European Journal of Cancer

Spatial variation in stage distribution in colorectal cancer in the Netherlands

M.A.G. Elferink, E. Pukkala, J.M. Klaase, S. Siesling — 2011-08-01

Abstract: Background: In the Netherlands the incidence of colorectal cancer has increased, mainly in the eastern part of the country. Patient delay due to unawareness or ignorance of symptoms and differences in use of diagnostic tools could have influence on the stage distribution. The aim of this study was to evaluate geographical differences in stage-specific incidence rates of colon and rectal cancer in the Netherlands.Methods: Age-adjusted incidence rates for cancers of the colon and rectum diagnosed in 2001–2005 and registered in the Netherlands Cancer Registry were calculated for each municipality and stage. The incidence for each 500m by 500m grid was estimated as a weighted average of the incidence rates of the neighbouring municipalities. The incidence rates and the stage distribution are both presented as maps. Geographic variation in stage-specific incidence was evaluated using spatial scan statistic.Results: In both colon and rectal cancer, significant spatial variation in stage-specific incidences was found, except for colon cancer of stages III and IV. The regions with a higher stage-specific incidence were almost all in the south eastern part of the Netherlands, however, these differences were not seen in the stage distribution. There were no differences in stage distribution between large cities and the rest of the country.Conclusions: These maps give insight into differences in stage-specific incidences of colon and rectal cancer in the Netherlands. Educational interventions to increase the awareness of symptoms of colorectal cancer may be especially useful for the population in regions with high incidence of advanced stages.

Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: Results from a large treatment observational cohort study

2012-03-19

Abstract: Background: Bevacizumab prolongs overall and progression-free survival when added to fluorouracil-based chemotherapy in patients with metastatic colorectal cancer in randomised controlled trials (RCTs). However, gastrointestinal perforation (GIP) occurs in 1–2% of treated patients. We sought to describe the incidence, temporal pattern, outcomes and potential risk factors for GIP in a large, community-based observational cohort study of patients treated with bevacizumab.Patients and methods: Baseline patient and tumour characteristics, including potential GIP risk factors, were collected at study entry. Treatment, targeted adverse events, progression events and survival data were recorded every 3months. Detailed clinical information was collected for all patients experiencing a GIP event. Effects of baseline risk factors on GIP risk were investigated using Cox proportional hazards regression.Results: Of 1953 evaluable patients followed for a median of 20.1months, 37 (1.9%) experienced GIP. Most GIP events were surgically managed with successful outcomes; four events were fatal. The majority of GIP events (26/37) occurred ⩽6months after starting bevacizumab (median, 3.35months). Univariate and multivariate analyses showed that age ⩾65years was significantly associated with lower GIP risk. In multivariate analyses, intact primary tumour and prior adjuvant radiotherapy were significantly associated with increased risk of GIP within 6months after starting bevacizumab. A regression analysis that assessed the risk of GIP over time showed no cumulative risk associated with bevacizumab exposure.Conclusion: The observed rate of GIP in this large, community-based experience was consistent with rates reported in RCTs. Most events were successfully managed with surgical intervention.

Quality indicators for testicular cancer: A population-based study

2011-11-21

Abstract: Purpose: This study aimed at developing and measuring an indicator set to monitor the quality of testicular cancer care, to make comparisons over time and to support quality improvement for all practitioners and centres involved in the care of testicular cancer patients.Methods: Quality indicators were identified from a systematic literature search and from the 2010 Belgian evidence-based clinical practice guidelines. The selection process involved an expert panel evaluating reliability, relevance, interpretability and actionability of each indicator. The quality indicators were pilot tested using the Belgian Cancer Registry (BCR) data linked with claims data for 1307 men with testicular cancer diagnosed between 2001 and 2006. The variability between centres was displayed using funnel plots.Results: Of the 12 finally selected indicators, 5 were fully and 1 was partly measurable, while 2 indicators were measurable using proxy information. Five-year relative survival was 97%, 95% and 76% for pStage I–III, respectively. Overall 5-year survival slightly improved from 91% in 2001 to 94% in 2004. Between 2004 and 2006, 14 of 97 centres performed ⩾10 orchidectomies. Large variability was found between centres. The nine centres with a 5-year observed survival below the lower limit treated less than 20 patients between 2001 and 2006.Conclusions: The present study demonstrates the feasibility to develop a multidisciplinary set of quality indicators for testicular cancer. Using national cancer registry data linked to claims data, eight indicators were measurable, showing a mixed picture of the quality of care for testicular cancer patients in Belgium.

Accelerated MVAC chemotherapy in patients with advanced bladder cancer previously treated with a platinum–gemcitabine regimen

2012-02-24

Abstract: Background: Gemcitabine plus cisplatinum was shown to exert comparable activity and a different toxicity profile when compared to the methotrexate, vinblastine, doxorubicin, cisplatinum (MVAC) regimen in patients with advanced bladder cancer. Accelerated MVAC (aMVAC, the four drugs being administered every 2weeks with granulocyte colony-stimulating factor (G-CSF)) is better tolerated than conventional MVAC, with a trend for improved activity. There is no standard of care after failure of gemcitabine–platinum (GP) chemotherapy. Our aim was to assess the activity and toxicity of accelerated MVAC as second-line treatment.Methods: We reviewed data from patients previously treated with GP who had received aMVAC at two institutions at the time of disease progression.Results: Forty-five patients received aMVAC after GP: 18 (40%) and 27 (60%) had received GP in the adjuvant and the metastatic settings, respectively. The median time to progression (TTP) after first-line GP was 9.3months. The response rate for aMVAC was 61%, including 4/38 (10%) complete responses. Median time to progression and median overall survival (OS) were 5.8 and 14.2months, respectively. Median TTP and OS were 9.6 and 16.5months when GP was used in the adjuvant setting and 4.4 and 5.7months when GP was used in the metastatic setting. Grade 3–4 toxicities were observed in 31 patients (69%), including four sepsis-related deaths.Conclusion: aMVAC exerts clinical activity after previous treatment with GP, especially when GP was used in the adjuvant setting. aMVAC should however be administered with caution due to toxicity.

Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: Results from a randomised controlled trial

2012-05-01

Abstract: Aim: To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety.Methods: Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs.Results: The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107min, and median length of hospital stay was 2 and 5days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006).Conclusions: Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.

Previous extensive sun exposure and subsequent vitamin D production in patients with basal cell carcinoma of the skin, has no protective effect on internal cancers

2011-07-26

Abstract: Background: It has been suggested that sunlight through production of vitamin D might have a protective effect on a number of internal cancers. Consequently, in spite of the well known skin cancer risks, some researchers advocate more exposure to ultraviolet radiation, supported by the solarium industry. We estimated the risk of internal cancer before the patient contracted a basal cell carcinoma (BCC) of the skin, the most common cancer in white populations and strongly associated with extensive sun exposure.Methods: A nested case control study was undertaken in the whole Swedish population. 115,016 patients with BCC and 987,893 controls were linked to population based registers.Findings: The cases had an increased risk of getting another form of cancer before the BCC diagnosis: odds ratio (OR)=1.84; 95% confidence interval (CI) 1.81–1.86. This risk was mainly due to skin cancer: OR=4.95; 95% CI 4.81–5.09 but also non-skin cancer risk was elevated: OR=1.37; 95% CI 1.35–1.39. We adjusted the estimates for age, level of income, occupational status in national censuses, place of living and sex, where appropriate. Of the cancers specifically suggested to be related to vitamin D status: colon, prostate, breast, and ovary cancer, all had slightly increased ORs whilst for pancreatic and gastric cancer no increased OR was found.Interpretation: Patients with BCC, a proxy for extensive sun exposure, run an increased risk of other forms of cancer prior to the diagnosis of BCC. The findings in this study contradict that vitamin D production through extensive sun exposure has any protective effect on internal cancer but emphasise the increased risk for skin cancer.

Adrenal function in adult long-term survivors of nephroblastoma and neuroblastoma

2012-04-18

Abstract: Background: Adrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy.Objective: To assess adrenal function and its metabolic effects in survivors after adrenalectomy.Methods: In this cross-sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1μg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t=30) and 60min. Homoeostatic Model Assessment (HOMA) was calculated.Results: Adrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503nmol/l) (N=46) than in survivors with both adrenals intact (mean 393nmol/l, P=0.002) (N=52), and than in controls (mean 399nmol/l, P=0.013) (N=49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P<0.001), LDL-C (P=0.004), apolipoprotein-B (P<0.001) and HOMA (P=0.008).Conclusions: No adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma.

Descriptive epidemiology of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe

2011-11-28

Abstract: This work provides descriptive epidemiological data of malignant mucosal and uveal melanomas and adnexal skin carcinomas in Europe as defined as in the RARECARE project. We analysed 8669 incident cases registered in the period 1995–2002 by 76 population-based cancer registries (CRs), and followed up for vital status to 31st December 2003. Age-standardised incidence to the European standard population was obtained restricting the analysis to 8416 cancer cases collected by 64 not specialised CRs or with information available only for some anatomical sites. Period survival rates at 2000–2002 were estimated on 45 CRs data. Twenty-two CRs which covered the period 1988–2002 were analysed to obtain the 15-year prevalence (1st January 2003 as reference date). Complete prevalence was calculated by using the completeness index method which estimates surviving cases diagnosed prior to 1988 (‘unobserved’ prevalence). The expected number of new cases per year and of prevalent cases in Europe was then obtained multiplying the crude incidence and complete prevalence rates to the European population at 2008. We estimated 5204 new cases per year (10.5per million) to occur in Europe, of which 48.7% were melanomas of uvea, 24.8% melanomas of mucosa and 26.5% adnexal carcinomas of the skin. Five-year relative survival was 40.6% and 68.9% for mucosal and uveal melanomas, respectively. Adnexal skin carcinomas showed a good prognosis with a survival of 87.7% 5years after diagnosis. Northern Europe, United Kingdom (UK) and Ireland showed the highest 5-year survival rate for uveal melanomas (72.6% and 73.4%), while Southern Europe showed the lowest rate (63.7%). More than 50,000 persons with a past diagnosis of one of these rare cancers were estimated to be alive at 2008 in Europe, most of them (58.8%, n=29,676) being patients with uveal melanoma. Due to the good prognosis and high incidence of uveal melanomas, these malignancies are highly represented among the long-term survivors of the studied rare cancer types. Therefore, maximising quality of life is particularly important in treatment of uveal melanoma. As regards mucosal melanomas, the centralisation of treatment to a select number of specialist centres as well as the establishment of expert pathology panels should be promoted. The geographical differences in incidence and survival should be further investigated analysing the centre of treatment, the stage at diagnosis and the treatment.

New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials

2012-03-30

Abstract: Background: Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).Methods: Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient’s age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.Results: Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.Conclusions: This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Characteristics and outcome of patients with ganglioneuroblastoma, nodular subtype: A report from the INRG project

2011-12-05

Abstract: Aim: Describe characteristics and outcome of INRG patients with ganglioneuroblastoma, nodular subtype (GNBn).Patients and methods: Amongst 4071 patients in the INRG database with known INPC histological category, 232 patients with GNBn were identified. Patients were categorised by clinical, pathological and genetic characteristic. For event-free survival (EFS) and overall survival (OS), Kaplan–Meier curves and lifetables were generated, and the outcome of subgroups was compared using log rank test.Results: Patients with GNBn were older (83% >18 months), a higher proportion had unfavourable INPC pathology (83%), and rarely had MYCN gene amplified tumours (2%). Otherwise, the distribution of clinical and biological risk factors including stage, ferritin, initial treatment, grade of NB differentiation, MKI, 11q, 1p, and 17q were similar between patients with GNBn and the overall INRG cohort. EFS and OS were 54%±5% and 68%±5%, respectively. A cohort with superior outcome was identified: OS for GNBn patients younger than 18 months was 95%±5% (n=39) and for GNBn patients with stage 1, 2, 3, 4s was 95%±3% (n=125). Conversely, a poor outcome sub-group could also be identified: OS for stage 4 was 35%±7% (n=107).Conclusions: Patients with GNBn tumours are rare and have a very heterogeneous outcome. Except for LDH and MKI, the factors prognostic in the overall NB cohort are also prognostic in patients with GNBn. Similar to the overall NB cohort, patients with GNBn older than 18 months of age, with stage 4 disease represent a high-risk sub-group and should be considered for aggressive treatment upfront.

Predictors of prescription errors involving anticancer chemotherapy agents

2012-01-30

Abstract: Aim: The majority of medication errors that harm patients relate to the prescribing process. Our study aimed to identify the predictors of prescription errors involving anticancer chemotherapy agents.Methods: All consecutive antineoplastic prescriptions from June 2006 to May 2008 were analysed, with medication errors being captured. Potential risk factors for medication prescribing errors were defined in relation to the patient, chemotherapy regimen and hospital organisation. The relationship between these risk factors and observed medication errors or dose medication errors was assessed by univariate and multivariate logistic-regression analyses.Results: Among the 17,150 chemotherapy prescriptions, 540 contained at least one error (3.15%). The following independent predictors of risk of medication errors were identified: patients with a body surface area >2m2 (odds ratio (OR): 1.3, 95% confidence interval (CI) 1.01–1.67, p=0.04), protocols with more than three drugs (OR: 1.91, 95%CI 1.59–2.31, p<0.001), protocols involving carboplatin (OR: 2.33, 95%CI 1.85–2.95, p<0.001), protocols requiring at least one modification by the physician (OR: 1.32, 95%CI 1.09–1.61, p=0.005), inpatient care (OR: 1.58, 95%CI 1.28–1.93, p<0.001) and prescriptions by a resident physician (OR: 1.83, 95%CI 1.50–2.22, p<0.001). The risk of medication dose prescribing errors was significantly associated with three independent factors: protocols involving carboplatin (OR: 4.47, 95%CI 3.45–5.79, p<0.001), protocols with more than three drugs (OR: 2.4, 95%CI 1.92–3.00, p<0.001) and protocols requiring at least one modification (OR: 1.33, 95%CI 1.04–1.69, p=0.02).Conclusion: In this epidemiologic study, the independent risk factors identified should be targeted for preventive measures in order to improve anticancer agent prescriptions and reduce the risk of medication errors.

Do discordant cancers share familial susceptibility?

Kari Hemminki, Jan Sundquist, Andreas Brandt — 2011-10-28

Abstract: Aims: Cancer syndromes manifest at many sites albeit with variable penetrance. Genome-wide association (GWA) studies have identified susceptibility loci shared by many types of cancer. Yet, a population level search for shared susceptibility between discordant cancers has been hampered because of lacking population sizes.Methods: Over 1.1million patients in the nation-wide Swedish Family-Cancer Database were analysed for discordant familial cancers covering 33 sites. Standardised incidence ratios (SIRs) were calculated for patients whose family members had a defined cancer compared to those whose family members did not have that cancer. Three independent tests for each pair of cancer sites were done using different family relationships.Results: Lung cancer showed 13 significant discordant associations but most of them were with sites for which smoking is a risk factor. An exception was the clustering of lung cancer and endocrine cancers. Four discordant associations reached a minimal significance level of 5×10–6: colorectum–endometrium, breast–ovary, breast–prostate and melanoma–squamous cell carcinoma of the skin. The association of melanoma and nervous system cancer reached a minimal significance of 10−4. Discarding lung cancer, all other associations were based on a single test whereby they were liable to be chance associations.Conclusions: This study showed the extraordinary requirements for statistical power in study of multiple cancer sites. In addition to the smoking related sites, associations between breast and prostate cancers, melanoma and nervous system tumours and lung and endocrine tumours found strong statistical support. Within the present sample size limits, we found no evidence of an overall susceptibility to cancer.

Adenoviral vector expressing short hairpin RNA targeting Wnt2B has an effective antitumour activity against Wnt2B2-overexpressing tumours

2011-06-06

Abstract: Background: The Wnt family encodes multi-functional signalling glycoproteins regulating various normal and pathological processes including tumourigenesis. Wnt2B overexpression is thought to affect tumour progression through the activation of the canonical Wnt pathway.Method: Experimental studies were conducted using a Wnt2B-inhibiting vector to establish gene therapy against Wnt2B2-overexpressing tumours. A replication-deficient recombinant adenoviral vector expressing short hairpin RNA targeting Wnt2B (Ad-shWnt2B) was constructed. Three Wnt2B2-overexpressing human tumour cells, including A549 cells, Hela cells and PANC1 cells, were used. Thereafter, cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Next, a human tumour xenograft model in nude mice was prepared by subcutaneously implanting tumours derived from A549 cells. Ad-shWnt2B was administered via intratumoural injection every 4days.Results: First, immunohistochemical studies revealed that high levels of Wnt2B expression appeared in proliferative normal tissues and many human tumour tissues. Furthermore, the Wnt2B2 gene expression was associated with c-Myc and survivin expressions in human lung cancer. Transduction with Ad-shWnt2B effectively downregulated the Wnt2B2 expression in all the three Wnt2B2-overexpressing tumour cells (p<0.0001). The transduction with Ad-shWnt2B significantly reduced the percentage of viable cells in all the Wnt2B2-overexpressing tumour cells (p<0.005). In addition, transduction with Ad-shWnt2B significantly downregulated c-Myc and survivin in A549 cells (p<0.005). Furthermore, the treatment with Ad-shWnt2B exerted a significant antitumour effect against the Wnt2B2-overexpressing A549 xenografts by inducing apoptosis (p<0.01).Conclusions: Cancer gene therapy using an adenoviral vector expressing short hairpin RNA (shRNA) against Wnt2B was, therefore, found to have a strong antitumour effect against Wnt2B2-overexpressing tumours.

Over-expression of SERPINB3 in hepatoblastoma: A possible insight into the genesis of this tumour?

2011-07-07

Abstract: Background: The serpin SERPINB3 (SB3) found over-expressed in human hepatocellular carcinoma and in regenerating liver in mice has been shown to induce apoptosis resistance, epithelial-to-mesenchymal transition and increasing cellular invasion. It has also been hypothesised that SB3 may provide a pro-proliferative stimulus for liver cells in vivo. No information is available on SB3 in hepatoblastoma (HB). Aims of the study were to analyse SB3 expression in HB specimens and to investigate its possible correlation with Myc expression and tumour extension at diagnosis as evaluated by the pre-treatment extent of disease evaluation system (PRETEXT).Methods: Frozen tumour specimens from 42 children with HB were analysed for SB3 and Myc expression by real-time PCR. SB3 localisation in tumour specimens was assessed by immunohistochemistry.Results: At transcription level SB3 was positive in 79% of the cases. By immunohistochemistry, SB3 expression was found mainly in the embryonic, blastemal, small cell undifferentiated (SCUD) components of HB, while it was not detectable in normal hepatocytes. High SB3 reactivity was also detected in neoplastic cell clusters of portal vein tumour thrombosis. A direct correlation was observed between SB3 gene expression, the up-regulation of Myc (r=0.598, p<0.0001) and tumour extension (PRETEXT III/IV versus I/II, p=0.013).Conclusions: SB3 is over-expressed in HB and its expression is positively correlated with Myc expression and high tumour stage. The role of SB3 in the genesis of HB and in defining the risk profile of children affected by this tumour is hypothesised.

Yes-associated protein promotes tumour development in luminal epithelial derived breast cancer

Xiaodan Wang, Lili Su, Qishui Ou — 2011-11-07

Abstract: Yes-associated protein (YAP) is inactivated by the tumour suppressing Hippo pathway. The YAP gene is amplified in human liver cancer, and promotes tumour growth. However, there are contrasting reports about its function in breast cancer. Studies have demonstrated both oncogenic or tumour suppressor functions. Our study aims to clarify the role of YAP in breast cancer. We investigated the expression of YAP in 69 cases of human breast cancer tissue by immunohistochemistry (IHC). The role of YAP on cell growth in vitro and tumourigenesis in vivo were evaluated. We found that YAP was expressed in 75.4% (52/69) of breast cancer samples; amongst these cases YAP was overexpressed in 29% (20/69). There was no YAP expression in the remainder (17/69) cases. Breast cancer cell lines in which YAP was either overexpressed or depleted confirmed that YAP markedly promotes cell proliferation. This was confirmed in vivo: overexpression of YAP enhanced tumour formation and growth, whereas downregulation of YAP decreased the tumour formation and growth. Our results suggest that YAP acts as an oncogene in a subtype of breast cancer.

The differential impact of microsatellite instability as a marker of prognosis and tumour response between colon cancer and rectal cancer

2011-11-09

Abstract: Background: Microsatellite instability (MSI) is a distinct molecular phenotype of colorectal cancer related to prognosis and tumour response to 5-fluorouracil (5-FU)-based chemotherapy. We investigated the differential impact of MSI between colon and rectal cancers as a marker of prognosis and chemotherapeutic response.Methods: PCR-based MSI assay was performed on 1125 patients. Six hundred and sixty patients (58.7%) had colon cancer and 465 patients (41.3%) had rectal cancer.Results: Among 1125 patients, 106 (9.4%) had high-frequency MSI (MSI-H) tumours. MSI-H colon cancers (13%) had distinct phenotypes including young age at diagnosis, family history of colorectal cancer, early Tumor, Node, Metastasis (TNM) stage, proximal location, poor differentiation, and high level of baseline carcinoembryonic antigen (CEA), while MSI-H rectal cancers (4.3%) showed similar clinicopathological characteristics to MSS/MSI-L tumours except for family history of colorectal cancer. MSI-H tumours were strongly correlated with longer disease free survival (DFS) (P=0.005) and overall survival (OS) (P=0.009) than MSS/MSI-L tumours in colon cancer, while these positive correlations were not observed in rectal cancers. The patients with MSS/MSI-L tumours receiving 5-FU-based chemotherapy showed good prognosis (P=0.013), but this positive association was not observed in MSI-H (P=0.104).Conclusion: These results support the use of MSI status as a marker of prognosis and response to 5-FU-based chemotherapy in patients with colon cancers. Further study is mandatory to evaluate the precise role of MSI in patients with rectal cancers and the effect of 5-FU-based chemotherapy in MSI-H tumours.

Relationship between 18F-FDG uptake on positron emission tomography and molecular biology in malignant pleural mesothelioma

2012-02-13

Abstract: Background: The usefulness of 2-[18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET) can help for predicting the therapeutic response and outcome in malignant pleural mesothelioma (MPM). However, no satisfactory biologic explanation exists for this phenomenon. The aim of this study is to investigate the underlying biologic mechanisms of 18F-FDG uptake.Methods: Twenty-one patients with MPM who underwent 18F-FDG PET before treatment were included in this study. Tumour sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1α); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); cell proliferation (Ki-67 labelling index); Akt/mTOR signalling pathway (PTEN, p-Akt, p-mTOR and p-S6K); cell cycle control (p53 and pRb); apoptosis marker (bcl-2). We also conducted an in vitro study of 18F-FDG uptake in mesothelioma cell lines.Results: 18F-FDG uptake was significantly correlated with Glut1 (p<0.0001), HIF-1α (p=0.006), hexokinase I (p=0.0002), VEGF (p=0.0013), CD34 (p=0.0001), Ki-67(p=0.0047), mTOR (p=0.00478) and p53 (p=0.0004). High uptake of 18F-FDG was significantly associated with poor outcome in MPM. Our in vitro study showed that upregulation of Glut1 and HIF-1α was closely related with 18F-FDG uptake into mesothelioma cell, and mTOR inhibitor induced a decrease in Glut1 expression and 18F-FDG uptake.Conclusion: The amount of 18F-FDG uptake in MPM is determined by the presence of glucose metabolism, phosphorylation of glucose, hypoxia, angiogenesis, cell proliferation (Ki-67), cell cycle regulator, and mTOR signalling pathway.

Erratum to: “EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma” [Eur J Cancer 2012;48:599–641]

2012-04-09

was incomplete for BCLC stage A, and it has been corrected as per below. Patients at BCLC stage A and single tumours can be evaluated for surgical resection.