Josep Maria Augé

Serum matrix metalloproteinase 7 levels identifies poor prognosis advanced colorectal cancer patients

Metalloproteinase 7 (MMP‐7) plays an important role in tumor growth, invasion and dissemination, and is secreted to the media. Because of the close implication of MMP‐7 in cancer biology, we sought to define the prognostic significance of serum levels of MMP‐7 in metastatic colorectal cancer (CRC) and explore its possible impact in the daily clinical practice. MMP‐7 expression was determined by enzyme‐linked immunoabsorbent assay. We assessed serum MMP‐7 levels in 87 healthy controls, 96 patients with nonmetastatic CRC and 120 patients with advanced CRC. Clinical information was gathered from patient files. Cox proportional hazards model was used to assess survival. MMP‐7 and the variables associated with prognosis were entered and a backward elimination method was employed to adjust the model. Inclusion criteria was p ≤≤≤≤ 0.05 and exclusion criteria was p ≥≥≥≥ 0.10. Advanced CRC patients have a significant higher mean serum MMP‐7 levels (13.4 ng/ml) than those in nonmetastatic CRC (5.5 ng/ml; p < 0.001) and healthy controls (4.2 ng/ml; p < 0.001). In metastatic patients, after adjusting for other prognostic variables, MMP‐7 (entered as a continuous variable) is associated with decreased survival (HR 1.016, IC 95% 1.002–1.031). Serum MMP‐7 levels are significantly elevated in patients with advanced CRC. In conclusion, MMP‐7 is an independent prognostic factor for survival in advanced CRC. In our sample, the risk of death associated to MMP‐7 increase is much higher than the risk of death associated to lactate dehydrogenase elevation.

Usefulness of Serum Tumor Markers, Including Progastrin-Releasing Peptide, in Patients with Lung Cancer: Correlation with Histology

Background: Tumor markers have been extensively studied in lung cancer, reporting some relationship to the histology, but their clinical utility is not clear. Methods: ProGRP, CEA, SCC, CA 125, CYFRA 21-1 and NSE were studied prospectively in 155 patients with unconfirmed suspicion of lung cancer and in 647 patients with lung cancer: 182 squamous, 205 adenocarcinomas, 19 large-cell lung cancer (LCLC), 175 small-cell lung cancer (SCLC) and 66 unspecific non-small-cell lung cancer (NSCLC). Results: Abnormal tumor marker serum levels were found in less than 5.3% of the patients with benign diseases, excluding CA 125 (21.3%). Tumor markers were related to histological type and tumor extension with significantly higher CEA (p <0.01) and CA 125 (p <0.007) serum levels in adenocarcinomas, SCC (p <0.0001) and CYFRA 21-1 (p <0.008) in squamous tumors and ProGRP (p <0.0001) and NSE (p <0.0001) in SCLC. Tumor markers may be useful in the histological differentiation of NSCLC and SCLC. Patients with SCC serum levels >2 ng/ml were always NSCLC, while those with SCC <2 ng/ml and ProGRP >100 pg/ml and NSE >35 ng/ml were all SCLC patients. The sensitivity was 76.7 and 79.5%, specificity was 97.2 and 99.6%, with a positive predictive value of 98.6 and 98.6% and a negative predictive value of 60.7 and 92.9% in the differentiation of NSCLC and SCLC, respectively. Conclusions: Tumor marker determination in patients with suspicious signs of lung cancer suggests, in a few hours, the histological diagnosis in the majority of lung cancer patients.

The Role of MMP7 and Its Cross-Talk with the FAS/FASL System during the Acquisition of Chemoresistance to Oxaliplatin

Background The efficacy of oxaliplatin in cancer chemotherapy is limited by the development of drug resistance. MMP7 has been related to the loss of tumor cell response to cytotoxic agents although the exact mechanism is not fully understood. Moreover, MMP7 is an independent prognosis factor for survival in patients with colorectal cancer. The aim of the present study was to analyze the role of MMP7 and its cross-talk with the Fas/FasL system during the acquisition of oxaliplatin resistance in colon cancer cells. Principal Findings For this purpose we have developed three different oxaliplatin-resistant cell lines (RHT29, RHCT116 p53+/+, RHCT116 p53−/−) from the parental HT29, HCT116 p53+/+ and HCT116 p53−/− colon cancer cells. MMP7 basal expression was higher in the resistant compared to the parental cell lines. MMP7 was also upregulated by oxaliplatin in both HT29 (p53 mutant) and RHCT116 p53−/− but not in the RHCT116 p53+/+. Inhibition of MMP by 1,10-phenantroline monohydrate or siRNA of MMP7 restores cell sensitivity to oxaliplatin-induced apoptosis in both HT29 and RHCT116 p53−/− but not in the RHCT116 p53+/+. Some of these effects are caused by alterations in Fas receptor. Fas is upregulated by oxaliplatin in colon cancer cells, however the RHT29 cells treated with oxaliplatin showed a 3.8-fold lower Fas expression at the cell surface than the HT29 cells. Decrease of Fas at the plasma membrane seems to be caused by MMP7 since its inhibition restores Fas levels. Moreover, functional analysis of Fas demonstrates that this receptor was less potent in inducing apoptosis in RHT29 cells and that its activation induces MAPK signaling in resistant cells. Conclusions Taking together, these results suggest that MMP7 is related to the acquisition of oxaliplatin-resistance and that its inhibition restores drug sensitivity by increasing Fas receptor. Furthermore, Fas undergoes a change in its functionality in oxaliplatin-resistant cells inducing survival pathways instead of apoptotic signals.

PCA3 in the detection and management of early prostate cancer

Although widely used, the value of prostate-specific antigen (PSA) in the detection of prostate cancer is controversial. The percentage of free PSA increases the specificity of PSA, but results are not enough. Prostate cancer gene 3 (PCA3) has been proposed as an option that may complement these markers in the detection and management of early prostate cancer. Our aim has been to review the value of PCA3 as tumor marker. The available results suggest that PCA3 is particularly useful to select in which patients the biopsy should be repeated when the first biopsy was negative. However, some points should be specified with further studies, including the most appropriate PCA3 cutoff level and the significance of a high PCA3 score in patients with negative biopsy. False-negative results are also a conflictive point in the use of PCA3, because prostate cancer, including aggressive tumors, may be present in patients with a low PCA3 score. Probably, a proper interpretation of this test requires its management together with other tests, through multivariate models for the detection of prostate cancer. On the other hand, several studies showed the relation between PCA3 score and Gleason score, and also the utility of PCA3 to select patients for active surveillance. To summarize, the available studies show the utility of PCA3 in the detection and management of early prostate cancer, although some aspects referred to its use need to be retested after further studies to confirm the actual value and the limitations of this test.

Impact of Ultrasensitive Cardiac Troponin I Dynamic Changes in the New Universal Definition of Myocardial Infarction

We evaluated the impact of using the new universal definition of myocardial infarction (MI) criteria implemented with a 20% increment between 2 cardiac troponin I (cTnI) measurements. The study included 284 consecutive episodes of patients admitted to the emergency department with suspected acute coronary syndrome (ACS) and an initial cTnI measurement of 0.10 ng/mL (0.10 microg/L) or less followed by 1 or more measurements within 24 hours. Episodes with a maximum cTnI above the 99th percentile (0.04 ng/mL [0.04 microg/L]) and a dynamic increase between 2 measurements of 20% or more were considered to meet MI criteria. Of the 284 episodes, 109 (38.4%) had a maximum cTnI higher than 0.04 ng/mL (0.04 microg/L). However, only 66 episodes (23.2%) also had an increase of 20% or more in the cTnI concentration and met MI criteria. These 66 episodes included 37 patients diagnosed with an MI and 29 patients not diagnosed with an MI. The 29 patients who also met MI criteria were more frequently readmitted for ACS within 6 months.

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.

Prognostic Implications of Protein S-100β 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-100β protein in high-risk melanoma patients. Patients and Methods: Patients were tested for serum S-100β protein by luminoimmunometric assay after melanoma surgical excision, before starting interferon-α2b 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-100β levels were associated with positive lymph node status (p = 0.02). High S-100β 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-100β levels were associated with disease-free survival (p = 0.004) and overall survival (p = 0.0007). Similarly, high S-100β levels during therapy were associated with disease-free survival (p < 0.0001) and overall survival (p < 0.0001). In the multivariate analysis, high S-100β levels during therapy (hazard ratio 1.017, 95% CI 1.008–1.026; p < 0.0001) and high baseline S-100β 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-100β levels, respectively. Conclusions: These results provide evidence of the clinical usefulness of serum S-100β level determination in high-risk melanoma patients. S-100β serum determination should be considered to be included in clinical trials that test adjuvant therapies in melanoma patients.

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

Abstract 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.

Abstract 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.

Variability of assay methods for total and free PSA after WHO standardization

The variability of total PSA (tPSA) and free PSA (fPSA) results among commercial assays has been suggested to be decreased by calibration to World Health Organization (WHO) reference materials. To characterize the current situation, it is necessary to know its impact in the critical cutoffs used in clinical practice. In the present study, we tested 167 samples with tPSA concentrations of 0 to 20 μg/L using seven PSA and six fPSA commercial assays, including Access, ARCHITECT i2000, ADVIA Centaur XP, IMMULITE 2000, Elecsys, and Lumipulse G1200, in which we only measured tPSA. tPSA and fPSA were measured in Access using the Hybritech and WHO calibrators. Passing–Bablok analysis was performed for PSA, and percentage of fPSA with the Hybritech-calibrated access comparison assay. For tPSA, relative differences were more than 10 % at 0.2 μg/L for ARCHITECT i2000, and at a critical concentration of 3, 4, and 10 μg/L, the relative difference was exceeded by ADVIA Centaur XP and WHO-calibrated Access. For percent fPSA, at a critical concentration of 10 %, the 10 % relative difference limit was exceeded by IMMULITE 2000 assay. At a critical concentration of 20 and 25 %, ADVIA Centaur XP, ARCHITECT i2000, and IMMULITE 2000 assays exceeded the 10 % relative difference limit. We have shown significant discordances between assays included in this study despite advances in standardization conducted in the last years. Further harmonization efforts are required in order to obtain a complete clinical concordance.