIT is a good strategy to rule-out ACRN in symptomatic patients. The diagnostic yield of collecting two samples for FIT can be achieved with one sample, but a lower faecal haemoglobin concentrations (f-Hb) cut-off is required.

Clinical utility of %p2PSA and prostate health index in the detection of prostate cancer.

BACKGROUND: %p2PSA and prostate health index (phi) has shown valuable results in the detection of prostate cancer (PCa), improving the prediction of the aggressiveness of the tumor. The goal of the present study was to evaluate %p2PSA and phi in the detection of PCa, estimating their relationship with the aggressiveness of PCa. METHODS: A total of 354 patients with positive or negative prostatic biopsy were included. Prospectively, 150 were enrolled and 204 were enrolled retrospectively proceeding from our serum bank. RESULTS: The best performance was observed for %p2PSA and phi, obtaining an AUC of 0.723 and 0.732, respectively. The highest specificity at sensitivity around 90% was obtained for phi (27.4%). Using the cut-off of 31.94 for phi, a reduction of 19% biopsies could be obtained, while 17 PCa would have been missed, including only four patients with a Gleason score ≥7. Similarly, using a cut-off of 1.21 for %p2PSA, a reduction of 12.7% biopsies could be obtained, while 16 PCa would have been missed, including only four patients with a Gleason score ≥7. Moreover, among patients with PCa, phi (median: 69.75 vs. 48.04) and %p2PSA (median: 2.60 vs. 1.98) values are significantly higher (p<0.0001) in patients with a biopsy Gleason score ≥7. CONCLUSIONS: Our results confirm previous evaluations, showing similar AUCs and results in sensitivity and specificity to other studies.%p2PSA and phi raise the accuracy in the detection of prostate cancer, reducing the number of unnecessary biopsies and improving the prediction of the aggressiveness of the tumor.

Impact of demographics and comorbid conditions on plasma biomarkers concentrations and their diagnostic accuracy in a memory clinic cohort.

Plasma biomarkers have emerged as promising tools for identifying amyloid beta (Aß) pathology. Before implementation in routine clinical practice, confounding factors modifying their concentration beyond neurodegenerative diseases should be identified. We studied the association of a comprehensive list of demographics, comorbidities, medication and laboratory parameters with plasma p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) on a prospective memory clinic cohort and studied their impact on diagnostic accuracy for discriminating CSF/amyloid PET-defined Aß status. Three hundred sixty patients (mean age 66.5 years, 55% females, 53% Aß positive) were included. Sex, age and Aß status-adjusted models showed that only estimated glomerular filtration rate (eGFR, standardized ß -0.115 [-0.192 to -0.035], p = 0.005) was associated with p-tau181 levels, although with a much smaller effect than Aß status (0.685 [0.607-0.763], p < 0.001). Age, sex, body mass index (BMI), Charlson comorbidity index (CCI) and eGFR significantly modified GFAP concentration. Age, blood volume (BV) and eGFR were associated with NfL levels. p-tau181 predicted Aß status with 87% sensitivity and specificity with no relevant increase in diagnostic performance by adding any of the confounding factors. Using two cut-offs, plasma p-tau181 could have spared 62% of amyloid-PET/CSF testing. Excluding patients with chronic kidney disease did not change the proposed cut-offs nor the diagnostic performance. In conclusion, in a memory clinic cohort, age, sex, eGFR, BMI, BV and CCI slightly modified plasma p-tau181, GFAP and NfL concentrations but their impact on the diagnostic accuracy of plasma biomarkers for Aß status discrimination was minimal.

Serum 25-hydroxyvitamin D3 levels and vitamin D receptor variants in melanoma patients from the Mediterranean area of Barcelona.

BACKGROUND: Serum 25-hydroxyvitamin D3 (Vitamin D) insufficiency and single-nucleotide polymorphisms (SNPs) on its receptor, Vitamin D receptor (VDR), have been reported to be involved in melanoma susceptibility in populations mostly from northern countries. OBJECTIVE: To investigate 25-hydroxyvitamin D3 levels and VDR SNPs in melanoma patients from sunny area of Barcelona, two studies were carried out. The first study evaluated the levels of Vitamin D at time of melanoma diagnosis and the second one analyzed the association between VDR genetic variants and risk of having a high nevus number, the strongest phenotypic risk factor for melanoma. METHODS: The levels of 25-hydroxyvitamin D3 in 81 melanoma patients at diagnosis were measured. In a second group of melanoma patients, including 150 with low and 113 with high nevus number, 11 VDR SNPs were analyzed for their association with nevus number. RESULTS: In the first study, 68% of patients had insufficient levels of 25-hydroxyvitamin D3 (<25 ng/ml). Autumn-winter months and fair phototype were associated with 25-hydroxyvitamin D3 insufficiency; after multivariate analysis, season of sampling remained the only independent predictor of 25-hydroxyvitamin D3 levels. In the second study, VDR variant rs2189480 (P = 0.006) was associated with risk of high nevus number whereas rs2239179 (P = 0.044) and rs7975128 (P = 0.0005) were protective against high nevus number. After Bonferroni adjustment only rs7975128 remained significant. In stratified analysis, SNP rs7975128 was found protective against multiple melanomas (P = 0.021). CONCLUSION: This study showed that even in Barcelona, a sunny Mediterranean area, 25-hydroxyvitamin D3 levels were sub-optimal in the majority of melanoma patients at diagnosis. The involvement of VDR in nevi and, in turn, in melanoma susceptibility has also been suggested. Larger studies are needed to confirm our findings.

Sleep in Gerstmann-Straüssler-Scheinker disease.

BACKGROUND: Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. METHODS: We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. RESULTS: Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. CONCLUSIONS: In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.

A new approach to prostate cancer screening.

Prostate cancer screening based on prostate-specific antigen (PSA) testing has been a matter of controversy. Although screening for prostate cancer was effective in reducing mortality, it resulted in overdiagnosis, which translated into unnecessary treatments and numerous adverse effects. As a result, recommendations from scientific societies became increasingly restrictive. In the recent years, new approaches to prostate cancer screening have been proposed. These new approaches are aimed at solving the controversy between widespread screening vs. no screening, and reconsidering PSA testing as a screening tool with a good benefit/risk balance. In this context, the European Association of Urology submitted a proposal to the European Commission for prostate cancer screening to be performed as a function of baseline PSA concentrations. The European Commission recently recommended the implementation of organized prostate cancer screening programs for men aged ≤70 years based on PSA values in combination with follow-up magnetic resonance imaging.

Diagnostic Performance and Clinical Applicability of Blood-Based Biomarkers in a Prospective Memory Clinic Cohort.

BACKGROUND AND OBJECTIVES: Blood-based biomarkers have emerged as minimally invasive options for evaluating cognitive impairment. Most studies to date have assessed them in research cohorts, limiting their generalization to everyday clinical practice. We evaluated their diagnostic performance and clinical applicability in a prospective, real-world, memory clinic cohort. METHODS: All patients referred with suspected cognitive impairment between July 2019 and June 2021 were prospectively invited to participate. Five plasma biomarkers (tau phosphorylated at threonine 181 [p-tau181], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total tau [t-tau], and ubiquitin C-terminal hydrolase L1 [UCH-L1]) were determined with single-molecule array. Performance was assessed in comparison to clinical diagnosis (blinded to plasma results) and amyloid status (CSF/PET). A group of cognitively unimpaired (CU) controls was also included. RESULTS: Three hundred forty-nine participants (mean age 68, SD 8.3 years) and 36 CU controls (mean age 61.7, SD 8.2 years) were included. In the subcohort with available Alzheimer disease (AD) biomarkers (n = 268), plasma p-tau181 and GFAP had a high diagnostic accuracy to differentiate AD from non-neurodegenerative causes (area under the receiver operating characteristic curve 0.94 and 0.92, respectively), with p-tau181 systematically outperforming GFAP. Plasma p-tau181 levels predicted amyloid status (85% sensitivity and specificity) with accurate individual prediction in approximately 60% of the patients. Plasma NfL differentiated frontotemporal dementia (FTD) syndromes from CU (0.90) and non-neurodegenerative causes (0.93), whereas the discriminative capacity with AD and between all neurodegenerative and non-neurodegenerative causes was less accurate. A combination of p-tau181 and NfL identified FTD with 82% sensitivity and 85% specificity and had a negative predictive value for neurodegenerative diagnosis of 86%, ruling out half of the non-neurodegenerative diagnoses. In the subcohort without AD biomarkers, similar results were obtained. T-tau and UCH-L1 did not offer added diagnostic value. DISCUSSION: Plasma p-tau181 predicted amyloid status with high accuracy and could have potentially avoided CSF/amyloid PET testing in approximately 60% of subjects in a memory clinic setting. NfL was useful for identifying FTD from non-neurodegenerative causes but behaved worse than p-tau181 in all other comparisons. Combining p-tau181 and NfL improved diagnostic performance for FTD and non-neurodegenerative diagnoses. However, the 14% false-negative results suggest that further improvement is needed before implementation outside memory clinics. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that plasma p-tau181 correlates with the presence or absence of AD and a combination of plasma p-tau181 and NfL correlates moderately well with a diagnosis of FTD.

Performance evaluation of Siemens Atellica enhanced estradiol assay.

Background: Serum estradiol (E2) levels may be used in the diagnostic and/or monitoring of a broad variety of clinical conditions. The aims of this study were to evaluate the Siemens enhanced estradiol assay (eE2) on Atellica IM 1600 (Siemens Healthineers) and to perform a sample comparison with the Siemens ADVIA Centaur XP (Siemens Healthineers). Methods: Within-day and between-day coefficient of variation (CV) were determined using serum sample pools and quality control materials. Six serum samples with decreasing concentrations of E2 were used to assess the limit of quantification. Linearity was evaluated using two different serum samples. Accuracy was evaluated by measuring three certified reference materials. Passing-Bablok regression and Bland-Altman plot were used for comparing Atellica and Centaur XP in 119 serum samples ranging from 45 to 10,059 pmol/L. Results: Within-day and between-day imprecision was <6.6%. Accuracy was <6.0% for all values except for 114 pmol/L (22%). The study of limit of quantification resulted in an interday imprecision <20%. High correlation between measured and expected estradiol dilution results was observed (R = 0.99), with recoveries ranging from 77 to 93%. Comparison study showed good agreement and no significant bias. Conclusions: The study shows that Atellica eE2 assay presents acceptable imprecision and accuracy and correlates well with Centaur XP.

Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer.

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3-5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73-92) ng/ml, 2372 (95% CI, 2121-2623) ng/ml, and 10.6 (95% CI, 7.21-13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675-2292) and a significant increase in MMP-7 levels to 14.6 (7.6-21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.

Serum matrilysin levels predict outcome in curatively resected colorectal cancer patients.

BACKGROUND: Matrix metalloproteinase 7 (MMP-7) is involved in invasion, metastasis, growth, and angiogenesis. The aim of this study is to assess the prognostic role of serum MMP-7 in curatively resected colorectal cancer (CRC). MATERIALS AND METHODS: Patients undergoing resection for CRC (n = 175) were recruited from July 2003 to December 2004. MMP-7 was determined using a quantitative solid phase sandwich ELISA. Cox analysis was used to assess the role of MMP-7 in predicting overall survival (OS) and disease-free survival (DFS). RESULTS: The median length of follow-up was 45 months (range 1 to 59). Levels of MMP-7 are predictors of DFS (hazard ratio [HR] 1.119, 95% confidence interval [95% CI] 1.038-1.207) and of OS (HR 1.113, 95% CI 1.025-1.209). Patients with MMP-7 higher than the median (4.3 ng/ml) are more likely to relapse (29.5% vs 18.4%, P = .084); median time to progression in relapsed patients is 8 months if MMP-7 is > or =4.3 ng/ml and 18 months if MMP-7 is <4.3 ng/ml. Node-negative patients with low MMP-7 have a predicted probability of relapse-free survival at 4 years of 88% (95% CI 83-92%); if the MMP-7 is higher than the median value; this probability is 77% (95% CI 73-81%). CONCLUSION: MMP-7 predicts recurrence in curatively resected CRC patients.

Colorectal cancer after negative colonoscopy in fecal immunochemical test-positive participants from a colorectal cancer screening program.

Background and study aims Colorectal cancer (CRC) risk after a positive fecal immunochemical test (FIT) and negative colonoscopy is unknown. We aimed to ascertain the cumulative incidence of post-colonoscopy colorectal cancer (PCCRC) and the manifestation of other lesions that could explain the test positivity in individuals with a negative colonoscopy in a population screening program. Patients and method Observational study in participants from the first round of a CRC screening program (2010 - 2012) with positive-FIT (≥ 20 µg/g of feces) and negative colonoscopy (without neoplasia). A 42- to 76-month follow-up was performed searching in the National Health Service database and by a brief structured telephonic interview. Results Of 2659 FIT-positive individuals who underwent colonoscopy, 811 (30.5 %) had a negative colonoscopy. Three PCCRC (0.4 %) were detected within 11 - 28 months and accelerated carcinogenesis was ruled out. Among those with normal colonoscopy, 32 (5 %) relevant lesions were detected at follow-up. One-third of them (11/32) were significant neoplasias: a gastric cancer, a small-bowel lymphoma, six advanced colorectal adenomas, and the three PCCRC. The 21 remaining lesions were inflammatory, vascular disorders, or non-advanced colorectal adenomas. Conclusions The vast majority (95 %) of individuals did not present any subsequent lesion that could explain the FIT positivity. The very low incidence (0.4 %) and characteristics of PCCRC observed in our cohort reinforce the concept that, although a positive FIT preselects high risk individuals, a high quality colonoscopy is the paramount factor in preventing PCCRC. Improving quality standards of colonoscopy are required to strengthen the current CRC screening strategies.

Prognostic implications of protein S-100beta serum levels in the clinical outcome of high-risk melanoma patients.

OBJECTIVE: It was the aim of this study to analyze the clinical value of the determination of serum S-100beta protein in high-risk melanoma patients. PATIENTS AND METHODS: Patients were tested for serum S-100beta protein by luminoimmunometric assay after melanoma surgical excision, before starting interferon-alpha2b and every 3 months thereafter, until treatment was completed. RESULTS: Ninety-seven patients were included in the study. Median follow-up was 62.9 months (range 32.7-87.4). High baseline S-100beta levels were associated with positive lymph node status (p = 0.02). High S-100beta levels (during therapy) showed a relation with positive lymph node status (p = 0.014), number of positive lymph nodes (p = 0.01), macroscopic lymph node involvement (p = 0.002) and second melanoma diagnosis at study entry (p = 0.001). By univariate analysis, high baseline S-100beta levels were associated with disease-free survival (p = 0.004) and overall survival (p = 0.0007). Similarly, high S-100beta levels during therapy were associated with disease-free survival (p < 0.0001) and overall survival (p < 0.0001). In the multivariate analysis, high S-100beta levels during therapy (hazard ratio 1.017, 95% CI 1.008-1.026; p < 0.0001) and high baseline S-100beta levels (hazard ratio 3.31, 95% CI 1.10-9.89; p = 0.032) were independent prognostic factors for overall survival when compared with low levels while on therapy and low baseline S-100beta levels, respectively. CONCLUSIONS: These results provide evidence of the clinical usefulness of serum S-100beta level determination in high-risk melanoma patients. S-100beta serum determination should be considered to be included in clinical trials that test adjuvant therapies in melanoma patients.

Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion, in locally advanced pancreatic cancer.

PURPOSE: Pancreatic cancers are resistant to radiotherapy (RT) and current chemotherapy agents. Epidermal growth factor receptor is overexpressed in pancreatic cancer, and in vitro studies have shown that epidermal growth factor receptor inhibitors can overcome radio- and chemoresistance. The aim of the study was to determine whether the addition of gefitinib to RT and gemcitabine for patients with locally advanced pancreatic carcinoma (LAPC) was feasible and safe. METHODS AND MATERIALS: Eighteen patients with pathologically proven LAPC, based on major vascular invasion based on helical computed tomography (CT) and endoscopic ultrasound, were entered into the study. The targeted irradiated volume included the tumor and 2-cm margin. Prophylactic irradiation of regional nodes was not allowed. Patients with >500 cm(3) of planning tumor volume were excluded. An initial cohort of 6 patients was treated with RT (45 Gy/25 fractions/5 weeks) plus concomitant gefitinib (250 mg/day). Successive cohorts of patients received 100, 150, and 200 mg/m(2)/day of gemcitabine in a 2-h infusion over Weeks 1, 2, 3, 4, and 5 with gefitinib (250 mg/day) and RT. Gefitinib was continued after RT until progression. A pharmacodynamic study of angiogenic markers was also performed to evaluate a possible antiangiogenic effect. RESULTS: There were no dose-limiting toxicities. Common toxicities were mild neutropenia, asthenia, diarrhea, cutaneous rash and nausea/vomiting. The median (95% confidence interval [CI]) progression-free survival was 3.7 (95% CI = 1.9-5.5) months, and the median overall survival was 7.5 (95% CI = 5.2-9.9) months. No significant reduction of vascular endothelial growth factor and interleukin-8 was observed after treatment. CONCLUSION: Our results support that the combination of gefitinib, RT, and gemcitabine has an acceptable toxicity but with modest activity in LAPC.