Predictors of long-term outcome in patients with biopsy proven inflammatory cardiomyopathy

Background The objective of this study was to identify prognostic indicators in patients with inflammatory cardiomyopathy （iCM） on endomyocardial biopsy （EMB）. Methods and results Between 2007 and 2011 all consecutive patients with diagnosed with iCM at EMB were retrospectively analyzed. The combined primary endpoint （EP） （1E°P） was cardiac death, aborted sudden cardiac death/appropriate implantable cardioverter defibrillator （ICD） shock, progressive heart failure requiring left venWicular assist device （LVAD） implantation and heart transplantation. 503 patients （mean age 58 ° 12 years, 73% male） were available for analysis. Genomes of cardiotrophic viruses were detected in 396 patients （79%） and immuno-histochemical signs of inflammation were present in 223 individuals （44%）. After 3.6 ° 2.4 years of follow-up, cardiac mortality was 3.0% （n = 14） and a total of 8.6% （n = 40） reached the primary endpoint. Independent predictors for the 1 °EP were： age 〉 50 years, presence and duration （〈 28 days） of symptomatic heart failure. A risk stratification approach based on the results of the multivariate analysis demonstrated that absence of signs and/or symptoms of congestive heart failure in younger （〈 50 years） patients with longer （〉 28 days） duration of disease appear to have an excellent prognosis with 100% survival and no events during follow-up The presence of all above mentioned independent risk factors results in an 1°EP occurrence of 35.9%. Conclusions Symptoms of heart fail- ure, short duration of disease, and older age are indicators of poor outcome in patients with iCM.

Mutation Status of KRAS, BRAF, PIK3CA and Expression Level of AREG and EREG Identify Responders to Cetuximab in a Large Panel of Patient Derived Colorectal Carcinoma Xenografts of All Four UICC Stages

To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.