Multiorgan Metastasis of Human HER-2+ Breast Cancer in Rag2−/−;Il2rg−/− Mice and Treatment with PI3K Inhibitor

In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2−/−;Il2rg−/−, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2−/−;Il2rg−/− mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2−/−; Il2rg−/− mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2−/−;Il2rg−/− mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents

Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET

<p>Abstract</p> <p>Background</p> <p>Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging.</p> <p>Methods</p> <p>Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm³). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment.</p> <p>Results</p> <p>After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm³) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0.</p> <p>Conclusions</p> <p>As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.</p

Combined computed tomography and fluorodeoxyglucose positron emission tomography in the diagnosis of prosthetic valve endocarditis: A case series

Background: The diagnosis of prosthetic valve endocarditis is challenging. The gold standard for prosthetic valve endocarditis diagnosis is trans-esophageal echocardiography. However, trans-esophageal echocardiography may result in negative findings or yield images difficult to differentiate from thrombus in patients with prosthetic valve endocarditis. Combined computed tomography and fluorodeoxyglucose positron emission tomography is a potentially promising diagnostic tool for several infectious conditions and it has also been employed in patients with prosthetic valve endocarditis but data are still scant. Case presentations. We reviewed the charts of 6 patients with prosthetic aortic valves evaluated for suspicion of prosthetic valve endocarditis, at two different hospital, over a 3-year period. We found 3 patients with early-onset PVE cases and blood cultures yielding Pseudomonas aeruginosa, Staphylococcus epidermidis and Staphylococcus lugdunensis, respectively; and 3 late-onset cases in the remaining 3 patients with isolation in the blood of Streptococcus bovis, Candida albicans and P. aeruginosa, respectively. Initial trans-esophageal echocardiography was negative in all the patients, while fluorodeoxyglucose positron emission tomography showed images suspicious for prosthetic valve endocarditis. In 4 out of 6 patients valve replacement was done with histology confirming the prosthetic valve endocarditis diagnosis. After an adequate course of antibiotic therapy fluorodeoxyglucose positron emission tomography showed resolution of prosthetic valve endocarditis in all the patients. Conclusion: Our experience confirms the potential role of fluoroseoxyglucose positron emission tomography in the diagnosis and follow-up of prosthetic valve endocarditis. © 2014 Bartoletti et al.; licensee BioMed Central Ltd

First-episode psychosis in the Ferrara Mental Health Department: Incidence and clinical course within the first 2 years

none52noAim: To examine the incidence of with first-episode psychosis (FEP) in the Integrated Department of Mental Health and Pathological Addictions in Ferrara, Italy, and to examine the association between the Duration of Untreated Psychosis (DUP) and the clinical course. Methods: Participants recruited in 2013–2019 were assessed with the Health of the Nation Outcome Scale (HoNOS) every 6 months for 24 months. Hierarchical growth models analysed changes of global severity (HoNOS total scores) and symptom dimensions. Regression modelled factors associated with remission (HoNOS &lt; 8) and clinical improvement (&lt;12). Results: The incidence of FEP was 21.5 (95%CI: 21.2–21.9) cases per 100 000 person year. Among participants (n = 86, mean age 23, 76% males), baseline HoNOS scores were higher for those with a longer DUP. More than half subjects reached clinical remission (61.6%) or improvement (82.6%), while very few (2.3%) were re-hospitalized. HoNOS total scores decayed with a mixed linear/quadratic trend, with a slower decay among migrants. A longer DUP was associated with reduced improvements of positive symptoms and lower likelihood of clinical improvement (OR: 0.84; 95%CI: 0.73–0.96). Conclusions: Patients from the FEP program of Ferrara reached good clinical outcomes. Nonetheless, individuals with a longer DUP may need additional clinical attention. Systematic monitoring of clinical outcomes may be an optimal strategy to improve the outcomes of FEP in the real world.mixedBelvederi Murri M.; Bertelli R.; Carozza P.; Berardi L.; Cantarelli L.; Croce E.; Antenora F.; Curtarello E.M.A.; Simonelli G.; Recla E.; Girotto B.; Grassi L.; Callegari V.; Cardelli R.; Emanuelli F.; Garofani L.; Marangoni C.; Mazzoni P.; Nappi G.; Rossi G.; Sacco M.; Turilli P.D.; Vanni A.; Baglini G.; Bandiera A.; Baruffa R.; Beltrami D.; Bongiovanni L.; Canetti E.; Cocchi B.; Di Domizio C.; Guadagnino C.; Laghi G.; Lamponi C.; Marzola G.; Meloncelli A.; Morelli L.; Pavanati M.; Piccolo E.; Polmonari A.; Reali S.; Rizzo F.; Roccati V.; Roncagli M.; Sarela A.I.; Tome S.; Zotos S.; Caracciolo S.; Caruso R.; Nanni M.G.; Negrelli L.; Zerbinati L.Belvederi Murri, M.; Bertelli, R.; Carozza, P.; Berardi, L.; Cantarelli, L.; Croce, E.; Antenora, F.; Curtarello, E. M. A.; Simonelli, G.; Recla, E.; Girotto, B.; Grassi, L.; Callegari, V.; Cardelli, R.; Emanuelli, F.; Garofani, L.; Marangoni, C.; Mazzoni, P.; Nappi, G.; Rossi, G.; Sacco, M.; Turilli, P. D.; Vanni, A.; Baglini, G.; Bandiera, A.; Baruffa, R.; Beltrami, D.; Bongiovanni, L.; Canetti, E.; Cocchi, B.; Di Domizio, C.; Guadagnino, C.; Laghi, G.; Lamponi, C.; Marzola, G.; Meloncelli, A.; Morelli, L.; Pavanati, M.; Piccolo, E.; Polmonari, A.; Reali, S.; Rizzo, F.; Roccati, V.; Roncagli, M.; Sarela, A. I.; Tome, S.; Zotos, S.; Caracciolo, S.; Caruso, R.; Nanni, M. G.; Negrelli, L.; Zerbinati, L

Liver Match, a prospective observational cohort study on liver transplantation in Italy: study design and current practice of donor-recipient matching

The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation

Commento agli articoli 75-81 c.p.c., Delle parti, in Codice di procedura civile. Commentario diretto da Claudio Consolo. Vol. 1

Commento sistematico agli articoli da 75 a 81 del c.p.c. alla luce delle interpretazioni dottrinali e degli orientamenti giurisprudenzial

Commento agli articoli 90-98 c.p.c., Delle responsabilità delle parti per le spese e per i danni processuali

Commento sistematico agli articoli da 90 a 98 del c.p.c. alla luce delle interpretazioni dottrinali e degli orientamenti giurisprudenzial

Commento agli articoli 267-272 c.p.c., Dell’intervento di terzi

Commento sistematico agli articoli da 267-272 del c.p.c. alla luce delle interpretazioni dottrinali e degli orientamenti giurisprudenzial

Commento agli articoli 88-89 c.p.c., Dei doveri delle parti e dei difensori,

Commento sistematico agli articoli 88 e 89 del c.p.c. alla luce delle interpretazioni dottrinali e degli orientamenti giurisprudenzial