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1.  Effectiveness and cost-effectiveness of meaning-centered group psychotherapy in cancer survivors: protocol of a randomized controlled trial 
BMC Psychiatry  2014;14:22.
Background
Meaning-focused coping may be at the core of adequate adjustment to life after cancer. Cancer survivors who experience their life as meaningful are better adjusted, have better quality of life and psychological functioning. Meaning-Centered Group Psychotherapy for Cancer Survivors (MCGP-CS) was designed to help patients to sustain or enhance a sense of meaning and purpose in their lives. The aim of the proposed study is to evaluate the effectiveness and cost-effectiveness of MCGP-CS.
Methods/Design
Survivors diagnosed with cancer in the last 5 years and treated with curative intent, are recruited via several hospitals in the Netherlands. After screening, 168 survivors are randomly assigned to one of the three study arms: 1. Meaning-Centered Group Psychotherapy (MCGP-CS) 2. Supportive group psychotherapy (SGP) 3. Care as usual (CAU). Baseline assessment takes place before randomisation, with follow up assessments post-intervention and at 3, 6 and 12 months follow-up. Primary outcome is meaning making (PMP, PTGI, SPWB). Secondary outcome measures address quality of life (EORTC-30), anxiety and depression (HADS), hopelessness (BHS), optimism (LOT-R), adjustment to cancer (MAC), and costs (TIC-P, EQ-5D, PRODISQ).
Discussion
Meaning-focused coping is key to adjustment to life after cancer, however, there is a lack of evidence based psychological interventions in this area. Many cancer survivors experience feelings of loneliness and alienation, and have a need for peer support, therefore a group method in particular, can be beneficial for sustaining or enhancing a sense of meaning. If this MCGP-CS is effective for cancer survivors, it can be implemented in the practice of psycho-oncology care.
Trial registration
Netherlands Trial Register, NTR3571
doi:10.1186/1471-244X-14-22
PMCID: PMC3942178  PMID: 24467861
Cancer; Survivorship; Meaning; Psycho-oncology; Existential distress; Group psychotherapy; Effectiveness; Cost-effectiveness
2.  Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer 
BMC Cancer  2013;13:277.
Background
p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence. TP53 is mutated in around 50% of human cancers. Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear. Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice.
Methods
By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome. Moreover, survival effects of CSNK1A1 together with p53 were also studied.
Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue.
Results
Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0.009). Expression of CSNK1A1 modified p53 survival effects. Patients with low CSNK1A1 expression and non-functional p53 had a very poor survival both in the univariate (Log Rank p<0.001) and in the multivariate survival analysis (HR=4.74 95% CI 1.45 – 15.3 p=0.009).
Conclusion
The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients. This effect was specifically modified by CSKN1A1 expression.
doi:10.1186/1471-2407-13-277
PMCID: PMC3682902  PMID: 23739040
Colon cancer; p53; Prognosis; Survival; CSKN1A1
3.  The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery 
BMC Surgery  2011;11:34.
Background
The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer.
Methods/Design
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.
Discussion
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 clinicaltrials.gov (NCT01273051)
doi:10.1186/1471-2482-11-34
PMCID: PMC3295682  PMID: 22171697
4.  Allele-specific regulation of FGFR2 expression is cell type-dependent and may increase breast cancer risk through a paracrine stimulus involving FGF10 
Introduction
SNPs rs2981582 and rs2981578, located in a linkage disequilibrium block (LD block) within intron 2 of the fibroblast growth factor receptor 2 gene (FGFR2), are associated with a mildly increased breast cancer risk. Allele-specific regulation of FGFR2 mRNA expression has been reported previously, but the molecular basis for the association of these variants with breast cancer has remained elusive to date.
Methods
mRNA levels of FGFR2 and three fibroblast growth factor genes (FGFs) were measured in primary fibroblast and epithelial cell cultures from 98 breast cancer patients and correlated to their rs2981578 genotype. The phosphorylation levels of downstream FGFR2 targets, FGF receptor substrate 2α (FRS2α) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), were quantified in skin fibroblasts exposed to FGF2. Immunohistochemical markers for angiogenesis and lymphocytic infiltrate were semiquantitatively assessed in 25 breast tumors.
Results
The risk allele of rs2981578 was associated with increased FGFR2 mRNA levels in skin fibroblasts, but not in skin epithelial cell cultures. FGFR2 mRNA levels in skin fibroblasts and breast fibroblasts correlated strongly in the patients from whom both cultures were available. Tumor-derived fibroblasts expressed, on average, eight times more FGFR2 mRNA than the corresponding fibroblasts from normal breast tissue. Fibroblasts with higher FGFR2 mRNA expression showed more FRS2α and ERK1/2 phosphorylation after exposure to FGF2. In fibroblasts, higher FGFR2 expression correlated with higher FGF10 expression. In 25 breast tumors, no associations between breast tumor characteristics and fibroblast FGFR2 mRNA levels were found.
Conclusions
The influence of rs2981578 genotypes on FGFR2 mRNA expression levels is cell type-dependent. Expression differences correlated well with signaling levels of the FGFR2 pathway. Our results suggest that the increased breast cancer risk associated with SNP rs2981578 is due to increased FGFR2 signaling activity in stromal fibroblasts, possibly also involving paracrine FGF10 signaling.
doi:10.1186/bcr2917
PMCID: PMC3236336  PMID: 21767389
5.  EMT is the dominant program in human colon cancer 
Background
Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging.
Methods
We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence.
Results
Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10-135) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT.
Conclusions
These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer--previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis.
doi:10.1186/1755-8794-4-9
PMCID: PMC3032646  PMID: 21251323
6.  Specific genomic aberrations in primary colorectal cancer are associated with liver metastases 
BMC Cancer  2010;10:662.
Background
Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases.
Methods
Array Comparative Genomic Hybridization (aCGH) was employed to asses DNA copy number changes in primary colorectal tumors of three distinctive patient groups. This included formalin-fixed, paraffin-embedded tissue of patients who developed liver metastases (LM; n = 36), metastases (PM; n = 37) and a group that remained metastases-free (M0; n = 25).
A novel statistical method for identifying recurrent copy number changes, KC-SMART, was used to find specific locations of genomic aberrations specific for various groups. We created a classifier for organ specific metastases based on the aCGH data using Prediction Analysis for Microarrays (PAM).
Results
Specifically in the tumors of primary CRC patients who subsequently developed liver metastasis, KC-SMART analysis identified genomic aberrations on chromosome 20q. LM-PAM, a shrunken centroids classifier for liver metastases occurrence, was able to distinguish the LM group from the other groups (M0&PM) with 80% accuracy (78% sensitivity and 86% specificity). The classification is predominantly based on chromosome 20q aberrations.
Conclusion
Liver specific CRC metastases may be predicted with a high accuracy based on specific genomic aberrations in the primary CRC tumor. The ability to predict the site of metastases is important for improvement of personalized patient management.
doi:10.1186/1471-2407-10-662
PMCID: PMC3027605  PMID: 21126340
7.  The ladies trial: laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037) 
BMC Surgery  2010;10:29.
Background
Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy.
The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis).
Methods/Design
In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs.
Discussion
The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis.
Trial registration
Nederlands Trial Register NTR2037
doi:10.1186/1471-2482-10-29
PMCID: PMC2974662  PMID: 20955571
8.  A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment 
BMC Cancer  2010;10:545.
Background
About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.
Methods/design
The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.
Conclusion
The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.
Trial Registration
ClinicalTrials.gov Identifier NCT00394992
doi:10.1186/1471-2407-10-545
PMCID: PMC2958953  PMID: 20937118
9.  Integrating chromosomal aberrations and gene expression profiles to dissect rectal tumorigenesis 
BMC Cancer  2008;8:314.
Background
Accurate staging of rectal tumors is essential for making the correct treatment choice. In a previous study, we found that loss of 17p, 18q and gain of 8q, 13q and 20q could distinguish adenoma from carcinoma tissue and that gain of 1q was related to lymph node metastasis. In order to find markers for tumor staging, we searched for candidate genes on these specific chromosomes.
Methods
We performed gene expression microarray analysis on 79 rectal tumors and integrated these data with genomic data from the same sample series. We performed supervised analysis to find candidate genes on affected chromosomes and validated the results with qRT-PCR and immunohistochemistry.
Results
Integration of gene expression and chromosomal instability data revealed similarity between these two data types. Supervised analysis identified up-regulation of EFNA1 in cases with 1q gain, and EFNA1 expression was correlated with the expression of a target gene (VEGF). The BOP1 gene, involved in ribosome biogenesis and related to chromosomal instability, was over-expressed in cases with 8q gain. SMAD2 was the most down-regulated gene on 18q, and on 20q, STMN3 and TGIF2 were highly up-regulated. Immunohistochemistry for SMAD4 correlated with SMAD2 gene expression and 18q loss.
Conclusion
On basis of integrative analysis this study identified one well known CRC gene (SMAD2) and several other genes (EFNA1, BOP1, TGIF2 and STMN3) that possibly could be used for rectal cancer characterization.
doi:10.1186/1471-2407-8-314
PMCID: PMC2584339  PMID: 18959792
10.  A family history of breast cancer will not predict female early onset breast cancer in a population-based setting 
BMC Cancer  2008;8:203.
Background
An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting.
Methods
An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer.
Results
The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12–10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83–5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33–9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30.
Conclusion
Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age.
doi:10.1186/1471-2407-8-203
PMCID: PMC2515321  PMID: 18651949
11.  Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases 
Introduction
Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.
Methods
We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.
Results
Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.
Conclusion
Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.
doi:10.1186/bcr1793
PMCID: PMC2246176  PMID: 17997823

Results 1-11 (11)