Purpose: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adenoand squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer.Experimental Design: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-na€ ve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC.Results: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio !2.0 or average gene copy number per nucleus !6.0 or !10% of tumor cells containing !15 MET copies). The remaining cases can be subdivided into intermediate-(6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations.Conclusion: MET amplification is not a mutually exclusive genetic event in therapy-na€ ve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. Clin Cancer Res; 21(4); 907-15. Ó2014 AACR.

We recently reported fibroblast growth factor receptor-type 1 (FGFR1) amplification to be associated with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. This makes FGFR1 a novel target for directed therapy in these tumors. To reproducibly identify patients for clinical studies, we developed a standardized reading and evaluation strategy for FGFR1 fluorescence in-situ hybridization (FISH) and propose evaluation criteria, describe different patterns of low- and high-level amplifications and report on the prevalence of FGFR1 amplifications in pulmonary carcinomas. A total of 420 lung cancer patients including 307 squamous carcinomas, 100 adenocarcinomas of the lung and 13 carcinomas of other types were analyzed for FGFR1 amplification using a dual color FISH. We found heterogeneous and different patterns of gene copy numbers. FGFR1 amplifications were observed in 20% of pulmonary squamous carcinomas but not in adenocarcinomas. High-level amplification (as defined by an FGFR1/centromer 8 (CEN8) ratio ≥2.0, or average number of FGFR1 signals per tumor cell nucleus ≥6, or the percentage of tumor cells containing ≥15 FGFR1 signals or large clusters ≥10%) was detected at a frequency of 16% and low-level amplification (as defined by ≥5 FGFR1 signals in ≥50% of tumor cells) at a frequency of 4%. We conclude that FGFR1 amplification is one of the most frequent therapeutically tractable genetic lesions in pulmonary carcinomas. Standardized reporting of FGFR1 amplification in squamous carcinomas of the lung will become increasingly important to correlate therapeutic responses with FGFR1 inhibitors in clinical studies. Thus, our reading and evaluation strategy might serve as a basis for identifying patients for ongoing and upcoming clinical trials.

BackgroundOutcome prediction scoring systems are increasingly used in intensive care medicine, but most were not developed for use in cardiac surgery patients. We compared the performance of four intensive care outcome prediction scoring systems (Acute Physiology and Chronic Health Evaluation II [APACHE II], Simplified Acute Physiology Score II [SAPS II], Sequential Organ Failure Assessment [SOFA], and Cardiac Surgery Score [CASUS]) in patients after open heart surgery.MethodsWe prospectively included all consecutive adult patients who underwent open heart surgery and were admitted to the intensive care unit (ICU) between January 1st 2007 and December 31st 2008. Scores were calculated daily from ICU admission until discharge. The outcome measure was ICU mortality. The performance of the four scores was assessed by calibration and discrimination statistics. Derived variables (Mean- and Max- scores) were also evaluated.ResultsDuring the study period, 2801 patients (29.6% female) were included. Mean age was 66.9 ± 10.7 years and the ICU mortality rate was 5.2%. Calibration tests for SOFA and CASUS were reliable throughout (p-value not < 0.05), but there were significant differences between predicted and observed outcome for SAPS II (days 1, 2, 3 and 5) and APACHE II (days 2 and 3). CASUS, and its mean- and maximum-derivatives, discriminated better between survivors and non-survivors than the other scores throughout the study (area under curve ≥ 0.90). In order of best discrimination, CASUS was followed by SOFA, then SAPS II, and finally APACHE II. SAPS II and APACHE II derivatives had discrimination results that were superior to those of the SOFA derivatives.ConclusionsCASUS and SOFA are reliable ICU mortality risk stratification models for cardiac surgery patients. SAPS II and APACHE II did not perform well in terms of calibration and discrimination statistics.

Fluid resuscitation with only crystalloids was equally effective, resulted in a more positive fluid balance only on the first 2 days, and was associated with a lesser incidence of acute kidney injury.

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