Sant'Ambrogio di Torino, Italy
Sant'Ambrogio di Torino, Italy

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Ricci M.T.,Unit of Hereditary Cancer | Sciallero S.,Medical Oncology Unit 1 | Mammoliti S.,Medical Oncology Unit 1 | Gismondi V.,Unit of Hereditary Cancer | And 3 more authors.
Public Health Genomics | Year: 2015

Background/Aims: Nearly 15% of all ovarian cancer patients carry a germline BRCA mutation. A pilot project was started at IRCCS AOU San Martino - IST, Genoa, to assess the feasibility and consequences of offering genetic counselling to all ovarian cancer patients during routine oncology appointments. We present early results of this project. Methods: Patients who attended an oncology visit at the Medical Oncology Unit 1 between November 2012 and December 2013 were identified. Medical records were reviewed for clinical data, genetic counselling and testing outcomes. Results: Out of 104 women diagnosed with ovarian cancer undergoing an oncology visit, 94 had not had genetic counselling in the past. Twenty-nine patients (29/94, 31%) were referred to the Unit of Hereditary Cancer; of these, 14/26 (54%) were referred at the first visit and 15/68 (22%) at the follow-up visit (p = 0.003). Most referred women attended genetic counselling (22/29, 76%) and had BRCA genetic testing (21/22, 95%). Four BRCA1 mutations were detected (4/21, 19%). Conclusions: Oncologists discuss genetic counselling with a minority of ovarian cancer patients. Mainstreaming such practice is important to optimize the management of these patients and their families. Efforts are needed to identify new models for introducing ovarian cancer genetic risk assessment in oncology practice. © 2015 S. Karger AG, Basel.


Lambertini M.,U.O. Oncologia Medica 2 | Ceppi M.,Unit of Clinical Epidemiology | Poggio F.,U.O. Oncologia Medica 2 | Peccatori F.A.,Italian National Cancer Institute | And 8 more authors.
Annals of Oncology | Year: 2015

Background: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). Methods: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. Results: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I2 = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I2 = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I2 = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I2 = 68.0%, Pheterogeneity = 0.044). Conclusion: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis. © 2015 The Author.


Priola A.M.,University of Turin | Priola S.M.,University of Turin | Ciccone G.,Unit of Clinical Epidemiology | Evangelista A.,Unit of Clinical Epidemiology | And 7 more authors.
Radiology | Year: 2015

Purpose: To prospectively evaluate (a) effectiveness and limits of dualecho chemical-shift magnetic resonance (MR) imaging for distinguishing hyperplastic thymus from anterior mediastinal tumors in adulthood by using chemical-shift ratio (CSR) and signal intensity index (SII), with proposal of optimal threshold value for each, and (b) whether age affects these indexes.Materials and Study was institutional review board approved, with informed Methods: consent obtained. Ninety-two subjects (53 men, 39 women; age range, 18-84 years) were divided into a rebound and lymphoid hyperplasia group (group A, 30 patients) and a tumor group (group B, 62 patients). MR images were assessed; interrater reliability was evaluated. Differences in CSR and SII were tested with the Mann-Whitney U test and the Kruskal-Wallis test. Discrimination abilities of CSR and SII were evaluated with logistic regression models, and optimal cutoff points were proposed. Quantitative parameters were correlated with age by using Pearson correlation coefficients.Results: Interreader agreement was excellent (intraclass correlation coef-ficient: CSR, 0.893; SII, 0.898). Mean CSR and SII ± standard deviation were 0.545 ± 0.162 and 46.29% ± 18.41 for group A and 1.045 ± 0.094 and 20.06% ± 4.89 for group B, respectively, with significant differences for both indexes between groups (P < .0001). No overlap was found for SII between groups; CSR values overlapped in a few younger adults. Distinguishing hyperplastic thymus from tumors was better with SII than CSR. Respective sensitivity, specificity, and cutoff points were 100%, 100%, and 8.92% for SII and 100%, 96.7%, and 0.849 for CSR. Significant correlation was found for CSR (r = 20.761) and SII (r = 0.821) with age in group A (P < .001). For group B, significant correlation with age was seen for CSR (r = 0.702, P < .001) but not SII (r = 20.196, P = .127). All subjects but one in group A and none in group B had signal intensity decrease at chemical-shift MR imaging.Conclusion: With dual-echo chemical-shift MR imaging, SII and CSR have high accuracy to distinguish thymic hyperplasia from tumors, although overlapped CSR values can occur in early adulthood. © RSNA, 2014.


Del Sorbo L.,University of Turin | Del Sorbo L.,Care Network | Pisani L.,University of Bologna | Filippini C.,University of Turin | And 14 more authors.
Critical Care Medicine | Year: 2015

Objectives: To assess efficacy and safety of noninvasive ventilation- plus-extracorporeal Co2 removal in comparison to noninvasive ventilation-only to prevent endotracheal intubation patients with acute hypercapnic respiratory failure at risk of failing noninvasive ventilation. Design: Matched cohort study with historical control. Setting: Two academic Italian ICUs. Patients: Patients treated with noninvasive ventilation for acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease (May 2011 to November 2013). Interventions: Extracorporeal Co2 removal was added to noninvasive ventilation when noninvasive ventilation was at risk of failure (arterial pH ≤ 7.30 with arterial Pco2 > 20% of baseline, and respiratory rate ≥ 30 breaths/min or use of accessory muscles/ paradoxical abdominal movements). The noninvasive ventilationonly group was created applying the genetic matching technique (GenMatch) on a dataset including patients enrolled in two previous studies. Exclusion criteria for both groups were mean arterial pressure less than 60 mm Hg, contraindications to anticoagulation, body weight greater than 120 kg, contraindication to continuation of active treatment, and failure to obtain consent. Measurements and Main Results: Primary endpoint was the cumulative prevalence of endotracheal intubation. Twenty-five patients were included in the noninvasive ventilation-plus-extracorporeal Co2 removal group. The GenMatch identified 21 patients for the noninvasive ventilation-only group. Risk of being intubated was three times higher in patients treated with noninvasive ventilation- only than in patients treated with noninvasive ventilationplus- extracorporeal Co2 removal (hazard ratio, 0.27; 95% CI, 0.07-0.98; p = 0.047). Intubation rate in noninvasive ventilationplus- extracorporeal Co2 removal was 12% (95% CI, 2.5-31.2) and in noninvasive ventilation-only was 33% (95% CI, 14.6-57.0), but the difference was not statistically different (p = 0.1495). Thirteen patients (52%) experienced adverse events related to extracorporeal Co2 removal. Bleeding episodes were observed in three patients, and one patient experienced vein perforation. Malfunctioning of the system caused all other adverse events. Conclusions: These data provide the rationale for future randomized clinical trials that are required to validate extracorporeal Co2 removal in patients with hypercapnic respiratory failure and respiratory acidosis nonresponsive to noninvasive ventilation.


Moccia F.,University of Pavia | Zuccolo E.,University of Pavia | Poletto V.,Unit of Clinical Epidemiology | Cinelli M.,University of Naples Federico II | And 3 more authors.
Tumor Biology | Year: 2015

Endothelial progenitor cells (EPCs) have recently been shown to promote the angiogenic switch in solid neoplasms, thereby promoting tumour growth and metastatisation. The genetic suppression of EPC mobilization from bone marrow prevents tumour development and colonization of remote organs. Therefore, it has been assumed that anti-angiogenic treatments, which target vascular endothelial growth factor (VEGF) signalling in both normal endothelial cells and EPCs, could interfere with EPC activation in cancer patients. Our recent data, however, show that VEGF fails to stimulate tumour endothelial colony-forming cells (ECFCs), i.e. the only EPC subtype truly belonging to the endothelial lineage. The present article will survey current evidence about EPC involvement in the angiogenic switch: we will focus on the controversy about EPC definition and on the debate around their actual incorporation into tumour neovessels. We will then discuss how ECFC insensitivity to VEGF stimulation in cancer patients could underpin their well-known resistance to anti-VEGF therapies. © 2015, International Society of Oncology and BioMarkers (ISOBM).


Moccia F.,University of Pavia | Dragoni S.,University of Pavia | Lodola F.,University of Pavia | Bonetti E.,Unit of Clinical Epidemiology | And 5 more authors.
Current Medicinal Chemistry | Year: 2012

Endothelial progenitor cells (EPCs) have recently been employed in cell-based therapy (CBT) to promote neovascularization and regeneration of ischemic organs, such as heart and limbs. Furthermore, EPCs may be recruited from bone marrow by growing tumors to drive the angiogenic switch through physical engrafting into the lumen of nascent vessels or paracrine release of pro-angiogenic factors. CBT is hampered by the paucity of EPCs harvested from peripheral blood and suffered from several pitfalls, including the differentiation outcome of transplanted cells and low percentage of engrafted cells. Therefore, CBT will benefit from a better understanding of the signal transduction pathway(s) which govern(s) EPC homing, proliferation and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to combat tumoral neovascularization. We have recently found that storeoperated Ca2+ entry, a Ca 2+-permeable membrane pathway that is activated upon depletion of the inositol-1,4,5-trisphosphate-sensitive Ca2+ pool, is recruited by vascular endothelial growth factor to support proliferation and tubulogenesis in human circulating endothelial colony forming cells (ECFCs). ECFCs are a subgroup of EPCs that circulate in the peripheral blood of adult individuals and are able to proliferate and differentiate into endothelial cells and form capillary networks in vitro and contribute to neovessel formation in vivo. The present review will discuss the relevance of SOCE to ECFC-based cell therapy and will address the pharmacological inhibition of storedependent Ca2+ channels as a promising target for anti-angiogenic treatments. © 2012 Bentham Science Publishers.


Moccia F.,University of Pavia | Dragoni S.,University of Pavia | Cinelli M.,University of Naples Federico II | Montagnani S.,University of Naples Federico II | And 4 more authors.
BMC Surgery | Year: 2013

Endothelial dysfunction or loss is the early event that leads to a host of severe cardiovascular diseases, such as atherosclerosis, hypertension, brain stroke, myocardial infarction, and peripheral artery disease. Ageing is regarded among the most detrimental risk factor for vascular endothelium and predisposes the subject to atheroscleorosis and inflammatory states even in absence of traditional comorbid conditions. Standard treatment to restore blood perfusion through stenotic arteries are surgical or endovascular revascularization. Unfortunately, ageing patients are not the most amenable candidates for such interventions, due to high operative risk or unfavourable vascular involvement. It has recently been suggested that the transplantation of autologous bone marrow-derived endothelial progenitor cells (EPCs) might constitute an alternative and viable therapeutic option for these individuals. Albeit pre-clinical studies demonstrated the feasibility of EPC-based therapy to recapitulate the diseased vasculature of young and healthy animals, clinical studies provided less impressive results in old ischemic human patients. One hurdle associated to this kind of approach is the senescence of autologous EPCs, which are less abundant in peripheral blood and display a reduced pro-angiogenic activity. Conversely, umbilical cord blood (UCB)-derived EPCs are more suitable for cellular therapeutics due to their higher frequency and sensitivity to growth factors, such as vascular endothelial growth factor (VEGF). An increase in intracellular Ca2+concentration is central to EPC activation by VEGF. We have recently demonstrated that the Ca 2+signalling machinery driving the oscillatory Ca 2+response to this important growth factor is different in UCB-derived EPCs as compared to their peripheral counterparts. In particular, we focussed on the so-called endothelial colony forming cells (ECFCs), which are the only EPC population belonging to the endothelial lineage and able to form capillary-like structures in vitro and stably integrate with host vasculature in vivo. The present review provides a brief description of how exploiting the Ca2+toolkit of juvenile EPCs to restore the repairative phenotype of senescent EPCs to enhance their regenerative outcome in therapeutic settings. © 2013 Moccia et al; licensee BioMed Central Ltd.


Moccia F.,University of Pavia | Lodola F.,University of Pavia | Dragoni S.,University of Pavia | Bonetti E.,Unit of Clinical Epidemiology | And 5 more authors.
Current Vascular Pharmacology | Year: 2014

Endothelial progenitor cells (EPCs) have recently been employed in cell-based therapy (CBT) to promote regeneration of ischemic organs, such as heart and limbs. Furthermore, EPCs may sustain tumour vascularisation and provide an additional target for anticancer therapies. CBT is limited by the paucity of cells harvested from peripheral blood and suffers from several pitfalls, including the low rate of engrafted EPCs, whereas classic antiangiogenic treatments manifest a number of side effects and may induce resistance into the patients. CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) EPC proliferation, trafficking, and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to impair tumor neovascularisation and improve the therapeutic outcome of antiangiogenic strategies. An increase in intracellular Ca2+ concentration is the key signal in the regulation of cellular replication, migration, and differentiation. In particular, Ca2+ signalling may regulate cellcycle progression, due to the Ca2+-sensitivity of a number of cycline-dependent kinases, and gene expression, owing to the Ca2+-dependence of several transcription factors. Recent work has outlined the role of the so-called store-operated Ca2+ entry in driving EPC proliferation and migration. Unravelling the mechanisms guiding EPC engraftment into neovessels might supply the biological bases required to improve CBT and anticancer treatments. For example, genetic manipulation of the Ca2+ signalling machinery could provide a novel approach to increase the extent of limb regeneration or preventing tumour vascularisation by EPCs. © 2014 Bentham Science Publishers.


Dragoni S.,University of Pavia | Laforenza U.,University of Pavia | Bonetti E.,Unit of Clinical Epidemiology | Lodola F.,University of Pavia | And 9 more authors.
Stem Cells | Year: 2011

Endothelial progenitor cells (EPCs) home from the bone marrow to the site of tissue regeneration and sustain neovascularization after acute vascular injury and upon the angiogenic switch in solid tumors. Therefore, they represent a suitable tool for cell-based therapy (CBT) in regenerative medicine and provide a novel promising target in the fight against cancer. Intracellular Ca 2+ signals regulate numerous endothelial functions, such as proliferation and tubulogenesis. The growth of endothelial colony forming cells (ECFCs), which are EPCs capable of acquiring a mature endothelial phenotype, is governed by storedependent Ca 2+ entry (SOCE). This study aimed at investigating the nature and the role of VEGF-elicited Ca 2+ signals in ECFCs. VEGF induced asynchronous Ca 2+ oscillations, whose latency, amplitude, and frequency were correlated to the growth factor dose. Removal of external Ca 2+ (0Ca 2+) and SOCE inhibition with N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2, 3-thiadiazole-5-carboxamide (BTP-2) reduced the duration of the oscillatory signal. Blockade of phospholipase C-γ with U73122, emptying the inositol-1,4,5-trisphosphate (InsP3)-sensitive Ca 2+ pools with cyclopiazonic acid (CPA), and inhibition of InsP 3 receptors with 2-APB prevented the Ca 2+ response to VEGF. VEGF-induced ECFC proliferation and tubulogenesis were inhibited by the Ca 2+-chelant, BAPTA, and BTP-2. NF-κB activation by VEGF was impaired by BAPTA, BTP-2, and its selective blocker, thymoquinone. Thymoquinone, in turn, suppressed VEGF-dependent ECFC proliferation and tubulogenesis. These data indicate that VEGF-induced Ca 2+oscillations require the interplay between InsP3-dependent Ca 2+ release and SOCE, and promote ECFC growth and tubulogenesis by engaging NF-κB. This novel signaling pathway might be exploited to enhance the outcome of CBT and chemotherapy. © AlphaMed Press.


News Article | October 26, 2016
Site: www.eurekalert.org

The bellygenes initiative, coordinated by researchers at Karolinska Institutet and the University Medical Centre Groningen, will study the genetic makeup of 800,000 Europeans in relation to irritable bowel syndrome and associated symptoms. Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, reducing quality of life in 10-15% of people worldwide (women more than men). Although some contributing factors have been identified, IBS pathophysiology remains largely unknown. Human genetic studies are contributing to the development of personalized treatment options, but in IBS these have been few and underpowered to deal with its complex and heterogeneous nature. A large-scale project, the bellygenes initiative, is now aiming to overcome this issues by studying IBS in relation to the genetic makeup of some 800,000 Europeans from well-established cohorts, biobanks and patients' collections. "This represents an unmatched opportunity to tackle IBS genetics for the first time with adequate statistical power" says bellygenes coordinator Mauro D'Amato from the Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet. "We hope to reveal pathophysiological pathways that can help explain the etiology of IBS, inform a molecular reclassification of patients, and ultimately provide novel biological targets for increased therapeutic precision". The bellygenes initiative received support from the BioMolecular resources Research Infrastructure - large prospective cohorts, for accessing data from UK Biobank, LifeLines, Estonian Biobank EGCUT and HUNT. Several other population-based and case-control cohorts are studied as part of a large established IBS collaborative network of international scientists and clinicians.

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