[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Aim: To investigate the impact of KRAS mutation variants on the activity of regorafenib in SW48 colorectal cancer cells.
Activity of regorafenib was evaluated in isogenic SW48 KRAS wild-type (WT) and mutant cells. Subcutaneous xenografts (KRAS WT and G12C mutant variants) in NOD/SCID mice were analyzed to elucidate the effect of regorafenib treatment in vivo.
Compared with KRAS WT cells, all mutant variants seemed associated with some degree of resistance to regorafenib-treatment in vitro. In vivo, activation of apoptosis (TUNEL) and reduction of proliferation (Ki67) after treatment with regorafenib were more pronounced in KRAS WT tumors as compared with G12C variants.
In SW48 cells, exon 2 mutations of the KRAS gene may influence antitumor effects of regorafenib.
[Show abstract][Hide abstract] ABSTRACT: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated.
Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross-over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles.
Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first- and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056).
The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine-treated patients with advanced PC.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the impact of different KRAS mutations on the inhibitory potential of afatinib and gefitinib in SW48 colorectal cancer cells. The influence of afatinib/gefitinib on cell viability and cell cycle was evaluated in isogenic SW48 KRAS wild-type/mutant cells. Protein levels of phosphorylated/total EGFR, HER-2, HER-3, ERK, and AKT were compared between treated/untreated samples using western blotting. The activity of both afatinib and gefitinib was the lowest in KRAS G12C/G12S/G12D and the highest in G13D/G12A mutant subtypes. A 50% decrease in cell viability was achieved at concentrations of 3.0-7.7 μmol/l for afatinib and 5.4-19.5 μmol/l for gefitinib. The effect of both drugs on apoptosis appeared to be stronger than their influence on proliferation and was generally less pronounced in mutant cells than in wild-type cells. The average number of apoptotic cells after treatment with afatinib was 2.6 times as high as the corresponding value following treatment with gefitinib (P<0.01). Levels of pEGFR, pHER-2, pERK, and pAKT were reduced more extensively by afatinib than by gefitinib (P<0.001). Some KRAS mutations (G12C/G12S/G12D) appear to weaken the activity of afatinib and gefitinib whereas others seem to increase sensitivity to treatment (G13D/G12A) compared with the parental clone (KRAS wild-type). In SW48 colorectal cancer cells, afatinib seems to be more potent than gefitinib because of its superior efficacy in inhibiting both EGFR and HER-2, suppressing signaling along both MEK/ERK and PI3K/AKT pathways to a greater extent.
[Show abstract][Hide abstract] ABSTRACT: The present prospective single-center study investigated the prognostic role of novel serum biomarkers in advanced pancreatic cancer (PC). Patients (pts) with locally advanced or metastatic PC treated with first-line palliative chemotherapy were included. Among others, the serum markers CYFRA 21-1, haptoglobin, serum-amyloid A (SAA), and 25-OH vitamin D3 were determined at baseline and categorized by pre-defined cut-offs [median values (MV), upper limits of normal (ULN), lower limits of normal (LLN), or the natural logarithm (ln)] and correlated with overall survival (OS). Among the 59 pts included, pre-treatment CYFRA 21-1 levels showed a strong correlation with OS independent of the applied cut-off (MV 4.9 ng/ml-14.2 vs. 4.2 months, HR 0.18, p = 0.001; ULN 3.3 ng/ml-14.2 vs. 4.4 months, HR 0.28, p = 0.003; [ln] CYFRA 21-1-HR 0.77, p = 0.013). Lower values of haptoglobin were additionally associated with an improvement in OS (categorized by LLN of 2.05 g/l-10.4 vs. 5.5 months, HR 0.46, p = 0.023; [ln] haptoglobin-HR 0.51, p = 0.036). Pts with baseline SAA values below the MV of 22 mg/l also had a prolonged OS (10.4 vs. 5.0 months, HR 0.47, p = 0.036). For 25-OH vitamin D3 levels, no significant correlation with OS was found. In multivariate analyses, pre-treatment CYFRA 21-1 levels (categorized by MV-HR 0.15, p = 0.032) as well as [ln] haptoglobin (HR 0.30, p = 0.006) retained their independent prognostic significance for OS. CYFRA 21-1, haptoglobin, and SAA might provide useful prognostic information in advanced PC. An external multicenter validation of these results is necessary.
[Show abstract][Hide abstract] ABSTRACT: Isolated human primary hepatocytes are an essential in vitro model for basic and clinical research. For successful application as a model, isolated hepatocytes need to have a good viability and be available in sufficient yield. Therefore, this study aims to identify donor characteristics, intra-operative factors, tissue processing and cell isolation parameters that affect the viability and yield of human hepatocytes. Remnant liver pieces from tissue designated as surgical waste were collected from 1034 donors with informed consent. Human hepatocytes were isolated by a two-step collagenase perfusion technique with modifications and hepatocyte yield and viability were subsequently determined. The accompanying patient data was collected and entered into a database. Univariate analyses found that the viability and the yield of hepatocytes were affected by many of the variables examined. Multivariate analyses were then carried out to confirm the factors that have a significant relationship with the viability and the yield. It was found that the viability of hepatocytes was significantly decreased by the presence of fibrosis, liver fat and with increasing gamma-glutamyltranspeptidase activity and bilirubin content. Yield was significantly decreased by the presence of liver fat, septal fibrosis, with increasing aspartate aminotransferase activity, cold ischemia times and weight of perfused liver. However, yield was significantly increased by chemotherapy treatment. In conclusion, this study determined the variables that have a significant effect on the viability and the yield of isolated human hepatocytes. These variables have been used to generate an algorithm that can calculate projected viability and yield of isolated human hepatocytes. In this way, projected viability can be determined even before isolation of hepatocytes, so that donors that result in high viability and yield can be identified. Further, if the viability and yield of the isolated hepatocytes is lower than expected, this will highlight a methodological problem that can be addressed.
PLoS ONE 10/2014; 9(10):e107567. DOI:10.1371/journal.pone.0107567 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Conclusion: The length of the cochlea can be determined with good precision using a 3D-curved multiplanar reconstruction analysis technique and linear reconstruction of the cochlea. The method is not time-consuming and can be applied during clinical routine. Objective: A preoperative prediction of the best cochlear implant electrode length can help reduce the risk of intraoperative cochlear trauma in patients who need to retain residual acoustic hearing for electric-acoustic stimulation or in patients with anatomical anomalies or malformations. The goal of this study was to evaluate the accuracy and reliability of length measurement of the cochlea after linear reconstruction using 3D-curved multiplanar reconstrucion analysis of high resolution computed tomography (CT) scans. Methods: Human cadaveric temporal bone specimens underwent cochlear implantation using custom-made electrodes with two radiopaque markers of a defined length before CTscans were made. Length measurement was performed by four readers and the results were compared to the true value. Inter-reader reliability was calculated. The time needed for analysis was recorded. Results: The mean time needed for analysis of one specimen’s radiologic data was 6.1 (± 3.4) min. The mean deviation of the length measurement from the true value was 0.8 (± 0.7) mm. Inter-reader reliability was excellent (0.76, p = 0.006).
[Show abstract][Hide abstract] ABSTRACT: BackgroundThe role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined.MethodsWithin the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model.ResultsFifty-five out of 153 patients were classified as pERKlow and 98 patients as pERKhigh; median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKTlow and 14/35 pAKThigh with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53.ConclusionpERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash.Trial registrationNCT00440167 (registration date: February 22, 2007).Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-624) contains supplementary material, which is available to authorized users.
BMC Cancer 08/2014; 14(1):624. DOI:10.1186/1471-2407-14-624 · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
The purpose of this study was to investigate intracranial pressure and associated hemo- and hydrodynamic parameters in patients with cerebral arteriovenous malformations AVMs.
Thirty consecutive patients with arteriovenous malformations (median age 38.7 years, 27/30 previously treated with radiosurgery) and 30 age- and gender-matched healthy controls were investigated on a 3.0 Tesla MR scanner. Nidus volume was quantified on dynamic MR angiography. Total arterial cerebral blood flow (tCBF), venous outflow as well as aqueductal and craniospinal stroke volumes were obtained using velocity-encoded cine-phase contrast MRI. Intracranial volume change during the cardiac cycle was calculated and intracranial pressure (ICP) was derived from systolic intracranial volume change (ICVC) and pulse pressure gradient.
TCBF was significantly higher in AVM patients as compared to healthy controls (median 799 vs. 692 mL/min, p = 0.007). There was a trend for venous flow to be increased in both the ipsilateral internal jugular vein (IJV, 282 vs. 225 mL/min, p = 0.16), and in the contralateral IJV (322 vs. 285 mL/min, p = 0.09), but not in secondary veins. There was no significant difference in median ICP between AVM patients and control subjects (6.9 vs. 8.6 mmHg, p = 0.30) and ICP did not correlate with nidus volume in AVM patients (ρ=-0.06, p = 0.74). There was a significant positive correlation between tCBF and craniospinal CSF stroke volume (ρ=0.69, p = 0.02).
The elevated cerebral blood flow in patients with AVMs is drained through an increased flow in IJVs but not secondary veins. ICP is maintained within ranges of normal and does not correlate with nidus volume.
European Journal of Radiology 08/2014; 83(8). DOI:10.1016/j.ejrad.2014.05.011 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In patients with metastatic colorectal cancer (mCRC), radiological imaging represents the current standard to evaluate the efficacy of chemotherapy. However, with growing knowledge about tumor biology, other diagnostic tools become of interest which can supplement radiology. The aim of the present study was to examine the correlation of tumor and serum markers with radiological imaging in patients with mCRC receiving first-line therapy. Patients were included if tumor (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)) and serum marker (lactatdehydrogenase (LDH), γ-glutamyltransferase (γGT), alkaline phosphatase (AP), C-reactive protein (CRP), leucocyte count (WBC), hemoglobin (Hb)) levels were available at baseline and at least two times during treatment. The decline and increase of tumor and serum markers over time were approximated for each patient by estimating slopes depending on the radiological assessment. A linear mixed effects multiple regression model for each subject was used to evaluate the intra-class correlation of these slopes modeling tumor and serum marker changes with radiological imaging. Data of 124 patients (41 female, 83 male; median age 62.9 years, range 27-85) who received first-line chemotherapy for mCRC from 11/2007 to 04/2010 were analyzed retrospectively. CEA level slopes (n = 49; slopes = 102) differed between radiologically determined progressive disease (PD) and partial response (PR) (p = 0.005) and between PD and stable disease (SD) (p = 0.042). CA 19-9 level slopes (n = 57; slopes = 127) also showed a significant difference between PD and PR (p = 0.002) and PD and SD (p = 0.058). Furthermore, CRP slopes (n = 62; slopes = 134) differed significantly between PD and PR (p = 0.009). For LDH, ALP, γGT, Hb, and WBC, no correlations were observed. The results indicate the correlation of the tumor markers CEA, CA 19-9, and the serum marker CRP with radiological imaging in patients with mCRC receiving first-line chemotherapy. Further data analyses would be helpful to develop a predictive model for tumor response based on an early tumor marker increase or decrease.
[Show abstract][Hide abstract] ABSTRACT: Purpose. To evaluate progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) as potential surrogate endpoints (SEP) for overall survival (OS) in second-line treatment for metastatic colorectal cancer (mCRC). Methods. A systematic literature search of randomised trials of second-line chemotherapy for mCRC reported from January 2000 to July 2013 was performed. Correlation coefficients weighted by number of patients in the treatment arms between median PFS, ORR and DCR with median OS were estimated. Results. Twenty-three trials reflecting 10 800 patients met the inclusion criteria. Median PFS and OS across all trials were 4.5 months and 11.5 months and median ORR and DCR were 11.4% and 65%, respectively. PFS showed moderate correlation with OS [RPFS = 0.73; 95% confidence interval (CI) 0.61-0.82]. In contrast, ORR only weakly correlated with OS (RORR = 0.58; 95% CI 0.38-0.72, n = 22). Despite a small number of studies (n = 10) reporting on DCR, moderate correlation with OS was observed (RDCR = 0.74; 95% CI 0.56-0.86). Conclusion. Based on the available trial-level data, PFS may serve as an appropriate SEP in second-line chemotherapy for mCRC. A small number of studies revealed moderate correlation of DCR with OS that justifies further investigation.
[Show abstract][Hide abstract] ABSTRACT: Objectives
To evaluate the agreement between tumour volume derived from semiautomated volumetry (SaV) and tumor volume defined by spherical volume using longest lesion diameter (LD) according to Response Evaluation Criteria In Solid Tumors (RECIST) or ellipsoid volume using LD and longest orthogonal diameter (LOD) according to World Health Organization (WHO) criteria.
Materials and methods
Twenty patients with metastatic colorectal cancer from the CIOX trial were included. A total of 151 target lesions were defined by baseline computed tomography and followed until disease progression. All assessments were performed by a single reader. A variance component model was used to compare the three volume versions.
There was a significant difference between the SaV and RECIST-based tumour volumes. The same model showed no significant difference between the SaV and WHO-based volumes. Scatter plots showed that the RECIST-based volumes overestimate lesion volume. The agreement between the SaV and WHO-based relative changes in tumour volume, evaluated by intraclass correlation, showed nearly perfect agreement.
Estimating the volume of metastatic lesions using both the LD and LOD (WHO) is more accurate than those based on LD only (RECIST), which overestimates lesion volume. The good agreement between the SaV and WHO-based relative changes in tumour volume enables a reasonable approximation of three-dimensional tumour burden.
• Tumour response in patients undergoing chemotherapy is assessed using CT images
• Measurements are based on RECIST (unidimensional)-based or WHO (bidimensional)-based criteria
• We calculated tumour volume from bidimensional target lesion measurements
• This formula provides good tumour volume approximation, based on semiautomated volumetry
European Radiology 07/2014; 24(7). DOI:10.1007/s00330-014-3195-9 · 4.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The role of human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker for gemcitabine efficacy in advanced pancreatic cancer remains unclear to date. Patients and methods: AIO-PK0104 was a German multicenter phase III trial comparing gemcitabine/erlotinib followed by capecitabine (GEC) with capecitabine/erlotinib followed by gemcitabine (CEG) in advanced pancreatic cancer. Archival tumour tissue from 169 of the 274 eligible study patients was available for a central and standardised immunohistochemistry staining for hENT1 expression using the SP120 rabbit monoclonal anti-hENT1 antibody. Within a retrospective translational subgroup analysis, biomarker data were correlated with efficacy end-points. Results: Thirty-nine out of 130 fresh-cut slides were scored as hENT1(high) (30%), whereas 91 samples were classified as hENT1(low) (70%). For the 62 patients randomised to CEG median overall survival was estimated with 6.4 months in the hENT1(low) compared to 6.9 months in the hENT1(high) subgroup (Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.48-1.61, p = 0.67). For the 68 patients randomised to GEC survival was 5.7 months in the hENT1(low) compared to 4.4 months in the hENT1(high) subgroup (HR 1.16, 95% CI 0.69-1.96, p = 0.57). In 101 patients receiving gemcitabine at any time during study treatment (either within the 1st- or 2nd-line setting) hENT1(low) cases had a median overall survival of 7.5 months' and hENT1(high) patients an overall survival of 4.4 months (HR 1.30, 95% CI 0.84-2.03, p = 0.24), respectively. Conclusion: Within this subgroup analysis from Arbeitsgemeinschaft Internistische Onkologiepancreatic cancer (AIO-PK0104), no evidence supporting the use of hENT1 as a predictive biomarker for gemcitabine efficacy in patients with advanced pancreatic cancer was found.
European journal of cancer (Oxford, England: 1990) 05/2014; 50(11). DOI:10.1016/j.ejca.2014.04.023 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With one quarter of the world population infected, the intestinal nematode Ascaris lumbricoides is one of the most common infectious agents, especially in the tropics and sub-tropics. Infection is caused by oral intake of eggs and can cause respiratory and gastrointestinal problems. To identify high risk areas for intervention, it is necessary to understand the effects of climatic, environmental and socio-demographic conditions on A. lumbricoides infection.
Cross-sectional survey data of 6,366 study participants in the Mbeya region of South-Western Tanzania were used to analyze associations between remotely sensed environmental data and A. lumbricoides infection. Non-linear associations were accounted for by using fractional polynomial regression, and socio-demographic and sanitary data were included as potential confounders.
The overall prevalence of A. lumbricoides infection was 6.8%. Our final multivariable model revealed a significant non-linear association between rainfall and A. lumbricoides infection with peak prevalences at 1740 mm of mean annual rainfall. Mean annual land surface temperature during the day was linearly modeled and negatively associated with A. lumbricoides infection (odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.78-0.97). Furthermore, age, which also showed a significant non-linear association (infection maximum at 7.7 years), socio-economic status (OR = 0.82, CI = 0.68-0.97), and latrine coverage around the house (OR = 0.80, CI = 0.67-0.96) remained in the final model.
A. lumbricoides infection was associated with environmental, socio-demographic and sanitary factors both in uni- and multivariable analysis. Non-linear analysis with fractional polynomials can improve model fit, resulting in a better understanding of the relationship between environmental conditions and helminth infection, and more precise predictions of high prevalence areas. However, socio-demographic determinants and sanitary conditions should also be considered, especially when planning public health interventions on a smaller scale, such as the community level.
PLoS ONE 03/2014; 9(3):e92032. DOI:10.1371/journal.pone.0092032 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims: We investigated the impact of the diameter of the valvuloplasty balloon (VB) used for predilation before transcatheter aortic valve implantation (TAVI) on atrioventricular block formation with consecutive need for permanent pacemaker (PP) implantation. Methods and results: TAVI was performed in 269 consecutive patients using the CoreValve prosthesis (Medtronic) via transfemoral access under local anaesthesia with mild analgesic medication. After exclusion of 32 patients with previously implanted PP, 237 patients were included in a retrospective analysis of the impact of VB size on subsequent PP incidence. Implantation success rate was 99.3%. Periprocedural mortality was 0%, and 30-day mortality was 5.9%. PP implantation after TAVI was required by 21.1%. Of 114 patients treated by 25 mm balloon valvuloplasty, a PP was implanted in 27.1%. In 123 patients, who were treated by VB with a ≤23 mm diameter, the PP implantation rate decreased to 15.4% (p=0.04). In univariate analysis, larger VB size resulted in a greater prevalence of PP implantation after TAVI. After adjustment by multivariate analysis for baseline clinical and operative characteristics, VB size remained an independent predictor of PP implantation. Conclusions: Moderate balloon predilation in patients undergoing TAVI with the Medtronic CoreValve prosthesis reduces the PP rate without affecting procedural success.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 02/2014; 9(10):1151-7. DOI:10.4244/EIJV9I10A195 · 3.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The role of human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker for gemcitabine efficacy in advanced pancreatic cancer remains unclear to date.
Patients and methods
AIO-PK0104 was a German multicenter phase III trial comparing gemcitabine/erlotinib followed by capecitabine (GEC) with capecitabine/erlotinib followed by gemcitabine (CEG) in advanced pancreatic cancer. Archival tumour tissue from 169 of the 274 eligible study patients was available for a central and standardised immunohistochemistry staining for hENT1 expression using the SP120 rabbit monoclonal anti-hENT1 antibody. Within a retrospective translational subgroup analysis, biomarker data were correlated with efficacy end-points.
Thirty-nine out of 130 fresh-cut slides were scored as hENT1high (30%), whereas 91 samples were classified as hENT1low (70%). For the 62 patients randomised to CEG median overall survival was estimated with 6.4 months in the hENT1low compared to 6.9 months in the hENT1high subgroup (Hazard Ratio (HR) 0.88, 95% confidence interval (CI) 0.48–1.61, p = 0.67). For the 68 patients randomised to GEC survival was 5.7 months in the hENT1low compared to 4.4 months in the hENT1high subgroup (HR 1.16, 95% CI 0.69–1.96, p = 0.57). In 101 patients receiving gemcitabine at any time during study treatment (either within the 1st- or 2nd-line setting) hENT1low cases had a median overall survival of 7.5 months and hENT1high patients an overall survival of 4.4 months (HR 1.30, 95% CI 0.84–2.03, p = 0.24), respectively.
Within this subgroup analysis from Arbeitsgemeinschaft Internistische Onkologie-pancreatic cancer (AIO-PK0104), no evidence supporting the use of hENT1 as a predictive biomarker for gemcitabine efficacy in patients with advanced pancreatic cancer was found.