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Valotto C.,University of Padua | Falconieri G.,Azienda Ospedaliera Universitaria di Udine | Pizzolitto S.,Azienda Ospedaliera Universitaria di Udine | Cerruto M.A.,University of Verona | And 4 more authors.
Archivio Italiano di Urologia e Andrologia | Year: 2011

Introduction and objectives: The aim of our study was to verify the impact of benign and malignant residual glandular tissue on surgical bed after radical prostatectomy, in terms of both biochemical and clinical disease progression, in a group of patients with pathologically organ-confined cancer of the prostate (PCa). Material and methods: Files from 70 consecutive patients who undergone radical retropubic prostatectomy (RRP) for organ-confined PCa were retrospectively evaluated. During each intervention, after prostate removal, biopsies of the surgical bed were obtained from the following sites: urethral/periapical section margin, basal, left and right postero-lateral and under/retrotrigonal regions. No patient was been previously treated with either radiation or hormone therapy. We evaluated the relationship between the presence of either benign or malignant prostatic cells at surgical bed biopsies and the following parameters: postoperative serum PSA levels, definitive Gleason score, tumour staging, margin status. Results: In all cases pathological stage was pT2N0M0, an immediate postoperative PSA zeroing occurred and surgical margins were negative. Surgical bed biopsies after prostate removal were positive for malignant cells in 5/70 cases (7.1%) and for benign prostatic cells in 16/70 patients (22.9%). Overall a biochemical disease progression was observed in 13/70 cases (18.6%): 1 case with surgical bed biopsies positive for cancer; 3 cases with biopsies positive for benign prostatic tissue; 9 patients with biopsies negative for prostatic tissue residuals. In this latter group 2 cases of disease progression were observed. Stratifying patients according to biopsy features, we did not find any significant difference between groups concerning preoperative PSA (p = 0.319), prostate weight (p = 0.158), pathological staging (p = 0.371), Gleason score (p = 0.457), follow-up (p = 0.144), biochemical progression rates (p = 0.553). At logistic regression model the only statistically significant association was between disease progression and preoperative PSA (p = 0.026). Stratifying patients with no malignant biopsies in two sub-groups (presence and absence of residual benign prostate tissue) no statistically significant differences were detected in terms of disease relapse (p = 0.158). Conclusions: In patients with pathologically organ-confined PCa, minimal neoplastic tissue residuals might not significantly affect medium-long-term prognosis: 80% of patients with positive biopsy showed undetectable serum PSA levels after a median follow-up over 5 years. In contrast, surgical margins positive for benign prostatic glands was not significantly related to a possible disease relapse/progression.


Ruzzo A.,Urbino University | Graziano F.,Azienda Ospedaliera Ospedali Riuniti Marche Nord | Galli F.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Giacomini E.,Urbino University | And 25 more authors.
Scientific Reports | Year: 2014

We investigated 17 polymorphisms in 11 genes (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT1, GSTP1, GSTM1, ABCC1, ABCC2) for their association with the toxicity of fluoropyrimidines and oxaliplatin in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. The TOSCA Italian adjuvant trial was conducted in high-risk stage II-III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In the concomitant ancillary pharmacogenetic study, the primary endpoint was the association of polymorphisms with grade 3-4 CTCAE toxicity events (grade 2-4 for neurotoxicity). In 517 analyzed patients, grade ≥ 3 neutropenia and grade ≥ 2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade ≥ 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Hopefully, genome-wide association studies will identify new and more promising genetic variants to be tested in future studies.


Mimmi M.C.,University of Udine | Picotti P.,University of Udine | Picotti P.,ETH Zurich | Corazza A.,University of Udine | And 10 more authors.
Clinical Chemistry and Laboratory Medicine | Year: 2011

Background: The identification of reliable markers for diagnosis of breast cancer has been thoroughly addressed by metabolic profiling using nuclear magnetic resonance (NMR) spectroscopy or imaging. Several clear diagnostic indicators have emerged using either in vitro analysis of tissue extracts, ex vivo analysis of biopsies or in vivo direct spectral observations. Most of the breast cancer characteristic metabolites could be assayed by mass spectrometry (MS) to exploit the superior sensitivity of this technique and therefore reduce the traumatic impact of current biopsy procedures. Methods: Following extraction, aqueous metabolite mixtures were obtained that were submitted to liquid-chromatography, electrospray-ionization, mass spectrometry (LC/ESI-MS) analysis to estimate the content of choline (Cho) and its phosphorylated derivatives, phosphocholine (PCho) and glycerophosphocholine (GPCho). The determinations were performed using 10 samples from breast tissue biopsies, surgical specimens and one single sample of a hepatic metastasis. In addition, some measurements were also repeated using high-resolution 1H NMR spectroscopy to complement the mass spectrometry results. Results: The contents of Cho, PCho and GPCho in breast tissue extracts were estimated by LC/ESI-MS based on standard compound calibration curves. Sharply increased ratios of phosphorylated-to-unphosphorylated metabolites, PCho/ Cho and (PCho+GPCho)/Cho, were observed in all tumor samples, although without discrimination between benign and malignant lesions, contrary to samples from healthy individuals and from those with fibrocystic disease. Conclusions: The assessment of breast cancer markers by LC/ESI-MS is feasible and diagnostically valuable. In addition to high sensitivity, the approach also shows a resolution advantage for assaying choline derivatives compared to NMR, and could complement the latter. © 2011 by Walter de Gruyter.


Crow Y.J.,University of Paris Pantheon Sorbonne | Crow Y.J.,University of Manchester | Chase D.S.,University of Manchester | Lowenstein Schmidt J.,George Washington University | And 136 more authors.
American Journal of Medical Genetics, Part A | Year: 2015

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials. © 2015 Wiley Periodicals, Inc.

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