Lugano, Switzerland
Lugano, Switzerland

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Gonzalez A.,University of Basel | Schmitter K.,University of Basel | Hirsch H.H.,University of Basel | Garzoni C.,Clinica Luganese | And 8 more authors.
Genes and Immunity | Year: 2014

Previous studies have associated activating Killer cell Immunoglobulin-like Receptor (KIR) genes with protection from cytomegalovirus (CMV) replication after organ transplantation. Whether KIR-associated protection is operating in the context of primary infection, re-activation, or both, remains unknown. Here we correlated KIR genotype and CMV serostatus at the time of transplantation with rates of CMV viremia in 517 heart (n=57), kidney (n=223), liver (n=165) or lung (n=72) allograft recipients reported to the Swiss Transplant Cohort Study. Across the entire cohort we found B haplotypes-which in contrast to A haplotypes may contain multiple activating KIR genes-to be protective in the most immunosuppressed patients (receiving anti-thymocyte globulin induction and intensive maintenance immunosuppression) (hazard ratio after adjustment for covariates 0.46, 95% confidence interval 0.29-0.75, P=0.002). Notably, a significant protection was detected only in recipients who were CMV-seropositive at the time of transplantation (HR 0.45, 95% CI 0.26-0.77, P=0.004), but not in CMV seronegative recipients (HR 0.59, 95% CI 0.22-1.53, P=0.28). These data indicate a prominent role for KIR-and presumably natural killer (NK) cells-in the control of CMV replication in CMV seropositive organ transplant recipients treated with intense immunosuppression. © 2014 Macmillan Publishers Limited All rights reserved.


PubMed | Internal Medicine, Albert Ludwigs University of Freiburg, University of Zürich, ETH Zurich and 4 more.
Type: Journal Article | Journal: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | Year: 2016

Toxigenic Corynebacterium diphtheriae is an important and potentially fatal threat to patients and public health. During the current dramatic influx of refugees into Europe, our objective was to use whole genome sequencing for the characterization of a suspected outbreak of C.diphtheriae wound infections among refugees. After conventional culture, we identified C.diphtheriae using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and investigated toxigenicity by PCR. Whole genome sequencing was performed on a MiSeq Illumina with >70coverage, 2250bp read length, and mapping against a reference genome. Twenty cases of cutaneous C.diphtheriae in refugees from East African countries and Syria identified between April and August 2015 were included. Patients presented with wound infections shortly after arrival in Switzerland and Germany. Toxin production was detected in 9/20 (45%) isolates. Whole genome sequencing-based typing revealed relatedness between isolates using neighbour-joining algorithms. We detected three separate clusters among epidemiologically related refugees. Although the isolates within a cluster showed strong relatedness, isolates differed by >50 nucleotide polymorphisms. Toxigenic C.diphtheriae associated wound infections are currently observed more frequently in Europe, due to refugees travelling under poor hygienic conditions. Close genetic relatedness of C.diphtheriae isolates from 20 refugees with wound infections indicates likely transmission between patients. However, the diversity within each cluster and phylogenetic time-tree analysis suggest that transmissions happened several months ago, most likely outside Europe. Whole genome sequencing offers the potential to describe outbreaks at very high resolution and is a helpful tool in infection tracking and identification of transmission routes.


Franzini A.,Cantonal Hospital St Gallen | Baty F.,Cantonal Hospital St Gallen | Macovei I.I.,Victor Babes University of Medicine and Pharmacy Timisoara | Durr O.,ZHAW Zurich University of Applied Sciences | And 6 more authors.
Clinical Cancer Research | Year: 2015

Purpose:We aimed to identify gene expression signatures associated with angiogenesis andhypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients. Experimental Design: Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumorshrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients' outcome. Results: Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P=0.005), andmedian TTP 6.9months versus 2.9 months (P= 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001). Conclusions: We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response. © 2015 American Association for Cancer Research.


Len O.,Hospital Vall dHebron | Garzoni C.,Clinica Luganese | Garzoni C.,University of Bern | Lumbreras C.,Hospital 12 Of Octubre | And 4 more authors.
Clinical Microbiology and Infection | Year: 2014

In the context of solid organ transplantation, screening of recipients and organ donors is crucial, and should be performed with great rigour to minimize the reactivation or the risk of transmission of certain infectious processes. This review aims to update understanding of the possible pathologies involved, as well as of emerging infections that, as a result of globalization, are gaining increasing prominence on a daily basis. © 2014 European Society of Clinical Microbiology and Infectious Diseases.


Garchar D.,Ryan Foot and Ankle Clinic | DiDomenico L.A.,Ankle and Foot Care Centers | Klaue K.,Clinica Luganese
Journal of Foot and Ankle Surgery | Year: 2013

Lisfranc joint dislocation secondary to Charcot arthropathy is a debilitating condition that often leads to ulceration and infection. After conservative treatment, such as bracing and appropriate shoe wear fail, the only option might be amputation. However, we have seen good clinical outcomes from applying a plate to the plantar (tension) side of the medial midfoot. In our retrospective study, 24 consecutive patients (25 feet) from April 1999 through July 2004 underwent Charcot reconstruction for Lisfranc dislocation. Clinical and radiographic follow-up examinations were performed every 3 weeks during the postoperative course. Union was achieved in 24 (96%) of the 25 feet. The average time to ambulation was 11.68 (range 7 to 20) weeks for the 24 patients. The average follow-up period was 38.0 (range 17 to 64) months. The union and interval to ambulation rates showed that a plate applied to the plantar aspect of the medial midfoot provides a strong, sturdy construct for arthrodesis and ambulation. © 2013 American College of Foot and Ankle Surgeons.


PubMed | Mannedorf Hospital, Victor Babes University of Medicine and Pharmacy Timisoara, Swiss Group for Clinical Cancer Research Coordinating Center, ZHAW Zurich University of Applied Sciences and 3 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2015

We aimed to identify gene expression signatures associated with angiogenesis and hypoxia pathways with predictive value for treatment response to bevacizumab/erlotinib (BE) of nonsquamous advanced non-small cell lung cancer (NSCLC) patients.Whole-genome gene expression profiling was performed on 42 biopsy samples (from SAKK 19/05 trial) using Affymetrix exon arrays, and associations with the following endpoints: time-to-progression (TTP) under therapy, tumor-shrinkage (TS), and overall survival (OS) were investigated. Next, we performed gene set enrichment analyses using genes associated with the angiogenic process and hypoxia response to evaluate their predictive value for patients outcome.Our analysis revealed that both the angiogenic and hypoxia response signatures were enriched within the genes predictive of BE response, TS, and OS. Higher gene expression levels (GEL) of the 10-gene angiogenesis-associated signature and lower levels of the 10-gene hypoxia response signature predicted improved TTP under BE, 7.1 months versus 2.1 months for low versus high-risk patients (P = 0.005), and median TTP 6.9 months versus 2.9 months (P = 0.016), respectively. The hypoxia response signature associated with higher TS at 12 weeks and improved OS (17.8 months vs. 9.9 months for low vs. high-risk patients, P = 0.001).We were able to identify gene expression signatures derived from the angiogenesis and hypoxia response pathways with predictive value for clinical outcome in advanced nonsquamous NSCLC patients. This could lead to the identification of clinically relevant biomarkers, which will allow for selecting the subset of patients who benefit from the treatment and predict drug response.


PubMed | University of Basel, University of Zürich, Coordinating Center, Clinica Luganese and 2 more.
Type: Journal Article | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2014

Molecular subclassification of non small-cell lung cancer (NSCLC) is essential to improve clinical outcome. This study assessed the prognostic and predictive value of circulating micro-RNA (miRNA) in patients with non-squamous NSCLC enrolled in the phase II SAKK (Swiss Group for Clinical Cancer Research) trial 19/05, receiving uniform treatment with first-line bevacizumab and erlotinib followed by platinum-based chemotherapy at progression.Fifty patients with baseline and 24 h blood samples were included from SAKK 19/05. The primary study endpoint was to identify prognostic (overall survival, OS) miRNAs. Patient samples were analyzed with Agilent human miRNA 8x60K microarrays, each glass slide formatted with eight high-definition 60K arrays. Each array contained 40 probes targeting each of the 1347 miRNA. Data preprocessing included quantile normalization using robust multi-array average (RMA) algorithm. Prognostic and predictive miRNA expression profiles were identified by Spearmans rank correlation test (percentage tumor shrinkage) or log-rank testing (for time-to-event endpoints).Data preprocessing kept 49 patients and 424 miRNA for further analysis. Ten miRNAs were significantly associated with OS, with hsa-miR-29a being the strongest prognostic marker (HR=6.44, 95%-CI 2.39-17.33). Patients with high has-miR-29a expression had a significantly lower survival at 10 months compared to patients with a low expression (54% versus 83%). Six out of the 10 miRNAs (hsa-miRN-29a, hsa-miR-542-5p, hsa-miR-502-3p, hsa-miR-376a, hsa-miR-500a, hsa-miR-424) were insensitive to perturbations according to jackknife cross-validation on their HR for OS. The respective principal component analysis (PCA) defined a meta-miRNA signature including the same 6 miRNAs, resulting in a HR of 0.66 (95%-CI 0.53-0.82).Cell-free circulating miRNA-profiling successfully identified a highly prognostic 6-gene signature in patients with advanced non-squamous NSCLC. Circulating miRNA profiling should further be validated in external cohorts for the selection and monitoring of systemic treatment in patients with advanced NSCLC.


PubMed | Ospedale di Busto Arsizio, Unit of Pathology, Clinica Luganese, Institute of Pathology and 3 more.
Type: Journal Article | Journal: Clinical lung cancer | Year: 2016

In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs).We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DP patients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria.Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DP patients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DP patients experienced opposite responses to crizotinib.The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC.


Gottlieb T.,Teltower Damm 35 | Klaue K.,Clinica Luganese
Foot and Ankle Surgery | Year: 2013

Aftercare of surgical procedures is not consensual in the community of foot and ankle surgeons. Although the incidence of infections following foot and ankle surgery is rare, soft tissue healing might be jeopardized after extensive and multiple approaches. We define a precise fixation technique of the foot and ankle in the immediate post-operative phase by what we call "the Jones dressing cast". This technique is a modification of the Jones dressing bandage. We compared two groups of patients (20 and 23 patients) who underwent similar operative reconstructive procedures, with and without the application of the described cast, respectively, for one week. At the two-month follow-up, we observed that the group, which was treated with the cast required less analgetics, had a reduced hospitalization time and achieved faster autonomy using crutches. It may be assumed that reduced strain to the soft tissue around the foot due to the cast may reduce the complications in the post-operative period. © 2013 European Foot and Ankle Society.


Mittlmeier T.,University of Rostock | Klaue K.,Clinica Luganese | Haar P.,University of Rostock | Beck M.,University of Rostock
Clinical Orthopaedics and Related Research | Year: 2010

Charcot neuroosteoarthropathy of the feet can induce severe instability and deformity with subsequent plantar ulceration leading to substantial disability or even amputation. Traditionally, nonoperative treatment is regarded as the primary option of treatment while surgery is restricted to treating complications or failure of nonoperative treatment. Failed nonoperative treatment essentially prolongs treatment period. We retrospectively reviewed 22 patients (26 feet) with midfoot (n = 9) or hindfoot (n = 17) neuropathy who underwent primary surgical reconstruction and reorientation arthrodesis due to manifest instability, nonplantigrade foot position, and deformity with overt (n = 8) or what we judged was impending ulceration (n = 9). The minimum followup was 0.5 years (mean, 2.7 years; range 0.5-7 years). All eight ulcers healed without recurrence of ulceration or manifestation of new ulcers during the followup period. We observed complications leading to further surgery in nine patients: five with perioperative hematoma and four with instability. AOFAS scores rose from a preoperative mean of 39 to 70 points (hindfoot cases) and from 51 points to 84 (midfoot cases). Early surgical reconstruction in high-risk patients can provide timely restoration of a plantigrade and stable foot and improved quality of life of the patient at complication rates comparable to those after secondary surgery following failed nonoperative treatment; however we emphasize we had no control group in this small case series for which we could compare nonoperative treatment. Level of Evidence: Level IV, therapeutic study (case series). See Guidelines for Authors for a complete description of levels of evidence. © 2009 The Association of Bone and Joint Surgeons ®.

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