Abstract
Background. Adjuvant chemotherapy is established routine therapy for colon cancer (CC) patients with radically resected stage III and 'high-risk' stage II disease. The decision on ...recommending adjuvant chemotherapy, however, is based on data from older patient cohorts not reflecting improvements in pre-operative staging, surgery, and pathological examination. The aim is to review the current risk of recurrence in stage II and III patients and second, to estimate the relative importance of routinely assessed clinico-pathological variables.
Methods. The PubMed/MEDLINE and the Cochrane databases were systematically searched for randomized controlled studies and observational studies published after 1 January 2005 with patients included after January 1995 on prognosis in surgically treated stage II and III CC patients.
Results. Of 2596 studies identified, 37 met the inclusion criteria and 25 provided data for meta-analysis. The total patient sample size in the 25 studies reporting either disease-free (DFS) or recurrence-free survival was 15 559 in stage II and 18 425 in stage III. Five-year DFS for stage II patients operated without subsequent adjuvant chemotherapy was 81.4% 95% confidence interval (CI) 75.4-87.4; in studies with good/very good quality of reporting 82.7%, (95% CI 80.8-84.6). For stage II patients treated with adjuvant chemotherapy, the five-year DFS was 79.3% (95% CI 75.6-83.1). For stage III patients without chemotherapy, five-year DFS was 49.0% (95% CI 23.2-74.8) and for those treated with adjuvant chemotherapy, 63.6% (95% CI 59.3-67.9). The prognostic impact of commonly investigated clinico-pathological parameters, (pT-stage, pN-stage, differentiation, number of lymph nodes studied, MMR-status, and emergency surgery) were confirmed.
Conclusions. In this meta-analysis, studies with good quality of reporting show a five-year DFS of 82.7% for stage II CC without adjuvant chemotherapy, whereas the five-year DFS is 63.8% for stage III CC with adjuvant chemotherapy. Due to insufficient reporting on treatment quality the presented DFS is likely an under-estimation of what is achieved at high-quality centers today.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background/Aim: For patients with local gastrointestinal stromal tumor (GIST), risk stratification is used to assess the prognosis and identify patients to offer adjuvant treatment. For patients with ...advanced or metastatic GIST, no such risk stratification exists. This study aimed to investigate the prognostic value of 31 different plasma small extracellular vesicles' (SEVs) surface proteins in GIST patients. Materials and Methods: GIST patients from the two sarcoma centers in Denmark were included. Patients were divided into three groups; group 1: patients undergoing radical surgery; group 2: patients with local, locally advanced, or metastatic GIST; and group 3: patients without evidence of disease after radical surgery. Protein microarray technology was used for the analysis of plasma SEVs. The median plasma SEV marker level was used when comparing groups of patients. The primary endpoint was the progression of GIST. Iterative statistical modeling was used to identify a SEV marker profile/model with a prognostic value. Results: A total of 157 patients were included, with a median follow-up time of 2.05 years. In group 2, a high level of carcinoembryonic antigen (CEA) and a low level of glucose transporter 1 (GLUT-1) were found to be poor prognostic factors univariate analysis; GLUT-1: hazard ratio (HR)=0.47, 95% confidence interval (CI)=0.22-0.98; CEA: HR=2.12, 95%CI=1.02-4.44. Composing a model consisting of CEA and GLUT-1 adjusted for age at inclusion was found to have a prognostic value (HR=4.93, 95%CI=2.30-10.57, p<0.0001). Conclusion: Plasma SEVs in GIST showed that CEA and GLUT-1 might be of prognostic value. However, external validation is needed.
Background.
Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2‐deoxy‐2‐18Ffluoro‐d‐glucose positron‐emission tomography/computed tomography (PET/CT) ...and measurements of tissue inhibitor of metalloproteinases‐1 (TIMP‐1), carcinoembryonic antigen (CEA), and liberated domain I of urokinase plasminogen activator receptor (uPAR(I)) for early assessment of treatment response in mCC patients.
Methods.
Thirty‐three mCC patients scheduled for first‐line chemotherapy with capecitabine and oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria in Solid Tumors and European Organization for Research and Treatment of Cancer PET criteria. Plasma TIMP‐1, plasma uPAR(I), and serum CEA were determined.
Results.
Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80%, specificity of 69%, and odds ratio of 13.9 (95% confidence interval CI 1.9; 182). Early metabolically stable or progressive disease was associated with shorter progression‐free survival (hazard ratio HR = 3.2 CI 1.3; 7.8). Biomarker levels at early evaluation were associated with shorter OS (TIMP‐1 per unit increase on a log‐2‐transformed ng/mL scale: HR = 2.6 CI 1.4; 4.9; uPAR(I) per 25 fmol/mL increase: HR = 1.5 CI 1.1; 2.1).
Conclusion.
This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP‐1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP‐1, and uPAR(I) guided early treatment adaptation in mCC.
摘要
背景. 转移性结肠癌 (mCC) 的治疗选择日益增多。本文在 mCC 患者治疗反应的早期评估方面，前瞻性评价了 2‐脱氧‐2‐18F氟‐D‐葡萄糖正电子发射断层造影术/计算机断层扫描 (PET/CT) 系列应用和金属蛋白酶‐1 组织抑制剂 (TIMP‐1)、癌胚抗原 (CEA)、以及尿激酶型纤溶酶原激活物受体的自由域 (uPAR(I)) 的检测。
方法. 参与研究的有给与卡培他滨、奥沙利铂 (CAPOX) 和贝伐单抗一线化疗的33 名患者； 其中27 名在治疗前、治疗一个系列和四个系列后，采用 PET/CT 评估。根据实体瘤的疗效评价标准和欧洲癌症研究与治疗组织 PET 标准，分别单独进行形态学和代谢水平两方面的反应评估。测定血浆中 TIMP‐1 和 uPAR(I) 的浓度以及 CEA 血清水平。
结果. 根据一个疗程后的代谢反应，可以推测 CAPOX 和贝伐单抗在四个治疗系列后产生形态学反应的疗效作用，其灵敏度为 80%、特异性为 69% 、比值比为 13.9（95% 置信区间 CI 1.9; 182）。早期代谢稳定或疾病进展者的无进展存活期较短（风险比 HR = 3.2 CI 1.3; 7.8）。早期评价的生物标记物水平与较短的整体存活期 (OS) (ng/mL 量级 log2 对数转换后的 TIMP‐1 每单位增量：HR=2.6 CI 1.4; 4.9; uPAR(I) 每 25 fmol/mL 增量：HR = 1.5 CI 1.1; 2.1) 有关。
结论. 本单中心研究证实，在接受 CAPOX 与贝伐单抗治疗的 mCC 患者中，早期代谢性 PET 反应具有预测价值，TIMP‐1 的 uPAR(I) 具有预后价值。结果支持，检测 PET/CT、TIMP‐1 以及 uPAR (I) 对 mCC 患者的早期治疗适应有指导作用。The Oncologist 2014;19:1‐9
This monocentric study demonstrated predictive value of early metabolic positron‐emission tomography (PET) response and prognostic value of tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and liberated domain I of urokinase plasminogen activator receptor (uPAR(I)) levels in metastatic colon cancer (mCC) treated with capecitabine and oxaliplatin and bevacizumab. Results support investigation of PET/computed tomography, TIMP‐1, and uPAR(I) guided early treatment adaptation in mCC.
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653
Background: Positron emission tomography (PET) with the glucose analogue
18
F-fluorodeoxyglucose (FDG) is widely used in oncologic imaging. This study examines the molecular ...mechanism underlying the detection of colon cancer (CC) by FDG-PET. Methods: Pre-operative PET/CT scans and tissue samples from primary CC and surrounding normal mucosa were obtained from 42 patients. FDG uptake was quantified using maximal standardized uptake value (SUV
max
). The expression of ki67, glucose transporter 1 (GLUT-1), hexokinase 1 (HK1), hexokinase 2 (HK2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF1α) and carbonic anhydrase IX (CaIX) mRNA was examined by quantitative real time reverse transcriptase-polymerase chain reaction. Results: All primary tumours showed increased uptake of FDG. The mean SUV
max
was 15.0 (range 5.3 – 37.8). No correlation was found between tumour size and SUV
max
. Mean gene expression levels of GLUT1, HK2, ki67, HIF1α, VEGF and CaIX, but not HK1, were significantly higher in primary tumours than in surrounding normal colonic mucosa. Linear regressions pairing tumour SUV
max
with gene expression levels showed significant correlations between SUV
max
and HK2, ki67 and CaIX, respectively. Conclusions: These results confirm FDG PET/CT as a functional imaging method in CC, and that FDG accumulation reflects molecular events related to glycolysis, cell proliferation, hypoxia, but not angiogenesis.
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408
Background: Optimal management of colon cancer requires detailed assessment of extent of disease. Diagnostic accuracy of
18
F-fluorodeoxyglucose (FDG) positron emission tomography/ ...computed tomography (PET/CT) in primary colon cancer staging and for detection of recurrence was investigated. Methods: PET/CT for preoperative staging was performed on 66 prospectively included patients with primary colon cancer. Diagnostic accuracy for PET/CT and CT alone was analysed. Forty-two stage I-III colon cancer patients had PET/CT follow-up examinations every six months for two years. Serological levels of Tissue Inhibitor of Metalloproteinases (TIMP-1), Carcinoembryonic Antigen (CEA), and liberated domain I of urokinase Plasminogen Activator Receptor uPAR(I) and FDG-uptake related tumour gene expression were analysed. Results: Accuracy for T-, N- and M-staging by PET/CT were 82 % 95% Confidence Interval (CI) 70; 91, 66 % CI 51; 78 and 89 % CI 79; 96; for CT 77 % CI 64; 87, 60 % CI 46; 73 and 69 % CI 57; 80. Cumulative relapse incidences for stage I – III colon cancer at 6, 12, 18 and 24 months were 7.1 % CI 0; 14.9; 14.3 % CI 3.7; 24.9; 19.0 % CI 7.1; 30.9 and 21.4 % CI 9.0; 33.8. PET/CT diagnosed all relapses detected during the first two postoperative years. High preoperative TIMP-1 levels were associated with significant hazards towards both risk of recurrence and shorter overall survival. FDG-uptake in colon cancer showed significant correlation to hexokinase 2, the hypoxia marker carboanhydrase IX and the proliferation marker ki67. Conclusions: This study indicates PET/CT to be a valuable tool for staging and follow-up in colon cancer. TIMP-1 provided prognostic information potentially useful in selection of patients for intensive follow-up.
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614
Background: Treatment options for metastatic colon cancer (mCC) are widening. We prospectively evaluated serial 2-deoxy-2-18Ffluoro-D-glucose (FDG) positron emission tomography/ ...computed tomography (PET/CT) and measurements of tissue inhibitor of metalloproteinases type 1 (TIMP-1), carcinoembryonic antigen (CEA) and urokinase plasminogen activator receptor domain I uPAR(I) for early assessment of treatment response in mCC patients. Methods: Thirty-three mCC patients scheduled for first line chemotherapy with capecitabine, oxaliplatin (CAPOX) and bevacizumab participated; 27 were evaluated by PET/CT before treatment, after one and four treatment series. Morphological and metabolic response was independently assessed according to Response Evaluation Criteria In Solid Tumours (RECIST1.1) and EORTC PET criteria. Plasma TIMP-1, plasma uPAR(I) and serum CEA were determined. Results: Metabolic response after one treatment course predicted the ability of CAPOX and bevacizumab to induce morphological response after four treatment series with a sensitivity of 80 %, specificity of 69 % and an Odds Ratio of 13.9 CI 1.9; 182. Early metabolically stable or progressive disease was associated with shorter progression-free survival (PFS) (hazard ratio (HR) = 3.2 CI 1.3; 7.8). Biomarker levels at early evaluation were associated to shorter PFS (TIMP-1 per unit increase on a log-2 transformed ng/mL scale: HR = 2.23 CI 1.20; 4.14; uPAR(I) per 25 fmol/mL increase: HR = 1.36 CI 1.03; 1.79). Conclusions: This monocentric study demonstrated predictive value of early metabolic PET response and prognostic value of TIMP-1 and uPAR(I) levels in mCC treated with CAPOX and bevacizumab. Results support investigation of PET/CT, TIMP-1 and uPAR(I) guided early treatment adaptation in mCC.
: Serotonin (5‐HT) stimulates ion secretion in the gastrointestinal tract and the sensitivity for 5‐HT might be altered in dyspeptic patients infected with Helicobacter pylori. The purpose of the ...present study was to characterize the 5‐HT‐induced electrogenic ion transport in the duodenum of dyspeptic patients with or without Helicobacter pylori infection, and to determine the 5‐HT receptor subtypes functionally involved. Biopsies from the second part of duodenum were obtained from 43 dyspeptic patients during routine endoscopy. Biopsies were mounted in modified Ussing chambers with airsuction for measurements of short‐circuit current by a previously validated technique. Short‐circuit current was measured before and after application of graded cumulative doses of 5‐HT and a single dose of bumetanide (an inhibitor of chloride/bicarbonate transport), or one of the selective 5‐HT receptor antagonists: ketanserin, ondansetron, or SB‐204070 (1‐butyl‐4 piperidinmethyl‐8‐amino‐7‐chloro‐2,3‐dihydro‐1,4‐benzodioxin‐5‐carboxylate HCl). Histological examination was performed on duodenal biopsies. Helicobacter urease testing and histological examination determined Helicobacter pylori infection. 5‐HT induced a dose‐dependent and bumetanide‐sensitive short‐circuit current, which was independent of the presence of Helicobacter pylori infection. All the three 5‐HT receptor antagonists failed to significantly effect basal and 5‐HT‐induced short‐circuit current. Our results indicate that in human duodenum 1) 5‐HT is a potent stimulator of bumetanide‐sensitive secretion, 2) the serotonergic receptor subtype, which acts as the main mediator of 5‐HT‐induced secretion is different from the 5‐HT2, 5‐HT3, and the 5‐HT4 subtype and, 3) the sensitivity to 5‐HT is not altered by Helicobacter pylori infection.
The purpose of this study was to determine the effect of a selective cyclooxygenase (COX)-2 inhibitor as compared to non-selective COX and lipoxygenase (LOX) inhibitors in rat colon. Basal- and ...serotonin (5-hydroxytryptamine, 5-HT)-induced electrogenic ion transport (short circuit current, SCC), prostaglandin E
2 (PGE
2) release and histological characteristics were measured. Muscle-stripped mucosal sheets of the proximal and distal segment of rat colon were investigated by employing the Ussing chamber technique, radioimmunoassays for PGE
2 and light microscopy examinations for control of tissue integrity. 5-HT and PGE
2 both induced a concentration-dependent increase in SCC by activation of multiple receptors. The response to 5-HT was bumetanide-sensitive. Neither the non-selective COX inhibitor piroxicam, nor the selective COX-2 inhibitor SC-'236, altered basal- SCC or 5-HT-induced SCC. Indomethacin reduced both basal- and 5-HT-induced SCC in both segments. Nordihydroguaiaretic acid reduced the 5-HT-induced increase in SCC, but did not change basal SCC. 5-HT-induced a concentration-dependent release of PGE
2. Only high concentrations of piroxicam and indomethacin reduced basal PGE
2 release and 5-HT-induced PGE
2 release. Histological examination of the specimens demonstrated only minor changes following mounting in chambers. There were no apparent differences in the morphology following treatment with COX or LOX inhibitors. These results suggest that in rat colon only the COX-1 enzyme is expressed under basal conditions. Furthermore, data suggest neither the COX-1 nor the COX-2 enzyme to be of major importance for 5-HT-induced ion transport in rat colon in vitro. In conclusion, this study supports 5-HT as a mediator of chloride secretion by activating several receptor subtypes and the LOX enzyme, releasing mediators such as leucotrienes.
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