Fribourg, Switzerland
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PubMed | CeRMS, CTO Hospital, Institute for Cancer Research and Treatment, Clinic of Internal Medicine and 5 more.
Type: Journal Article | Journal: Oncotarget | Year: 2016

Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24-CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans.


Quartuccio L.,University of Santa María in Ecuador | Fabris M.,University of Santa María in Ecuador | Fabris M.,Institute of Clinical Pathology | Pontarini E.,University of Santa María in Ecuador | And 25 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Objective: The polymorphism 158V/F of Fc fragment of IgG (FCGR) type 3A may influence the response to rituximab (RTX) in rheumatoid arthritis (RA). We investigated the FCG3A polymorphism in a large cohort of RA patients treated with RTX, also by considering the possible loss of response from month +4 to +6 after RTX and the presence of established predictors of response. Methods: The study analysed 212 RA patients. European League Against Rheumatism (EULAR) response was evaluated at months +4 and +6 after the first RTX infusion. The FCGR3A polymorphism was analysed by PCR followed by Sanger sequencing. Results: The FCGR3A genotypes were associated with EULAR response (good or moderate) at month +6 (response in 34/38 (89.5%) VV vs 70/106 (66%) VF and in 51/77 (66.2%) FF patients; p=0.01), but not at month +4 (response in 32/37 (86.5%) VV vs 69/102 (67.6%) VF and 53/73 (72.6%) FF patients; p=0.09). Loss of response was observed only in VF and FF carriers ((VV vs VF vs FF: 0/37 (0%) vs 11/102 (10.8%) vs 12/73 (16.4%); p=0.02)). Probability of response at month +6 was very high when at least two of the three following items selected by multivariate analysis were present: positive rheumatoid factor and/or anticyclic citrullinated peptide antibodies, previous treatment with ≤1 anti-tumor necrosis factor (TNF) agent, and 158VV FCGR3A genotype (p<0.0001; OR 7.9, 95% CI 4.1 to 15.1). Conclusions: The 158VV FCGR3A genotype was associated with response to RTX in a large cohort of RA patients. Patient genotyping may be helpful to plan RTX treatment, and may be integrated with clinical predictors.


Blum C.A.,University of Basel | Blum C.A.,Medical University Clinic | Nigro N.,University of Basel | Briel M.,University of Basel | And 21 more authors.
The Lancet | Year: 2014

Background Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. Methods In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. Findings From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. Interpretation Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. Funding Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung. © 2015 Elsevier Ltd.


Bedogni A.,Unit of Oral and Maxillofacial Surgery | Saia G.,Unit of Maxillofacial Surgery | Bettini G.,Unit of Maxillofacial Surgery | Tronchet A.,Unit of Maxillofacial Surgery | And 10 more authors.
Oncologist | Year: 2012

Background. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a well-documented adverse event from treatment with nitrogen-containing bisphosphonates (NBPs). During a preliminary histomorphometric study aimed at assessing the rate of bone remodeling in the jaws of patients with surgically resected BRONJ, we found a defect of bone mineralization (unpublished data). We hypothesized that osteomalacia could be a risk factor for BRONJ in patients taking NBPs. Therefore, we looked for static and dynamic histomorphometric evidence of osteomalacia in biopsies from subjects with and without BRONJ. Methods. This case-control study used histomorphometric analysis of bone specimens of patients using NBPs (22 patients with BRONJ and 21 patients without BRONJ) who required oral surgical interventions for the treatment/ prevention of osteonecrosis. Patients were given tetracycline hydrochloride according to a standardized protocol before taking bone biopsies from their jaws. Biopsies with evidence of osteomyelitis or necrosis at histology were excluded from the study. Osteomalacia was defined as a mineralization lag time >100 days, a corrected mean osteoid thickness >12.5 mm, and an osteoid volume >10%. Results. In all, 77% of patients with BRONJ were osteomalacic compared with 5% of patients without BRONJ, according to histomorphometry. Because osteomalacia was found almost exclusively in NBP users with BRONJ, this is likely to be a generalized process in which the use of NBPs further deteriorates mechanisms of bone repair. Conclusions. Osteomalacia represents a new and previously unreported risk factor for disease development. This finding may contribute to a better understanding of the pathogenesis of this disease and help with the development of strategies to increase the safety of NBP administration. © AlphaMed Press.


Saeva J.R.,Clinic of Toxicology | Atanasov P.,Clinic of Internal Medicine
Acta Medica Bulgarica | Year: 2014

Cardiac glycosides are found in a diverse group of plants including Digitalis purpurea and Digitalis lanata (foxgloves), Nerium oleander, Convallaria ma-jalis (lily of the valley), Strophanthus gratus, etc. Nerium Oleander is an indoor and ornamental plant of an evergreen shrub. It's widespread in countries with a Mediter-ranean climate. Oleander is one of the most poisonous plants known to humans. All parts of the nerium oleander are poisonous, primarily due to the contained cardiac glycosides - oleandrin, nerin, digitoxigenin, and olinerin of which oleandrin is the principal toxin. The bark contains the toxic substances of rosagenin which causes strychnine-like effects. Signs of poisoning appear a few hours after the adoption of the parts of the plant. Two cases of Nerium Oleander poisoning were presented. Clinical picture included gastrointestinal, cardiovascular and central nervous system effects. The clinical symptoms were characterized by nausea, vomiting, salivation, colic, diarrhoea, ventricular tachycardia, dysrhythmia, heart block, ataxia, drowsi-ness, muscular tremor. Treatment included administration of activated charcoal, symptomatic and supportive care.


Cottagnoud P.,Clinic of Internal Medicine | Cottagnoud M.,Zieglerspital | Acosta F.,Zieglerspital | Stucki A.,Berner Reha Zentrum
Antimicrobial Agents and Chemotherapy | Year: 2013

Ceftaroline is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms, including methicillin- resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae, as well as common Gram-negative organisms. This study tested the prodrug, ceftaroline fosamil, against a penicillin-sensitive and a penicillin- resistant strain of S. pneumoniae in an experimental rabbit meningitis model. The penetration of ceftaroline into inflamed meninges was approximately 14%. Ceftaroline fosamil was slightly superior to ceftriaxone against the penicillinsensitive strain and significantly superior to the combination of ceftriaxone and vancomycin against the penicillinresistant strain. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Stucki A.,Reha Clinic | Acosta F.,Clinic of Internal Medicine | Cottagnoud M.,Ziegelspital | Cottagnoud P.,Clinic of Internal Medicine
Antimicrobial Agents and Chemotherapy | Year: 2013

In this study, the efficacy of ceftaroline fosamil was compared with that of cefepime in an experimental rabbit meningitis model against two Gram-negative strains (Escherichia coli QK-9 and Klebsiella pneumoniae 1173687). The penetration of ceftaroline into inflamed and uninflamed meninges was also investigated. Both regimens were bactericidal, but ceftaroline fosamil was significantly superior to cefepime against K. pneumoniae and E. coli in this experimental rabbit meningitis model (P < 0.0007 against K. pneumoniae and P < 0.0016 against E. coli). The penetration of ceftaroline was approximately 15% into inflamed meninges and approximately 3% into uninflamed meninges. Copyright © 2013, American Society for Microbiology. All Rights Reserved.


Mandery K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Bujok K.,Friedrich - Alexander - University, Erlangen - Nuremberg | Schmidt I.,Friedrich - Alexander - University, Erlangen - Nuremberg | Wex T.,Otto Von Guericke University of Magdeburg | And 7 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E2 with IC50 values of 6.2 ± 1.2 and 3.1 ± 1.2 μM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE2 transport by 162.7 ± 13.9, 77.2 ± 3.6, and 32.3 ± 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


PubMed | Clinic of Internal Medicine and Kantonsspital St. Gallen
Type: Journal Article | Journal: Case reports in gastroenterology | Year: 2016

Oesophageal involvement in Crohns disease (CD) is uncommon and most often accompanied by involvement of more distal parts. Its presentation is mostly non-specific, and therefore a diagnosis, especially in isolated oesophageal disease, is difficult. We present the case of a 42-year-old male patient who was referred to our gastroenterology department because of a para-oesophageal abscess. Under antibiotic treatment the abscess healed, but despite great diagnostic efforts, its aetiology remained unclear. Three years later the patient was hospitalized again because of an abscess at the same site. Endoscopy showed disseminated ulcerations of the lower oesophagus, raising suspicion of CD. After excluding other possible causes, we made the diagnosis of isolated CD of the oesophagus. We review the available literature on this topic and discuss the clinical presentation, symptoms, endoscopic findings, and histology as well as treatment of oesophageal CD.


PubMed | Clinic of Internal Medicine
Type: Journal Article | Journal: Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology | Year: 2014

Patients may develop kidney failure because of the contrast agent given during coronary angiography. Renal dysfunction and heart failure were previously shown to be associated with the development of contrast nephropathy. In our study, we aimed to investigate whether there is a relationship between subclinical renal (indicated by microalbuminuria) and/or cardiac (indicated by the height of the BNP) dysfunction between the development of contrast-induced nephropathy on patients undergoing angiography due to acute coronary syndrome.This is an observational prospective cohort study. A total of 170 patients hospitalized with a diagnosis of acute coronary syndrome in the coronary care unit were included in this study. Blood samples were collected from 145 patients without microalbuminuria and 25 patients with microalbuminuria to determine their BNP levels before coronary angiography. The patients urea and creatinine levels were examined before and 72 h after coronary angiography. Statistical analysis was performed using Kolmogorov-Smirnov test, Mann-Whitney U test, independent samples t-test and the chi-square test.The study subjects included 82 females and 88 males (average age, 64.414.5 years). The BNP levels and height distribution of the 145 patients without microalbuminuria were compared between those with and without contrast agent-induced nephropathy, but no significant difference was found (205.6280.6, 198.0310.0, p=0.817). Similarly, no relationship between the microalbumin level and contrast agent-induced nephropathy was found in 25 patients.A relationship between BNP, microalbuminuria, and contrast agent-induced nephropathy was not found in patients hospitalized in a coronary care unit with a diagnosis of acute coronary syndrome who were scheduled for coronary angiography. Additional multicenter studies with larger patient groups should be conducted to obtain more data.

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