Lothar Pilz

A comparison of transcatheter aortic valve implantation and surgical aortic valve replacement in 1,141 patients with severe symptomatic aortic stenosis and less than high risk

To assess outcomes for patients undergoing transcatheter aortic valve implantation (TAVI) versus surgical aortic valve replacement but with less than high risk.

Long-Term Results of Transapical Versus Transfemoral TAVI in a Real World Population of 1000 Patients With Severe Symptomatic Aortic Stenosis

Background—Transapical transcatheter aortic valve implantation is generally perceived to be associated with increased morbidity compared with transfemoral transcatheter aortic valve implantation. We aimed to compare access-related complications and survival using propensity score matching. Methods and Results—Prospective, single-center registry of 1000 consecutive patients undergoing transapical and transfemoral transcatheter aortic valve implantation between May 2008 and April 2012. Transapical was performed in 413 patients and transfemoral in 587 patients. Patients with transapical access were less often women and less had pulmonary hypertension. Further they had more peripheral arterial disease, coronary artery disease, carotid stenosis, and recurrent surgery and a higher logistic EuroSCORE I (24.3%±16.2% for transapical versus 22.2%±16.2% for transfemoral; P<0.01). After building 2 propensity score–matched groups of 354 patients each with either access route (total 708 patients), baseline characteristics were comparable. In this analysis, there was no significant difference in 30 day mortality (5.9% transapical versus 8.5% transfemoral; P=0.19), the rate of myocardial infarction (2.5% transapical versus 2.0% transfemoral; P=0.61), stroke (2.0% transapical versus 2.3% transfemoral; P=0.79), bleeding complications, pacemaker implantation rates, or moderate aortic insufficiency. Stage 1 renal complications were more common in transapical patients (odds ratio, 2.81; 95% confidence interval, 1.93–4.09), whereas major vascular complications were less common (odds ratio, 0.14; 95% confidence interval, 0.06–0.29). Survival probability over the long term was not statistically different (hazard ratio, 0.89; 95% confidence interval, 0.72–1.10; log-rank Test, P=0.27). Conclusions—The data demonstrate that in an experienced multidisciplinary heart team, either access route can be performed with comparable results.

Multi-parametric MRI of rectal cancer – Do quantitative functional MR measurements correlate with radiologic and pathologic tumor stages?

PURPOSE The purpose of this study is two-fold. First, to evaluate, whether functional rectal MRI techniques can be analyzed in a reproducible manner by different readers and second, to assess whether different clinical and pathologic T and N stages can be differentiated by functional MRI measurements. MATERIALS AND METHODS 54 patients (38 men, 16 female; mean age 63.2 ± 12.2 years) with pathologically proven rectal cancer were included in this retrospective IRB-approved study. All patients were referred for a multi-parametric MRI protocol on a 3 Tesla MR-system, consisting of a high-resolution, axial T2 TSE sequence, DWI and perfusion imaging (plasma flow -s PFTumor) prior to any treatment. Two experienced radiologists evaluated the MRI measurements, blinded to clinical data and outcome. Inter-reader correlation and the association of functional MRI parameters with c- and p-staging were analyzed. RESULTS The inter-reader correlation for lymph node (ρ 0.76-0.94; p<0.0002) and primary tumor (ρ 0.78-0.92; p<0.0001) apparent diffusion coefficient and plasma flow (PF) values was good to very good. PFTumor values decreased with cT stage with significant differences identified between cT2 and cT3 tumors (229 versus 107.6 ml/100ml/min; p=0.05). ADCTumor values did not differ significantly. No substantial discrepancies in lymph node ADCLn values or short axis diameter were found among cN1-3 stages, whereas PFLn values were distinct between cN1 versus cN2 stages (p=0.03). In the patients without neoadjuvant RCT no statistically significant differences in the assessed functional parameters on the basis of pathologic stage were found. CONCLUSION This study illustrates that ADC as well as MR perfusion values can be analyzed with good interobserver agreement in patients with rectal cancer. Moreover, MR perfusion parameters may allow accurate differentiation of tumor stages. Both findings suggest that functional MRI parameters may help to discriminate T and N stages for clinical decision making.

Progression-free survival and overall survival in phase III trials of molecular-targeted agents in advanced non-small-cell lung cancer.

BACKGROUND We examined how crossover therapy might affect the association between progression-free survival (PFS) and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS We extracted PFS- and OS-hazard ratios (HRs) in phase III trials of molecular-targeted agents for advanced NSCLC. Their relationship was modeled in a linear function with the coefficient of determination (R-squared) to assess the correlation between PFS and OS. RESULTS Thirty-four trials with 35 pairs for the investigational and reference arms were identified (24,158 patients). Overall, there was little correlation between PFS- and OS-HRs (R-squared = 0.14), suggesting PFS-HR could account only for 14% of variation in OS-HR. The median proportion of crossover therapy per trial was 20%. If patients seldom crossed over (none or <1%), the association between PFS- and OS-HRs was strong (R-squared = 0.69). When the proportion of crossover was ≥1%, however, R-squared declined considerably (≥1% to <20% crossover, R-squared = 0.27; ≥20% to <40%, R-squared = 0.06; and ≥40%, R-squared = 0.27). CONCLUSIONS A PFS advantage seldom is associated with an OS advantage any longer. Our analysis suggests this is due to a high level of crossover now that an increasing number of active agents are available for NSCLC.

EBUS-TBNA Provides Highest RNA Yield for Multiple Biomarker Testing from Routinely Obtained Small Biopsies in Non-Small Cell Lung Cancer Patients - A Comparative Study of Three Different Minimal Invasive Sampling Methods

Background Multiple biomarker testing is necessary to facilitate individualized treatment of lung cancer patients. More than 80% of lung cancers are diagnosed based on very small tumor samples. Often there is not enough tissue for molecular analysis. We compared three minimal invasive sampling methods with respect to RNA quantity for molecular testing. Methods 106 small biopsies were prospectively collected by three different methods forceps biopsy, endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA), and CT-guided core biopsy. Samples were split into two halves. One part was formalin fixed and paraffin embedded for standard pathological evaluation. The other part was put in RNAlater for immediate RNA/DNA extraction. If the pathologist confirmed the diagnosis of non-small cell lung cancer(NSCLC), the following molecular markers were tested: EGFR mutation, ERCC1, RRM1 and BRCA1. Results Overall, RNA-extraction was possible in 101 out of 106 patients (95.3%). We found 49% adenocarcinomas, 38% squamouscarcinomas, and 14% non-otherwise-specified(NOS). The highest RNA yield came from endobronchial ultrasound guided needle aspiration, which was significantly higher than bronchoscopy (37.74±41.09 vs. 13.74±15.53 ng respectively, P = 0.005) and numerically higher than CT-core biopsy (37.74±41.09 vs. 28.72±44.27 ng respectively, P = 0.244). EGFR mutation testing was feasible in 100% of evaluable patients and its incidence was 40.8%, 7.9% and 14.3% in adenocarcinomas, squamouscarcinomas and NSCLC NOS subgroup respectively. There was no difference in the feasibility of molecular testing between the three sampling methods with feasibility rates for ERCC1, RRM1 and BRCA1 of 91%, 87% and 81% respectively. Conclusion All three methods can provide sufficient tumor material for multiple biomarkers testing from routinely obtained small biopsies in lung cancer patients. In our study EBUS guided needle aspiration provided the highest amount of tumor RNA compared to bronchoscopy or CT guided core biopsy. Thus EBUS should be considered as an acceptable option for tissue acquisition for molecular testing.

Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection

Isolated limb perfusion (ILP) is an effective limb salvage strategy in patients with advanced soft tissue sarcoma (STS) where surgery alone would result in significant functional morbidity or mandate an amputation. Most previous reports of patients undergoing ILP focus on limb salvage rates rather than local and distant relapse rates. Here, we report the oncological outcome of sarcoma patients treated by ILP and surgery.

Dynamic volume perfusion CT in patients with lung cancer: Baseline perfusion characteristics of different histological subtypes

OBJECTIVE To evaluate dynamic volume perfusion CT (dVPCT) tumor baseline characteristics of three different subtypes of lung cancer in untreated patients. MATERIALS AND METHODS 173 consecutive patients (131 men, 42 women; mean age 61 ± 10 years) with newly diagnosed lung cancer underwent dVPCT prior to biopsy. Tumor permeability, blood flow (BF), blood volume (BV) and mean transit time (MTT) were quantitatively assessed as well as tumor diameter and volume. Tumor subtypes were histologically determined and compared concerning their dVPCT results. dVPCT results were correlated to tumor diameter and volume. RESULTS Histology revealed adenocarcinoma in 88, squamous cell carcinoma in 54 and small cell lung cancer (SCLC) in 31 patients. Tumor permeability was significantly differing between adenocarcinoma, squamous cell carcinoma and SCLC (all p<0.05). Tumor BF and BV were higher in adenocarcinomathan in SCLC (p = 0.001 and p=0.0002 respectively). BV was also higher in squamous cell carcinoma compared to SCLC (p = 0.01). MTT was not differing between tumor subtypes. Regarding all tumors, tumor diameter did not correlate with any of the dVPCT parameters, whereas tumor volume was negatively associated with permeability, BF and BV (r = -0.22, -0.24, -0.24, all p<0.05). In squamous cell carcinoma, tumor diameter und volume correlated with BV (r = 0.53 and r = -0.40, all p<0.05). In SCLC, tumor diameter und volume correlated with MTT (r = 0.46 and r = 0.39, all p<0.05). In adenocarcinoma, no association between morphological and functional tumor characteristics was observed. CONCLUSIONS dVPCT parameters are only partially related to tumor diameter and volume and are significantly differing between lung cancer subtypes.

Cetuximab Attenuates Metastasis and u-PAR Expression in Non-Small Cell Lung Cancer: u-PAR and E-Cadherin are Novel Biomarkers of Cetuximab Sensitivity

Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (b) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63% of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.

Predicting malignancy in mediastinal lymph nodes by endobronchial ultrasound: A new ultrasound scoring system

Background and objective:  Endobronchial ultrasound (EBUS) is now widely used in patients with resectable non‐small‐cell lung cancer to sample mediastinal lymph nodes (LN) for preoperative staging. The aim of this study was to investigate prospectively the utility of six ultrasound criteria to predict malignancy in mediastinal LN.

Standard versus Dose-Intensified Chemotherapy with Sequential Reinfusion of Hematopoietic Progenitor Cells in Small Cell Lung Cancer Patients with Favorable Prognosis

Purpose: The combination of ifosfamide, carboplatin, and etoposide (ICE) is highly effective in treating small cell lung cancer (SCLC). Myelosuppression resulting in leukopenia and thrombocytopenia is the dose-limiting toxicity. Patients and Methods: This phase 3 study assessed 2-year survival improvement with dose intensification of ICE chemotherapy (ICT) in patients with good-prognosis SCLC. Patients received up to six cycles of ICT with filgrastim-supported sequential reinfusion of peripheral blood progenitor cells every 14 days, or standard ICE (SCT) every 28 days. Results: Eighty-three patients were randomized to ICT (n = 42) or SCT (n = 41). Median survival was significantly improved with ICT (30.3 mo) versus SCT (18.5 mo; p = 0.001); 2-year survival was 55% for ICT and 39% for SCT (p = 0.151). Time to progression (TTP) was significantly improved, with 15 months for ICT versus 11.1 months for SCT (p = 0.0001). Overall response rates were 100 and 88% for ICT and SCT, respectively (p = 0.0258). SCT was associated with significantly less grade 3 and 4 leukopenia at day 8 (p < 0.0001), less thrombocytopenia at day 14 (p < 0.0001), and more favorable platelet nadir (p < 0.0001). The need for platelet and red blood cell transfusions significantly increased in the ICT group (p < 0.0001). Nonhematologic adverse events in both groups were comparable and mostly grade 1 or 2. Conclusion: Patients receiving ICT with filgrastim achieved significant increases in median survival and TTP despite an increased need for transfusions.