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1.  Risk-adapted single or fractionated stereotactic high-precision radiotherapy in a pooled series of nonfunctioning pituitary adenomas 
Strahlentherapie Und Onkologie  2014;190(12):1095-1103.
The purpose of this work was to evaluate a prospectively initiated two-center protocol of risk-adapted single-fraction (SRS) or fractionated radiotherapy (SRT) in patients with nonsecretory pituitary adenomas (NSA).
Patients and methods
A total of 73 NSA patients (39 men/34 women) with a median age of 62 years were prospectively included in a treatment protocol of SRS [planning target volume (PTV) < 4 ccm, > 2 mm to optic pathways = low risk] or SRT (PTV ≥ 4 ccm, ≤ 2 mm to optic pathways = high risk) in two Novalis® centers. Mean tumor volume was 7.02 ccm (range 0.58–57.29 ccm). Based on the protocol guidelines, 5 patients were treated with SRS and 68 patients with SRT.
Median follow-up (FU) reached 5 years with 5-year overall survival (OS) of 90.4 % (CI 80.2–95 %) and 5-year local control and progression-free survival rates of 100 % (CI 93.3–100 %) and 90.4 % (CI 80.2–95 %), respectively. A post-SRS/SRT new visual disorder occurred in 2 patients (2.7 %), a new oculomotor nerve palsy in one pre-irradiated patient, in 3 patients (4.1 %) a pre-existing visual disorder improved. New complete hypopituitarism occurred in 4 patients (13.8 %) and in 3 patients (25 %) with pre-existing partial hypopituitarism. Pituitary function in 26 % of patients retained normal. Patients with tumor shrinkage (65.75 %) had a significantly longer FU (p = 0.0093). Multivariate analysis confirmed correlation of new hypopituitarism with duration of FU (p = 0.008) and correlation of new hypopituitarism and tumor volume (p = 0.023). No significant influence factors for occurrence of visual disorders were found.
Our SRS/SRT protocol proved to be safe and successful in terms of tumor control and protection of the visual system, especially for large tumors located close to optic pathways.
PMCID: PMC4240908  PMID: 25091268
Nonsecretory pituitary adenoma; Radiosurgery; Stereotactic radiotherapy; Hypopituitarism; Hormoninaktive Hypophysenadenome; Radiochirurgie; Stereotaktische Radiotherapie; Hypophyseninsuffizienz
2.  Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer* 
Background and Purpose
Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict for rectal bleeding, and genetic factors may be important.
Materials and Methods
A genome-wide association study (GWAS) was performed to identify SNPs associated with development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites.
rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10−8 and 6.9×10−7 respectively). Several other SNPs had p-values trending towards genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0×10−12 in the replication cohort).
This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified.
PMCID: PMC3787843  PMID: 23719583
radiogenomics; prostate cancer; rectal toxicity; genome-wide association study
3.  Interobserver Reproducibility of Diffusion-Weighted MRI in Monitoring Tumor Response to Neoadjuvant Therapy in Esophageal Cancer 
PLoS ONE  2014;9(4):e92211.
To investigate the reproducibility of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing tumor response early in the course of neoadjuvant chemoradiotherapy in patients with operable esophageal cancer.
Eleven male patients (mean age 54.8 years) with newly diagnosed esophageal cancer underwent DW-MRI before and 10 days after start of chemoradiotherapy. Reproducibility of apparent diffusion coefficient (ADC) measurements by manual (freehand) and semi-automated volumetric methods was assessed.
Interobserver reproducibility for the assessment of mean tumor ADC by the manual measurement method was good, with an ICC of 0.69 (95% CI, 0.36 to 0.85; P = 0.001). Interobserver reproducibility for the assessment of mean tumor ADC by the semi-automated volumetric measurement method was very good, with an ICC of 0.96 (95% CI, 0.91 to 0.98; P<0.001).
Semi-automated volumetric ADC measurements have higher reproducibility than manual ADC measurements in assessing tumor response to chemoradiotherapy in patients with esophageal adenocarcinoma.
PMCID: PMC3976260  PMID: 24704912
4.  Increased CD44s and decreased CD44v6 RNA expression are associated with better survival in myxofibrosarcoma patients: a pilot study 
New prognostic markers may be of value in determining survival and informing decisions of adjuvant treatment in the heterogeneous group of soft tissue sarcomas known as malignant fibrous sarcomas (MFS). Increased CD44 expression has been associated with a better outcome in cancers such as bladder tumors and could potentially relate to cell-cell interaction as a marker for potential invasion/metastasis. The aim of this pilot study was to determine if there is a correlation between the expression rate of CD44 in adult patients with MFS and clinical outcomes.
The clinical outcome of 34 adult MFS patients (19 males and 15 females, average age 62 years, median 63 years, range: 38–88 years) who underwent surgical treatment were evaluated. Twenty-five of these patients had additional adjuvant radiotherapy. Extracted RNA from sarcoma tissues was used to measure the transcripts of CD44s (standard form) and isoform expression.
The pooled data for each variant of CD44 was divided in half at the median expression value into two equally sized groups (low and high). Survival modeling and multivariate analysis were used with these two groups to determine if there were differences in survival times and whether this was independent of known factors such as tumor stage/grade, patient age and resection margin status.
High CD44s and low of CD44v6 expression significantly correlated with an improved outcome (P <0.05 and P <0.02, respectively) whereas CD44v8 and hCD44 (isoforms) did not. Differences in survival were apparent within 6–12 months of operation with >30% difference in survival between low/high expressions at 5 years. These finding were independent of the other measured MFS survival predictors, though the group was homogenous.
High CD44s and low CD44v6 expression may be an independent predictor of improved survival in MFS patients in this pilot data. This is contrary to other MFS data, which did not account for the CD44 isoforms but is confirmed by data from other cancer types. Further investigation is needed to confirm CD44 isoform expression data as a relevant survival biomarker and whether it could be used to inform clinical decisions such as adjuvant therapy.
PMCID: PMC3942188  PMID: 24491153
CD44; Malignant fibrous histiocytoma; MFS; Myxofibrosarcoma; Soft tissue sarcoma; Survival; Tumor prognosis
5.  A Two-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated with Development of Erectile Dysfunction Following Radiotherapy for Prostate Cancer* 
To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiotherapy.
Methods and Materials
A two-stage genome-wide association study (GWAS) was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays.
12 SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiotherapy (Fisher combined p-values 2.1×10−5 to 6.2×10−4). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including non-genetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers’ D p-value = 1.7×10−29). A one-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (p-value = 2.1×10−19). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiotherapy planning stage.
This GWAS identified a set of SNPs that are associated with development of ED following radiotherapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.
PMCID: PMC3616619  PMID: 23021708
prostate cancer; genetic predictors; late effects; brachytherapy
6.  The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery 
BMC Surgery  2011;11:34.
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer.
Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response.
Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol.
The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at (NCT01273051)
PMCID: PMC3295682  PMID: 22171697
7.  Value of ADC measurements for nodal staging after chemoradiation in locally advanced rectal cancer—a per lesion validation study 
European Radiology  2010;21(2):265-273.
To evaluate the performance of diffusion-weighted MRI (DWI) in addition to T2-weighted (T2W) MRI for nodal restaging after chemoradiation in rectal cancer.
Thirty patients underwent chemoradiation followed by MRI (1.5 T) and surgery. Imaging consisted of T2W-MRI and DWI (b0, 500, 1000). On T2W-MRI, nodes were scored as benign/malignant by two independent readers (R1, R2). Mean apparent diffusion coefficient (ADC) was measured for each node. Diagnostic performance was compared for T2W-MRI, ADC and T2W+ADC, using a per lesion histological validation.
ADC was higher for the malignant nodes (1.43 ± 0.38 vs 1.19 ± 0.27 *10−3 mm2/s, p < 0.001). Area under the ROC curve/sensitivity/specificity were 0.88/65%/93% (R1) and 0.95/71%/91% (R2) using T2W-MRI; 0.66/53%/82% using ADC (mean of two readers); and 0.91/56%/98% (R1) and 0.96/56%/99% (R2) using T2W+ADC. There was no significant difference between T2W-MRI and T2W+ADC. Interobserver reproducibility was good for T2W-MRI (κ0.73) and ADC (intraclass correlation coefficient 0.77).
After chemoradiation, ADC measurements may have potential for nodal characterisation, but DWI on its own is not reliable. Addition of DWI to T2W-MRI does not improve accuracy and T2W-MRI is already sufficiently accurate.
PMCID: PMC3034880  PMID: 20730540
Nodal restaging; Diffusion-weighted imaging; Apparent diffusion coefficient; MRI; Locally advanced rectal cancer
8.  Epidermal Growth Factor Receptor Dependence of Radiation-induced Transcription Factor Activation in Human Breast Carcinoma Cells 
Molecular Biology of the Cell  2002;13(7):2233-2244.
Ionizing radiation (1–5 Gy) activates the epidermal growth factor receptor (EGFR), a major effector of the p42/44 mitogen-activated protein kinase (MAPK) pathway. MAPK and its downstream effector, p90 ribosomal S6 kinase (p90RSK), phosphorylate transcription factors involved in cell proliferation. To establish the role of the EGFR/MAPK pathway in radiation-induced transcription factor activation, MDA-MB-231 human breast carcinoma cells were examined using specific inhibitors of signaling pathways. Gel-shift analysis revealed three different profile groups: 1) transcription factors that responded to both radiation (2 Gy) and epidermal growth factor (EGF) (CREB, Egr, Ets, and Stat3); 2) factors that responded to radiation, but not EGF (C/EBP and Stat1); and 3) those that did not respond significantly to either radiation or EGF (AP-1 and Myc). Within groups 1 and 2, a two- to fivefold maximum stimulation of binding activity was observed at 30–60 min after irradiation. Interestingly, only transcription factors that responded to EGF had radiation responses significantly inhibited by the EGFR tyrosine kinase inhibitor, AG1478; these responses were also abrogated by farnesyltransferase inhibitor (FTI) or PD98059, inhibitors of Ras and MEK1/2, respectively. Moreover, radiation-induced increases in CREB and p90RSK phosphorylation and activation of Stat3 and Egr-1 reporter constructs by radiation were all abolished by AG1478. These data demonstrate a distinct radiation response profile at the transcriptional level that is dependent on enhanced EGFR/Ras/MAPK signaling.
PMCID: PMC117308  PMID: 12134064

Results 1-8 (8)