Apodemus Species Mice Are Reservoir Hosts of Borrelia garinii OspA Serotype 4 in Switzerland

Among Borrelia burgdorferi sensu lato isolates, seven outer surface protein A (OspA) serotypes have been described: serotypes 1 and 2 correspond to B. burgdorferi sensu stricto and Borrelia afzelii, respectively, and serotypes 3 to 7 correspond to Borrelia garinii. In Europe, serotype 4 has never been isolated from Ixodes ricinus ticks until recently, although this serotype has been frequently isolated from cerebrospinal fluid from patients. In Europe, B. afzelii and B. burgdorferi sensu stricto were found associated with rodents and B. garinii was found associated with birds. In this study, the reservoir role of Apodemus mice for B. garinii OspA serotype 4 was demonstrated by xenodiagnosis. Apodemus mice are the first identified reservoir hosts for B. garinii OspA serotype 4

The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin

The leukemic fusion gene AML1-MDS1-EVI1 (AME) encodes a chimeric transcription factor that results from the t(3,21)(q26;q22) translocation seen in patients with acute myeloid leukemia, with therapy-related myelodysplastic syndrome, or with chronic myeloid leukemia in blast crisis. The myeloid transcription factor CEBPA is crucial for normal granulopoiesis. Here, we found that conditional expression of AME suppresses CEBPA protein by 90.8% and DNA-binding activity by 93.9%. In contrast, CEBPA mRNA levels remained unchanged. In addition, we detected no differences in CEBPA mRNA levels in leukemic blasts of patients carrying the AME translocation (n = 8) compared to acute myeloid leukemia patients with a normal karyotype (n = 9). CEBPA protein and binding activity, however, were reduced significantly (100% and 92.1%, respectively) in AME patient samples. Furthermore, we observed that calreticulin (CRT), a putative inhibitor of CEBPA translation, was strongly activated after induction of AME in the cell-line system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA powerfully restored CEBPA levels. These results identify CEBPA as a key target of the leukemic fusion protein AME and suggest that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias

Prospective evaluation of circulating VEGF in patients with advanced non-small cell lung cancer treated with bevacizumab, pemetrexed and cisplatin in the trial SAKK19/09.

Aim: Bevacizumab is a monoclonal antibody directed against the vascular endothelial growth factor (VEGF). The previous phase II trial ABIGAIL (Reck, 2010) suggested circulating VEGF as a prognostic, but not predictive, biomarker for patients (pts) with non-small cell lung cancer (NSCLC) treated with bevacizumab. We prospectively measured VEGF in the multicenter phase II trial SAKK19/09 (NCT01116219). Methods: SAKK19/09 enrolled 77 evaluable patients (pts) with previously untreated, advanced nonsquamous NSCLC and EGFR wild type. Pts received 4 cycles of cisplatin 75mg/m2 (or carboplatin AUC5), pemetrexed 500mg/m2 and bevacizumab 7.5mg/kg, followed by maintenance therapy with pemetrexed and bevacizumab until progression by RECIST1.1. Follow-up CT scans were performed every 6 weeks until week 54 and every 12 weeks thereafter. Baseline EDTA blood samples were sent by same-day courier to the central laboratory for centrifugation, aliquoting, and freezing. Upon completion of enrollment, aliquots were thawed, and VEGF quantification was performed centrally using Luminex® Performance Assay Human Base Kit A (R&D Systems, Abingdon, UK). The mean value was used to stratify pts into two groups (low versus high VEGF). Best response rate assessed by RECIST1.1 (CR + PR versus SD + PD). Results: Clinical results of the SAKK19/09 trial were reported previously (Gautschi, 2013). Baseline plasma VEGF was detectable in 71 of 77 (92%) evaluable patients treated with chemotherapy and bevacizumab. The mean value was 74.9 pg/ml, the median 47.5 pg/ml, and the range 3.55 to 310 pg/ml. Using the mean as a predefined cutoff value, 50 patients had low VEGF levels and 21 patients had high VEGF levels. High VEGF was significantly associated with shorter PFS (4.1 vs 8.3 months, HR = 2.56; 95%CI: 1.43- 4.57; p = 0.0015) and OS (8.7 vs 17.5 months, HR = 2.67; 95% CI: 1.37-5.20; p = 0.0041), but not with best response rate ( p = 0.2256). Conclusions: Consistent with the ABIGAIL trial, circulating VEGF was prognostic, but not predictive for response, in the current trial. Further work is ongoing to identify potentially predictive biomarkers for bevacizumab, using comprehensive proteomic analyses. Disclosure: S.I. Rothschild: I received honoraria for the participation in advisory boards from Eli Lilly and Roche and for presentations at scientific symposiums sponsored by Roche; O. Gautschi: Honoraria for advisory boards of Eli Lilly and Roche; R. Cathomas: Advisory board member: Eli Lilly. All other authors have declared no conflicts of interest

Origin and prognostic value of circulating KRAS mutations in lung cancer patients

Because of the current controversy on the origin and clinical value of circulating KRAS codon 12 mutations in lung cancer, we screened 180 patients using a combined restriction fragment-length polymorphism and polymerase chain reaction (RFLP-PCR) assay. We detected KRAS mutations in 9% plasma samples and 0% matched lymphocytes. Plasma KRAS mutations correlated significantly with poor prognosis. We validated the positive results in a second laboratory by DNA sequencing and found matching codon 12 sequences in blood and tumor in 78% evaluable cases. These results support the notion that circulating KRAS mutations originate from tumors and are prognostically relevant in lung cancer