An evaluation of the SENTiFIT 270 analyser for quantitation of faecal haemoglobin in the investigation of patients with suspected colorectal cancer.

BACKGROUND: An evaluation of SENTiFIT® 270 (Sentinel Diagnostics, Italy; Sysmex, Spain) analyser for the quantitation of faecal haemoglobin (f-Hb) was performed. METHODS: The analytical imprecision, linearity, carry over and f-Hb stability were determined. Evaluation of the diagnostic accuracy was performed on 487 patients. RESULTS: Within-run and between-run imprecision ranged 1.7%-5.1% and 3.8%-6.2%, respectively. Linearity studies revealed a mean recovery of 101.1% (standard deviation, 6.7%) for all dilutions. No carry over was detected below 7650 μg Hb/g faeces. Decay of f-Hb in refrigerated samples ranged 0.2%-0.5% per day. f-Hb in patients with advanced colorectal neoplasia (ACRN) (colorectal cancer [CRC] plus advanced adenoma [AA]) were significantly higher than from those with a normal colonoscopy. Sensitivity for ACRN at f-Hb cutoffs from 10 to 60 μg Hb/g faeces ranged from 28.9% (95% confidence interval [CI], 21.7%-37.2%) to 46.5% (95% CI, 38.1%-55%), the specificity ranged from 85% (95% CI, 82.3%-87.3%) to 93.2% (95% CI, 91.2%-94.8%), positive predictive values for detecting CRC and AA ranged from 11.6% (95% CI, 7.6%-17.2%) to 20.6% (95% CI, 13.3%-30.3%) and from 34.7% (95% CI, 28.1%-42%) to 42.3% (95% CI, 32.4%-52.7%), respectively, and the negative predictive value for ACRN ranged from 90.2% (95% CI, 87.9%-92.2%) to 88.4% (95% CI, 86%-90.4%). Using two samples per patient sensitivity increased with a slight decrease in specificity. CONCLUSIONS: The analytical and clinical performances of SENTiFIT assay demonstrate a specific and accurate test for detecting ACRN in symptomatic patients and those undergoing surveillance. KEYWORDS: adenoma; analyser evaluation; colorectal cancer; faecal haemoglobin; faecal immunochemical tes

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

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

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

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 [Aβ42], 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 Aβ 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

Estimació del risc de neoplàsia colorectal avançada a partir de la quantificació de l’hemoglobina fecal en el cribratge del càncer de còlon i recte

[cat] INTRODUCCIÓ: A nivell mundial el càncer de còlon i recte (CCR) és el segon i el tercer en freqüència en homes i en dones, respectivament. La seva història natural és coneguda, se sap que habitualment es desenvolupa a partir de pòlips, existint evidències que la seva extirpació redueix la mortalitat causada per aquesta malaltia. Principalment existeixen dues formes per identificar aquestes lesions, per una banda l’exploració directa del còlon utilitzant tècniques endoscòpiques, i per l’altra la realització d’una prova no invasiva per seleccionar els individus als que realitzar l’exploració endoscòpica. A l’actualitat, aquesta prova no invasiva, es basa en la detecció d’hemoglobina en femta (f-Hb), ja sigui a partir de la prova del Guaiac (inespecífica, subjectiva i poc manejable) o bé utilitzant la prova immunoquímica (FIT, del anglès Faecal Immunochemical Testing) molt més específica, objectiva, pràctica i higiènica que la prova del Guaiac. Una de les grans avantatges de la FIT és poder disposar d’un resultat quantitatiu, fet que permet establir valors discriminants per seleccionar la població a la que es realitzarà l’exploració endoscòpica. OBJECTIUS: El principal objectiu d’aquesta Tesi és establir un mètode que permeti estratificar els participants en un programa de cribratge de CCR amb resultat de FIT positiu en funció de la probabilitat de presentar neoplàsia colorectal avançada (NCRA), constituïda per els adenomes de risc intermig i alt i els CCRs. Com a objectius secundaris es van establir identificar diferències entre variables demogràfiques i definir l’eficàcia diagnòstica de la prova per identificar NCRA utilitzant una mostra o dues mostres corresponents a moviments intestinals diferents. RESULTATS: Es varen analitzar de forma retrospectiva 3109 participants inclosos en la primera ronda del programa de detecció precoç de CCR de Barcelona amb FIT positiu (≥20 µg Hemoglobina/g femta), classificant-los en dos grups en funció de la presència o absència a la colonoscòpia de NCRA. L’anàlisi multivariant de regressió logística va identificar el sexe masculí, el grup d’ edat entre 60–69 anys i la concentració de f-Hb com a factors predictius independents de NCRA. Combinant aquests factors es varen establir 16 categories de risc associades a diferents probabilitats d’identificar NCRA. Incrementant 11,46 vegades en aquells participants inclosos en la categoria de major risc (homes entre 60 i 69 anys d’edat i una concentració de f-Hb >177 µg/g) quan es comparava amb els que pertanyien a la categoria de risc més baix (dones de 50 a 59 anys i concentració de f-Hb entre 20 i 32 µg/g). El valor predictiu positiu per NCRA va oscil·lar entre 21,3% i 75,5%. Per altra banda es van estudiar de forma prospectiva 208 pacients simptomàtics als que, prèviament a una colonoscòpia diagnòstica, se’ls va demanar dues mostres de femta de dos moviments intestinals diferents. La colonoscòpia va identificar la presència de NCRA a 29 pacients. Es van observar diferències en funció del sexe, obtenint una millor sensibilitat diagnòstica per NCRA i concentracions més elevades de f-Hb en el grup d’homes quan es comparava amb el de dones. Utilitzant dues mostres per individu s’aconseguia un augment en la sensibilitat diagnòstica, obtenint resultats molt similars valorant el resultat de la primera mostra amb un valor discriminant inferior. CONCLUSIONS: La concentració de f-Hb de la població que participa en un programa de cribratge juntament amb la informació aportada per el sexe i l’edat, permet estratificar el risc de NCRA. La FIT es comporta de forma diferent en funció del sexe i dels grups d’edat. S’observa una eficàcia diagnòstica similar per NCRA tant quan es valora la concentració de f-Hb més elevada de dues mostres com el resultat d’una sola mostra utilitzant un valor discriminant inferior.[eng] INTRODUCTION: Colorectal cancer (CRC) is an important health problem all over the world. In industrialized countries, CRC is the second most common malignancy in men and the third most common in women. Screening for CRC can identify the disease at an earlier stage or at a premalignant phase. The latest generation of fecal immunochemical tests (FIT) allows for quantitation of hemoglobin in feces (f-Hb), allowing for selection of optimal cut-off concentrations. Furthermore the utility of fecal immunochemical tests (FIT) in assessment of symptomatic patients with lower gastrointestinal symptoms has not been well explored. AIMS: We investigated, in a screening setting, whether individuals with positive results from quantitative FITs, in combination with other factors, could be identified as being at greatest risk for advanced colorectal neoplasia (ACRN). We also evaluated the diagnostic yield for ACRN in symptomatic patients using the first of two FIT samples (FIT/1) and the higher concentration of two FIT samples (FIT/max). RESULTS AND CONCLUSIONS: Median fecal hemoglobin concentrations were significantly higher in participants with ACRN compared with participants with non ACRN. Positive predictive values for ACRN, determined using arbitrary fecal hemoglobin concentrations, differed with sex and age. Multivariate logistic regression analysis identified male gender, older age (60–69 y) and fecal hemoglobin concentration as independent predictive factors for ACRN. Combining these factors, we identified 16 risk categories associated with different probabilities of identifying ACRN. Regarding to the symptomatic cohort, colonoscopy detected ACRN in 29 patients. In these patients, FIT/1 and FIT/max were significantly higher than in patients with low-risk adenoma. We observed differences between gender, obtaining the highest sensitivity and the highest f-Hb concentration in men when compared with women. Moreover, the diagnostic yield of collecting two samples for FIT can be achieved with one sample, albeit using a lower f-Hb cut-off

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

Prognostic velue of IL-6 in the localized prostatic cancer

AIM: The usefulness of interleukin 6 (IL-6) and its soluble receptor IL-6sR in the prediction of the biochemical recurrence was evaluated in patients with prostate cancer treated with radical prostatectomy. PATIENTS AND METHODS: IL-6 and sIL-6R serum levels were measured in 96 patients with prostate cancer. RESULTS: Using the log-rank test, it was evident that patients with preoperative serum levels of IL-6 higher than 1.2 pg/ml had a significantly increased probability of biochemical recurrence (p=0.031). We also observed that the Gleason score was associated with the risk of progression (p=0.033), but no relation was observed with TNM classification, PSA, % free PSA or sIL-6R. In a multivariate analysis, only IL-6 serum levels remained as a predictor of biochemical recurrence (p=0.040). CONCLUSION: The results presented here demonstrated the usefulness of IL-6 in predicting the biochemical progression of prostate cancer, pointing towards an association between inflammation and the aggressiveness of the tumor

Prognostic value of IL-6 in the localized prostatic cancer

AIM: The usefulness of interleukin 6 (IL-6) and its soluble receptor IL-6sR in the prediction of the biochemical recurrence was evaluated in patients with prostate cancer treated with radical prostatectomy. PATIENTS AND METHODS: IL-6 and sIL-6R serum levels were measured in 96 patients with prostate cancer. RESULTS: Using the log-rank test, it was evident that patients with preoperative serum levels of IL-6 higher than 1.2 pg/ml had a significantly increased probability of biochemical recurrence (p=0.031). We also observed that the Gleason score was associated with the risk of progression (p=0.033), but no relation was observed with TNM classification, PSA, % free PSA or sIL-6R. In a multivariate analysis, only IL-6 serum levels remained as a predictor of biochemical recurrence (p=0.040). CONCLUSION: The results presented here demonstrated the usefulness of IL-6 in predicting the biochemical progression of prostate cancer, pointing towards an association between inflammation and the aggressiveness of the tumor