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1.
Background:
We performed a cost-effectiveness analysis of trastuzumab plus chemotherapy for human epidermal growth factor type-2 (HER2)-positive advanced gastric cancer (GC) based on data obtained from the Trastuzumab for Gastric Cancer (ToGA) trial from a Japanese perspective.Methods:
The following Japanese and Korean populations of the ToGA trial were analysed to obtain mean overall and progression-free survival times: (1) all HER2-positive populations, (2) immunohistochemical (IHC) 2+/fluorescence in situ hybridisation (FISH)+ or IHC 3+ populations, and (3) IHC 3+ only population. The effect of trastuzumab treatment on mean survival time was estimated by fitting a Weibull parametric function. Costs were calculated from the perspective of health-care payer. Neither costs nor outcomes were discounted because of short life expectancy.Results:
In the base-case analysis, the incremental cost-effectiveness ratio was (1) JPY 12 million (€110 000) per quality-adjusted life year (QALY) gained and JPY 8.9 million (€81 000) per life-year gained (LYG) for all HER2-positive populations, (2) JPY 9.1 million (€83 000) per QALY gained and JPY 6.6 million (€60 000) per LYG for the IHC 2+/FISH+ or IHC 3+ population, and (3) JPY 6.1 million (€55 000) per QALY gained and JPY 4.3 million (€39 000) per LYG for the IHC 3+ population.Conclusion:
Trastuzumab treatment for IHC 3+ populations is cost effective. Our analysis can find a cost-effective subgroup when advanced GC is treated by trastuzumab. 相似文献2.
Barton S Zabaglo L A'Hern R Turner N Ferguson T O'Neill S Hills M Smith I Dowsett M 《British journal of cancer》2012,106(11):1760-1765
Background:
The immunohistochemical (IHC) 4+C score is a cost-effective prognostic tool that uses clinicopathologic factors and four standard IHC assays: oestrogen receptor (ER), PR, HER2 and Ki67. We assessed its utility in personalising breast cancer treatment in a clinical practice setting, through comparison with Adjuvant! Online (AoL) and the Nottingham Prognostic Index (NPI).Methods:
We prospectively gathered clinicopathologic data for postmenopausal patients with hormone receptor-positive, HER2-negative, N0-3 resected early breast cancer treated consecutively at our institution. We retrospectively calculated and compared prognostic scores. The primary endpoint was the proportion of patients reclassified from AoL-defined intermediate-risk by application of the IHC4+C score.Results:
The median age of the 101 patients included in the analysis was 63. In all, 15 of the 26 patients classified as intermediate-risk by AoL were reallocated to a low-risk group by application of the IHC4+C score and no patient was reclassified as high-risk group. Of the 59 patients classified as intermediate-risk group by the NPI, 24 were reallocated to a low-risk group and 13 to a high-risk group.Conclusion:
IHC4+C reclassifies more than half of the patients stratified as being in intermediate-risk group by the AoL and NPI. The use of IHC4+C may substantially improve decision-making on adjuvant chemotherapy. 相似文献3.
Harder J Ihorst G Heinemann V Hofheinz R Moehler M Buechler P Kloeppel G Röcken C Bitzer M Boeck S Endlicher E Reinacher-Schick A Schmoor C Geissler M 《British journal of cancer》2012,106(6):1033-1038
Background:
New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression.Methods:
Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression.Results:
Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months.Conclusion:
This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer. 相似文献4.
R E Board G Ellison M C M Orr K R Kemsley G McWalter L Y Blockley S P Dearden C Morris M Ranson M V Cantarini C Dive A Hughes 《British journal of cancer》2009,101(10):1724-1730
Background:
This study investigated the potential clinical utility of circulating free DNA (cfDNA) as a source of BRAF mutation detection in patients enrolled into a phase II study of AZD6244, a specific MEK1/2 inhibitor, in patients with advanced melanoma.Methods:
BRAF mutations were detected using Amplification Refractory Mutation System allele-specific PCR. BRAF mutation status was assessed in serum-derived cfDNA from 126 patients enrolled into the study and from 94 matched tumour samples.Results:
Of 94 tumour samples, 45 (47.9%) were found to be BRAF mutation positive (BRAF+). Serum-derived cfDNA was BRAF+ in 33 of 126 (26.2%) samples, including in five samples for which tumour data were unavailable. Of BRAF+ tumours, 25 of 45 (55.6%) were BRAF+ in cfDNA. In three cases in which the tumour was negative, cfDNA was BRAF+. Progression-free survival (PFS) of patients with BRAF+ tumour and cfDNA was not significantly different compared with tumour BRAF+ but cfDNA BRAF-negative patients, indicating that cfDNA BRAF detection is not associated with poorer prognosis on PFS in stage III/IV advanced melanoma.Conclusions:
These data demonstrate the feasibility of BRAF mutation detection in cfDNA of patients with advanced melanoma. Future studies should aim to incorporate BRAF mutation testing in cfDNA to further validate this biomarker for patient selection. 相似文献5.
D Loussouarn L Campion F Leclair M Campone C Charbonnel G Ricolleau W Gouraud R Bataille P J��z��quel 《British journal of cancer》2009,101(1):166-173
Background:
We recently identified and validated UBE2C RNA as a prognostic marker in 252 node-positive (N+) breast cancers by means of a microarray study. The aim of this study was to validate UBE2C protein as a prognostic marker in N+ breast cancer by immunohistochemistry (IHC).Methods:
To this end, 92 paraffin-embedded blocks were used. The impact of UBE2C IHC value on metastasis-free survival (MFS) and overall survival (OS) was evaluated and compared with Ki-67 and Nottingham prognostic index (NPI) performances.Results:
In accordance with genomic data, UBE2C IHC had a significant impact both on MFS and OS (hazard ratio=6.79 – P=0.002; hazard ratio=7.14 – P=0.009, respectively). Akaike information criterion proved that the prognostic power of UBE2C IHC was stronger than that of Ki-67 (and close to that of NPI). Furthermore, multivariate analyses with NPI showed that, contrary to Ki-67 IHC, UBE2C IHC remained an independent factor, both for MFS (adjusted P=0.02) and OS (adjusted P=0.04).Conclusion:
We confirmed that UBE2C protein measured by IHC could be used as a prognostic marker in N+ breast cancer. The potential predictive interest of UBE2C as a marker of proteasome activity needs further investigations. 相似文献6.
Background:
Only 40–70% of metastatic colorectal cancers (mCRCs) with wild-type (WT) KRAS oncogene respond to anti-epidermal growth factor receptor (anti-EGFR) antibody treatment. EGFR amplification has been suggested as an additional marker to predict the response. However, improved methods for bringing the EGFR analysis into routine laboratory are needed.Methods:
The material consisted of 80 patients with mCRC, 54 of them receiving anti-EGFR therapy. EGFR gene copy number (GCN) was analysed by automated silver in situ hybridisation (SISH). Immunohistochemical EGFR protein analysis was used to guide SISH assessment.Results:
Clinical benefit was seen in 73% of high (⩾4.0) EGFR GCN patients, in comparison with 59% of KRAS WT patients. Only 20% of low EGFR GCN patients responded to therapy. A high EGFR GCN number associated with longer progression-free survival (P<0.0001) and overall survival (P=0.004). Together with KRAS analysis, EGFR GCN identified the responsive patients to anti-EGFR therapy more accurately than either test alone. The clinical benefit rate of KRAS WT/high EGFR GCN tumours was 82%.Conclusion:
Our results show that automated EGFR SISH, in combination with KRAS mutation analysis, can be a useful and easily applicable technique in routine diagnostic practise for selecting patients for anti-EGFR therapy. 相似文献7.
Page K Hava N Ward B Brown J Guttery DS Ruangpratheep C Blighe K Sharma A Walker RA Coombes RC Shaw JA 《British journal of cancer》2011,104(8):1342-1348
Background:
Human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in 20–25% of breast cancers. This study investigated circulating free DNA (cfDNA) for detection of HER2 gene amplification in patients with breast cancer.Methods:
Circulating free DNA was extracted from plasma of unselected patients with primary breast cancer (22 before surgery and 68 following treatment), 30 metastatic patients and 98 female controls using the QIAamp Blood DNA Mini Kit (Qiagen). The ratio of HER2 to an unamplified reference gene (contactin-associated protein 1 (CNTNAP1)) was measured in cfDNA samples by quantitative PCR (qPCR) using SK-BR-3 cell line DNA as a positive control.Results:
We validated the qPCR assay with DNA extracted from 23 HER2 3+ and 40 HER2-negative tumour tissue samples; the results agreed for 60 of 63 (95.2%) tumours. Amplification was detected in cfDNA for 8 of 68 patients following primary breast cancer treatment and 5 of 30 metastatic patients, but was undetected in 22 patients with primary breast cancer and 98 healthy female controls. Of the patients with amplification in cfDNA, 10 had HER2 3+ tumour status by immunohistochemistry.Conclusions:
The results demonstrate for the first time the existence of amplified HER2 in cfDNA in the follow-up of breast cancer patients who are otherwise disease free. This approach could potentially provide a marker in patients with HER2-positive breast cancer. 相似文献8.
M Murohashi K Hinohara M Kuroda T Isagawa S Tsuji S Kobayashi K Umezawa A Tojo H Aburatani N Gotoh 《British journal of cancer》2010,102(1):206-212
Background:
Tumour-initiating cells (TICs) or cancer stem cells can exist as a small population in malignant tissues. The signalling pathways activated in TICs that contribute to tumourigenesis are not fully understood.Methods:
Several breast cancer cell lines were sorted with CD24 and CD44, known markers for enrichment of breast cancer TICs. Tumourigenesis was analysed using sorted cells and total RNA was subjected to gene expression profiling and gene set enrichment analysis (GSEA).Results:
We showed that several breast cancer cell lines have a small population of CD24−/low/CD44+ cells in which TICs may be enriched, and confirmed the properties of TICs in a xenograft model. GSEA revealed that CD24−/low/CD44+ cell populations are enriched for genes involved in transforming growth factor-β, tumour necrosis factor, and interferon response pathways. Moreover, we found the presence of nuclear factor-κB (NF-κB) activity in CD24−/low/CD44+ cells, which was previously unrecognised. In addition, NF-κB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) prevented tumourigenesis of CD24−/low/CD44+ cells in vivo.Conclusion:
Our findings suggest that signalling pathways identified using GSEA help to identify molecular targets and biomarkers for TIC-like cells. 相似文献9.
The role of zinc in the anti-tumour and anti-cachectic activity of D-myo-inositol 1,2,6-triphosphate
Background:
D-myo-inositol-1,2,6-triphosphate (α-trinositol, AT) is a polyanionic molecule capable of chelating divalent metal ions with anti-tumour and anti-cachectic activity in a murine model.Methods:
To investigate the role of zinc in this process, mice bearing cachexia-inducing MAC16 tumour were treated with AT, with or without concomitant administration of ZnSO4.Results:
At a dose of 40 mg kg−1, AT effectively attenuated both weight loss and growth of the MAC16 tumour, and both effects were attenuated by co-administration of Zn2+. The concentration of zinc in gastrocnemius muscle increased with increasing weight loss, whereas administration of AT decreased the levels of zinc in plasma, skeletal muscle and tumour, which were restored back to control values after administration of ZnSO4.Conclusion:
These results suggest that zinc is important in both tumour growth and cachexia in this animal model. 相似文献10.
Abnet CC Zheng W Ye W Kamangar F Ji BT Persson C Yang G Li HL Rothman N Shu XO Gao YT Chow WH 《British journal of cancer》2011,104(9):1511-1516
Background:
Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case–control study nested in a prospective cohort.Methods:
We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.Results:
Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml–1 (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86–9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml–1 (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85–7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.Conclusion:
Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer. 相似文献11.
O Shinto M Yashiro H Kawajiri K Shimizu T Shimizu A Miwa K Hirakawa 《British journal of cancer》2010,102(5):844-851
Background:
Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-β (TGF-β) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-β receptor (TβR) phosphorylation inhibitor on the invasiveness of gastric cancer cells.Methods:
Four gastric cancer cell lines, including two scirrhous-type cell lines and two non-scirrhous-type cell lines, were used. A TβR type I (TβR-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of TβR-I. We investigated the expression levels of TβR and phospho-Smad2, and the effects of TGF-β in the presence or absence of Ki26894 on Smad2 phosphorylation, invasion, migration, epithelial-to-mesenchymal transition (EMT), Ras homologue gene family member A (RhoA), ZO-2, myosin, and E-cadherin expression of gastric cancer cells.Results:
TβR-I, TβR-II, and phospho-Smad2 expressions were found in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. Ki26894 decreased Smad2 phosphorylation induced by TGF-β1 in scirrhous gastric cancer cells. Transforming growth factor-β1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-β1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-β1 decreased ZO-2 and E-cadherin expression in scirrhous gastric cancer cells. Interestingly, Ki26894 inhibited these characteristics in scirrhous gastric cancer cells. In contrast, non-scirrhous gastric cancer cells were not affected by TGF-β1 or Ki26894 treatment.Conclusion:
A TβR-I kinase inhibitor decreases the invasiveness and EMT of scirrhous gastric cancer cells. Ki26894 is therefore considered to be a promising therapeutic compound for the metastasis of scirrhous gastric carcinoma. 相似文献12.
C Kameda M Nakamura H Tanaka A Yamasaki M Kubo M Tanaka H Onishi M Katano 《British journal of cancer》2010,102(4):738-747
Background:
Oestrogen receptor-alpha (ERα) is highly expressed in diffuse-type gastric cancer and oestrogen increases the proliferation of ERα-positive gastric cancer. However, a detailed mechanism by which oestrogen increases the proliferation of these cells is still unclear.Methods:
We used 17-β-oestradiol (E2) as a stimulator against the ERα pathway. Pure anti-oestrogen drug ICI 182 780 (ICI) and small interfering RNA against ERα (ERα siRNA) were used as inhibitors. Cyclopamine (Cyc) was used as the hedgehog (Hh) pathway inhibitor. Two human ERα-positive gastric cancer cells were used as target cells. Effects of the stimulator and inhibitor on E2-induced cell proliferation were also examined.Results:
In ERα-positive cells, E2 increased not only cell proliferation but also one of the ligands of the Hh pathway, Shh expression. 17-β-Oestradiol-induced cell proliferation was suppressed by ICI, ERα siRNA or Cyc. The increased expression of Shh induced by E2 was suppressed by ICI and ERα siRNA but not by Cyc. Furthermore, recombinant Shh activated the Hh pathway and increased cell proliferation, whereas anti-Shh antibody suppressed E2-induced cell proliferation. When a relationship between ERα and Shh expressions was analysed using surgically resected gastric cancer specimens, a positive correlation was found, suggesting a linkage between the ERα and Hh pathways.Conclusion:
Our data indicate that activation of the ERα pathway promotes cell proliferation by activating the Hh pathway in a ligand-dependent manner through Shh induction of ERα-positive gastric cancer. 相似文献13.
Fuyuhiro Y Yashiro M Noda S Kashiwagi S Matsuoka J Doi Y Kato Y Hasegawa T Sawada T Hirakawa K 《British journal of cancer》2011,105(7):996-1001
Background:
Myofibroblasts in the cancer microenvironment have recently been implicated in tumour growth and metastasis of gastric cancer. However, the mechanisms responsible for the regulation of myofibroblasts in cancer-associated fibroblasts (CAFs) remain unclear. This study was performed to clarify the mechanisms for regulation of myofibroblasts in gastric cancer microenvironment.Methods:
Two CAFs (CaF-29 and CaF-33) from the tumoural gastric wall and a normal fibroblast (NF-29) from the nontumoural gastric wall, 4 human gastric cancer cell lines from scirrhous gastric cancer (OCUM-2MD3 and OCUM-12), and non-scirrhous gastric cancer (MKN-45 and MKN-74) were used. Immunofluorescence microscopy by triple-immunofluorescence labelling (α-SMA, vimentin, and DAPI) was performed to determine the presence of α-SMA-positive myofibroblasts. Real-time RT–PCR was performed to examine α-SMA mRNA expression.Results:
Immunofluorescence microscopy showed that the frequency of myofibroblasts in CaF-29 was greater than that in NF-29. The number of myofibroblasts in gastric fibroblasts gradually decreased with serial passages. Transforming growth factor-β (TGF-β) significantly increased the α-SMA expression level of CAFs. Conditioned medium from OCUM-2MD3 or OCUM-12 cells upregulated the α-SMA expression level of CAFs, but that from MKN-45 or MKN-74 cells did not. The α-SMA upregulation effect of conditioned medium from OCUM-2MD3 or OCUM-12 cells was significantly decreased by an anti-TGF-β antibody or Smad2 siRNA.Conclusion:
Transforming growth factor-β from scirrhous gastric carcinoma cells upregulates the number of myofibroblasts in CAFs. 相似文献14.
Background:
MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification.Methods:
With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays.Results:
We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling.Conclusion:
Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification. 相似文献15.
Background:
The evidence on the relationship between coffee intake and cancer of the oral cavity and oesophagus is conflicting and few follow-up studies have been done.Methods:
A total of 389 624 men and women 40–45 years who participated in a national survey programme were followed with respect to cancer for an average of 14.4 years by linkage to the Cancer Registry of Norway. Coffee consumption at baseline was reported as a categorical variable (0 or <1 cup, 1–4, 5–8, 9+ cups per day).Results
Altogether 450 squamous oral or oesophageal cancers were registered during follow-up. The adjusted hazard ratios with 1–4 cups per day as reference were 1.01 (95% confidence interval: 0.70, 1.47), 1.16 (0.93, 1.45) and 0.96 (0.71, 1.14) for 0 or <1 cup, 5–8 and 9+ cups per day, respectively. Stratification by sex, type of coffee, smoking status and dividing the end point into oral and oesophageal cancers gave heterogeneous and non-significant estimates.Conclusion:
This study does not support an inverse relationship between coffee intake and incidence of cancer in the mouth or oesophagus, but cannot exclude a weak inverse relationship. 相似文献16.
Deevi R Fatehullah A Jagan I Nagaraju M Bingham V Campbell FC 《British journal of cancer》2011,105(9):1313-1321
Background:
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) regulation of the Rho-like GTPase Cdc42 has a central role in epithelial polarised growth, but effects of this molecular network on apoptosis remain unclear.Methods:
To investigate the role of Cdc42 in PTEN-dependent cell death, we used flow cytometry, in vitro pull-down assays, poly(ADP ribose) polymerase (PARP) cleavage and other immunoblots in isogenic PTEN-expressing and -deficient colorectal cells (HCT116PTEN+/+, HCT116PTEN−/−, Caco2 and Caco2 ShPTEN cells) after transfection or treatment strategies.Results:
The PTEN knockout or suppression by short hairpin RNA or small interfering RNA (siRNA) inhibited Cdc42 activity, PARP cleavage and/or apoptosis in flow cytometry assays. Transfection of cells with wild-type or constitutively active Cdc42 enhanced PARP cleavage, whereas siRNA silencing of Cdc42 inhibited PARP cleavage and/or apoptosis. Pharmacological upregulation of PTEN by sodium butyrate (NaBt) treatment enhanced Cdc42 activity, PARP cleavage and apoptosis, whereas Cdc42 siRNA suppressed NaBt-induced PARP cleavage. Cdc42-dependent signals can suppress glycogen synthase kinase-β (GSK3β) activity. Pharmacological inhibition of GSK3β by lithium chloride treatment mimicked effects of Cdc42 in promotion of PARP cleavage and/or apoptosis.Conclusion:
Phosphatase and tensin homologue deleted on chromosome 10 may influence apoptosis in colorectal epithelium through Cdc42 signalling, thus providing a regulatory framework for both polarised growth and programmed cell death. 相似文献17.
T Boysen M Mohammadi M Melbye S Hamilton-Dutoit B Vainer A V Hansen J Wohlfahrt J Friborg 《British journal of cancer》2009,101(3):530-533
Background:
Approximately 10% of gastric carcinomas are associated with Epstein–Barr virus (EBV). The Inuit in Greenland have a high incidence of EBV-associated nasopharyngeal carcinoma.Methods:
We conducted a population-based case–control study comparing gastric carcinomas in Greenland and in Denmark.Results:
The prevalence rate of EBV-associated gastric carcinomas was 8.5% in both populations.Conclusion:
The findings of this study argue against a general susceptibility to EBV-associated carcinomas among the Inuit. 相似文献18.
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J Kantelinen M Kansikas M K Korhonen S Ollila K Heinimann R Kariola M Nystr?m 《British journal of cancer》2010,102(6):1068-1073