Immunological comorbity in coeliac disease: associations, risk factors and clinical implications.

PURPOSE: Coeliac disease is frequently associated with other immunomediated diseases. Our aim was to identify immunological comorbidities and possible risk factors for their development in coeliac patients. METHODS: We recruited a cohort of 1,015 coeliac patients followed from 0 to 46 years in a single tertiary referral centre. Data were collected from the yearly scheduled clinical and serological evaluations. Possible risk factors such as demographic parameters, type of symptomatic presentation, gluten exposure, gluten-free diet compliance and family history were all evaluated. Subjects (848,606) from the regional health registry were investigated as controls. RESULTS: The prevalence of immunomediated diseases was higher in patients with coeliac disease compared to the registry population (23 % vs 0.4 %, p < 0.001). Diagnosis during paediatric age represented a risk factor for the presence of at least an immunomediated disease (hazard ratio = 1.62, 95 % confidence interval 1.15-2.29, p = 0.0061). Type of presentation and dietetic compliance did not represent risk factors. Long-standing gluten exposure reduced the risk of developing immunomediated diseases in coeliac subjects (hazard ratio for 1 year longer exposure 0.23, 95 % confidence interval 0.16-0.33, p < 0.0001). A familiar background characterized by the presence of immunological disorders was not a risk factor, although 419 (13 %) first degree relatives of coeliac patients out of 3,195 had an immunomediated disease. CONCLUSIONS: Our study suggests the need to investigate coeliac patients for other associated immunomediated diseases, independently of sex, gluten exposure and compliance to therapy; also subjects diagnosed in paediatric age should be carefully screened during follow up.

Association between miR-200c and the survival of patients with stage I epithelial ovarian cancer: a retrospective study of two independent tumour tissue collections.

BACKGROUND: International Federation of Gynecology and Obstetrics stage I epithelial ovarian cancer (EOC) has a significantly better prognosis than stage III/IV EOC, with about 80% of patients surviving at 5 years (compared with about 20% of those with stage III/IV EOC). However, 20% of patients with stage I EOC relapse within 5 years. It is therefore crucial that the biological properties of stage I EOCs are further elucidated. MicroRNAs (miRNAs) have shown diagnostic and prognostic potential in stage III and IV EOCs, but the small number of patients diagnosed with stage I EOC has so far prevented an investigation of its molecular features. We profiled miRNA expression in stage I EOC tumours to assess whether there is a miRNA signature associated with overall and progression-free survival (PFS) in stage I EOC. METHODS: We analysed tumour samples from 144 patients (29 of whom relapsed) with stage I EOC gathered from two independent tumour tissue collections (A and B), both with a median follow-up of 9 years. 89 samples from tumour tissue collection A were stratified into a training set (51 samples, 15 of which were from patients who relapsed) for miRNA signature generation, and into a validation set (38 samples, seven of which were from patients who relapsed) for signature validation. Tumour tissue collection B (55 samples, seven of which were from patients who relapsed) was used as an independent test set. The Cox proportional hazards model and the log-rank test were used to assess the correlation of quantitative reverse transcription PCR (qRT-PCR)-validated miRNAs with overall survival and PFS. FINDINGS: A signature of 34 miRNAs associated with survival was generated by microarray analysis in the training set. In both the training set and validation set, qRT-PCR analysis confirmed that 11 miRNAs (miR-214, miR-199a-3p, miR-199a-5p, miR-145, miR-200b, miR-30a, miR-30a*, miR-30d, miR-200c, miR-20a, and miR-143) were expressed differently in relapsers compared with non-relapsers. Three of these miRNAs (miR-200c, miR-199a-3p, miR-199a-5p) were associated with PFS, overall survival, or both in multivariate analysis. qRT-PCR analysis in the test set confirmed the downregulation of miR-200c in relapsers compared with non-relapsers, but not the upregulation of miR-199a-3p and miR-199a-5p. Multivariate analysis confirmed that downregulation of miR-200c in the test set was associated with overall survival (HR 0·094, 95% CI 0·012-0·766, p=0·0272) and PFS (0·035, 0·004-0·311; p=0·0026), independent of clinical covariates. INTERPRETATION: miR-200c has potential as a predictor of survival, and is a biomarker of relapse, in stage I EOC. FUNDING: Nerina and Mario Mattioli Foundation, Cariplo Foundation (Grant Number 2010-0744), and the Italian Association for Cancer Research.

Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis.

Surgery of liver metastases can be effective, and the appropriate selection of surgical candidates relies first on imaging. Different techniques are available, but information on their relative performance is unclear. The aim of this overview is to assess the imaging modality performance in the diagnosis of colorectal cancer (CRC) liver metastases. MEDLINE and EMBASE were searched for articles published from January 2000 to August 2008. Eligible trials had to be conducted on patients with diagnosis/suspicion of CRC liver metastases, comparing more than two modalities among MRI, computed tomography (CT), positron emission tomography using fluoro-18-deoxyglucose (FDG-PET), ultrasonography (US). Pooled estimates of sensitivity, specificity were calculated and pair-wise comparisons were performed. Of 6030 screened articles, 25 were eligible. Sensitivity and specificity on a per-patient basis for US, CT, MRI, and FDG-PET were 63.0% and 97.6%, 74.8% and 95.6%, 81.1% and 97.2, and 93.8% and 98.7%, respectively. On a per-lesion basis, sensitivity was 86.3%, 82.6%, 86.3%, and 86.0%, respectively. Specificity was reported in few studies. MRI showed a better sensitivity than CT in per-patient (odds ratio [OR]: 0.69; 95% confidence interval [CI]: 0.47-0.99; P = 0.05) and in per-lesion analysis (OR: 0.66; 95% CI: 0.55-0.80; P < 0.0001). In per-lesion analysis, the difference was higher when liver-specific contrast agents were administered. Available evidence supports the MRI use for the detection of CRC liver metastases.

Evaluation of the weight loss of raw beef cuts vacuumpackaged with two different techniques.

In the present study, 25 cuts of shank form adult cattle coming from the same slaughtering batch, were withdrawn just after manual sectioning/deboning, and each divided into two pieces (Prox and Dist) of approximately the same weight, that were vacuum packaged by using two different packaging systems: vacuum chamber machine with a bag material and a thermoforming packaging machine with top and bottom webs named BAG and THF respectively. The packed cuts were stored at 2-3°C for 20 days. The drip loss was calculated at the end of the storage as the difference between drained weight and net. Internal muscle pH and pH of the exudate present in the package and microbiological analyses (by pooling the samples) were performed at T0 and at the end of the storage. The drip loss, was significantly lower with BAG packaging: this difference was evident after 20 days of storage (average ± STD BAG vs THF = 1.04±0.36% vs 1.71±0.42%; P<0.01). The values were, in general, low for both the packaging systems, never above 2%. Moreover, shrink bag packages are characterized by better overall pack appearance and less plastic weight per pack. Forming step reduce the thickness of thermoforming material lowering the mechanical resistance and the barrier to oxygen, on the contrary after shrinking bag materials are thickened. The pH of muscles was stable, although a slight increase was evidenced after 20 (average ± STD BAG vs THF= 5.73±0.05 vs 5.78±0.09; P<0.01), due to the ageing of meat. The pH of the exudate was equal at T20 (average ± STD BAG vs THF = 5.34±0.20 vs 5.33±0.17). The drip loss didn't influence the development of all the microflora; in particular LAB, that represented the main microbial population, showed a gradual increase from T0 (2.20±0.41 Log CFU/g) to T20 (average ± STD BAG vs THF= 4.76±0.29 Log CFU/g vs 4.75±0.0.15 Log CFU/g). Enterobacteriaceae showed an increase, if compared to the initial counts, due to the prolonged storage and the gradual growth of ephemeral microorganisms, without differences among the two series (Enterobacteriaceae: T0=<1.7 Log CFU/g to T20 average ± STD BAG vs THF = 2.83±0.77 Log CFU/g vs 3.09±0.0.70 Log CFU/g). In conclusion, the use of the BAG system demonstrated to have an effect in reducing the drip loss of beef cuts during the refrigerated storage, with only slight influence on the other characteristics of raw meat.

Changes in plasma mass-spectral profile in course of treatment of non-small cell lung cancer patients with epidermal growth factor receptor tyrosine kinase inhibitors.

INTRODUCTION: Our previous study showed that pretreatment serum or plasma Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry may predict clinical outcome of non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, plasma proteomic profiles of NSCLC patients were evaluated in the course of EGFR TKIs therapy. MATERIALS AND METHODS: Plasma samples were collected at baseline, in the course of gefitinib therapy and at treatment withdrawal. Samples were analyzed by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. Acquired spectra were classified by the VeriStrat test into "good" and "poor" profiles. The association between VeriStrat classification and progression-free survival (PFS) and overall survival (OS), and types of clinical progression, was analyzed. RESULTS: Plasma samples from 111 NSCLC patients treated with gefitinib were processed. VeriStrat "good" classification at baseline correlated with longer PFS (hazard ratio [HR], 0.54; 95% confidence interval, 0.35-0.83; p = 0.005) and OS (HR, 0.40; 95% confidence interval, 0.26-0.61; p < 0.0001), when compared with VeriStrat "poor." Multivariate analysis confirmed longer PFS (HR, 0.52; p = 0.025) and OS (HR, 0.44; p = 0.001) in patients classified as VeriStrat "good", when VeriStrat was considered as a time-dependent variable. About one-third of baseline "good" classifications had changed to "poor" at the time of treatment withdrawal; progression in these patients was associated with the development of new lesions. CONCLUSIONS: Our findings support the role of VeriStrat in the assistance in treatment selection of NSCLC patients for EGFR TKI therapy and its potential utility in treatment monitoring.

Randomized phase III clinical trial evaluating weekly cisplatin for advanced epithelial ovarian cancer.

This randomized, open label, phase III clinical trial (1988-1992) compared the efficacy and safety of a dose-dense regimen of single-agent cisplatin with a standard 3-weekly schedule in first-line chemotherapy for advanced epithelial ovarian cancer. Two hundred eighty-five patients were randomly assigned to the experimental dose-dense arm (cisplatin 50 mg/m(2) weekly × nine cycles) or to the control (standard treatment) arm (cisplatin 75 mg/m(2), administered on day 1 every 21 days × six cycles). The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall response to chemotherapy, and toxicity. Toxicity and response to treatment were compared with the χ(2) test using trend or exact correction. PFS and OS were estimated by Kaplan-Meier analyses and treatment hazard ratios (HRs) with the Cox proportional hazards model. All statistical tests were two-sided. After a median follow-up of 16.8 years, no differences were observed between the two treatments in PFS (experimental arm: 17.2 months; control arm: 18.1 months; HR = 1.08, 95% confidence interval [CI] = 0.83 to 1.40; P = .57) and in OS (experimental arm: 35 months; control arm: 32 months; HR = 0.97, 95% CI = 0.75 to 1.26; P = .97). Thus, increasing dose intensity of cisplatin does not improve PFS or OS compared with standard chemotherapy.

Association of cytidine deaminase and xeroderma pigmentosum group D polymorphisms with response, toxicity, and survival in cisplatin/gemcitabine-treated advanced non-small cell lung cancer patients.

BACKGROUND: Selecting patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in non-small cell lung cancer (NSCLC). Genetic variations in drug metabolism may affect the clinical response, toxicity, and prognosis of NSCLC patients treated with cisplatin/gemcitabine-based therapy. PATIENTS AND METHODS: We evaluated seven single-nucleotide polymorphisms of six genes CDA Lys27Gln (A/C); CDA C435T; ERCC1 C118T; XRCC3 Thr241Met (C/T); XPD Lys751Gln (A/C); P53 Arg72Pro (G/C), and RRM1 C524T in 192 chemotherapy-naive patients with advanced NSCLC treated with cisplatin/gemcitabine-based regimen by TaqMan probe-based assays with 7300 Real-Time PCR System, using genomic DNA extracted from blood samples. RESULTS: The CDA 435 T/T genotype was significantly associated with better response (p = 0.03). The CDA 435 C/T genotype was associated with a significantly increased risk of nonhematological toxicity of grade ≥3 (p = 0.02) after adjusting for performance status, age, and type of treatment regimen. In the multivariate Cox model, the XPD 751 C/C genotype was a significant prognostic factor of longer progression-free survival (p = 0.006). CONCLUSION: Our data suggest polymorphic variations of drug metabolic gene were associated with response and toxicity of cisplatin/gemcitabine-based therapy and progression-free survival of patients with advanced NSCLC.