To explore the impact of KRAS, NRAS and BRAF mutations as well as KRAS mutation variants in patients with metastatic colorectal cancer (mCRC) receiving first-line therapy.
A total of 1239 patients ...from five randomized trials (FIRE-1, FIRE-3, AIOKRK0207, AIOKRK0604, RO91) were included into the analysis. Outcome was evaluated by the Kaplan–Meier method, log-rank tests and Cox models.
In 664 tumors, no mutation was detected, 462 tumors were diagnosed with KRAS-, 39 patients with NRAS- and 74 patients with BRAF-mutation. Mutations in KRAS were associated with inferior progression-free survival (PFS) and overall survival (OS) multivariate hazard ratio (HR) for PFS: 1.20 (1.02–1.42), P = 0.03; multivariate HR for OS: 1.41 (1.17–1.70), P < 0.001. BRAF mutation was also associated with inferior PFS multivariate HR: 2.19 (1.59–3.02), P < 0.001 and OS multivariate HR: 2.99 (2.10–4.25), P < 0.001. Among specific KRAS mutation variants, the KRAS G12C-variant (n = 28) correlated with inferior OS compared with unmutated tumors multivariate HR 2.26 (1.25–4.1), P = 0.001. A similar trend for OS was seen in the KRAS G13D-variant n = 71, multivariate HR 1.46 (0.96–2.22), P = 0.10. More frequent KRAS exon 2 variants like G12D n = 152, multivariate HR 1.17 (0.86–1.6), P = 0.81 and G12V n = 92, multivariate HR 1.27 (0.87–1.86), P = 0.57 did not have significant impact on OS.
Mutations in KRAS and BRAF were associated with inferior PFS and OS of mCRC patients compared with patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared with unmutated tumors with KRAS G12C and G13D (trend) being associated with rather poor survival.
Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for ...Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on colonoscopic surveillance following adenoma removal includes 24 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of surveillance and other elements in the screening process, including multi-disciplinary diagnosis and management of the disease.
Malignant gliomas are the most common and lethal primary intracranial tumors. To date, no reliable biomarkers for the detection and risk stratification of gliomas have been identified. Recently, we ...demonstrated significant levels of microRNAs (miRNAs) to be present in cerebrospinal fluid (CSF) samples from patients with primary CNS lymphoma. Because of the involvement of miRNA in carcinogenesis, miRNAs in CSF may serve as unique biomarkers for minimally invasive diagnosis of glioma. The objective of this pilot study was to identify differentially expressed microRNAs in CSF samples from patients with glioma as potential novel glioma biomarkers. With use of a candidate approach of miRNA quantification by reverse-transcriptase polymerase chain reaction (qRT-PCR), miRNAs with significant levels in CSF samples from patients with gliomas were identified. MiR-15b and miR-21 were differentially expressed in CSF samples from patients with gliomas, compared to control subjects with various neurologic disorders, including patients with primary CNS lymphoma and carcinomatous brain metastases. Receiver-operating characteristic analysis of miR-15b level revealed an area under the curve of 0.96 in discriminating patients with glioma from patients without glioma. Moreover, inclusion of miR-15b and miR-21 in combined expression analyses resulted in an increased diagnostic accuracy with 90% sensitivity and 100% specificity to distinguish patients with glioma from control subjects and patients with primary CNS lymphoma. In conclusion, the results of this pilot study demonstrate that miR-15b and miR-21 are markers for gliomas, which can be assessed in the CSF by means of qRT-PCR. Accordingly, miRNAs in the CSF have the potential to serve as novel biomarkers for the detection of gliomas.
Population-based screening for early detection and treatment of colorectal cancer (CRC) and precursor lesions, using evidence-based methods, can be effective in populations with a significant burden ...of the disease provided the services are of high quality. Multidisciplinary, evidence-based guidelines for quality assurance in CRC screening and diagnosis have been developed by experts in a project co-financed by the European Union. The 450-page guidelines were published in book format by the European Commission in 2010. They include 10 chapters and over 250 recommendations, individually graded according to the strength of the recommendation and the supporting evidence. Adoption of the recommendations can improve and maintain the quality and effectiveness of an entire screening process, including identification and invitation of the target population, diagnosis and management of the disease and appropriate surveillance in people with detected lesions. To make the principles, recommendations and standards in the guidelines known to a wider professional and scientific community and to facilitate their use in the scientific literature, the original content is presented in journal format in an open-access Supplement of
Endoscopy.
The editors have prepared the present overview to inform readers of the comprehensive scope and content of the guidelines.
Previous studies have shown that endoscopic ultrasonography (EUS) sensitively detects morphologic abnormalities due to chronic pancreatitis. However, morphologic EUS findings have limited ...specificity, particularly at the early stages of chronic pancreatitis. Our aims were to study pancreatic morphology and inflammation in patients with chronic pancreatitis, using EUS and fine-needle aspiration cytology (EUS-FNA), and to compare the results with those of endoscopic retrograde cholangiopancreatography (ERCP) and pancreatic function tests.
37 patients (48 +/- 13 years) with clinical symptoms and laboratory test findings suggestive of chronic pancreatitis were prospectively studied. Patients with malignancy or major concomitant disorders were excluded. Clinical evaluation included indirect pancreatic function tests. Morphologic criteria for chronic pancreatitis included echo-intense septae/echo-reduced foci (i. e. pseudolobularity), ductal irregularities, and calcifications. EUS-FNA was performed in 27/37 patients, by means of the Hitachi FG34-UX echo endoscope and a 22-gauge needle, and tissue specimens were submitted for standard cytological evaluation. ERCP served as reference in all patients, using the Cambridge classification.
31 patients had chronic pancreatitis while six had normal findings at ERCP. EUS showed morphologic abnormalities of the pancreas in 33 patients. Morphologic abnormalities alone reached a sensitivity of 97 % for chronic pancreatitis with a specificity of only 60 %, while the positive predictive value (PPV) was 94 %, and the negative predictive value (NPV) was 75 %. EUS-FNA increased the negative predictive value to 100 % and the specificity to 67 %. On average, 2.3 needle passes were necessary to obtain sufficient amounts of tissue. The correlation of EUS findings with pancreatic function tests was poor. EUS results were in agreement with regard to the severity of chronic pancreatitis in 5/8 patients with grade I disease, in 11/13 patients with grade II, and in 10/10 patients with grade III disease. Minor complications occurred in two patients (7 %).
EUS is as sensitive and effective as ERCP in the detection of chronic pancreatitis, particularly when only mild disease is present. However, EUS findings have limited specificity, particularly in patients with mild disease. EUS-FNA with cytology is safe and improves the negative predictive value. Negative EUS-FNA findings rule out chronic pancreatitis, but cytological investigation alone does not improve the specificity of EUS findings, suggesting that further improvements in tissue sampling and analysis are necessary to support routine use of FNA in patients with chronic pancreatitis.
Endoscopy plays a major role in early recognition of cancer which is not externally accessible and therewith in increasing the survival rate. Raman spectroscopic fiber-optical approaches can help to ...decrease the impact on the patient, increase objectivity in tissue characterization, reduce expenses and provide a significant time advantage in endoscopy. In gastroenterology an early recognition of malign and precursor lesions is relevant. Instantaneous and precise differentiation between adenomas as precursor lesions for cancer and hyperplastic polyps on the one hand and between high and low-risk alterations on the other hand is important. Raman fiber-optical measurements of colon biopsy samples taken during colonoscopy were carried out during a clinical study, and samples of adenocarcinoma (22), tubular adenomas (141), hyperplastic polyps (79) and normal tissue (101) from 151 patients were analyzed. This allows us to focus on the bioinformatic analysis and to set stage for Raman endoscopic measurements. Since spectral differences between normal and cancerous biopsy samples are small, special care has to be taken in data analysis. Using a leave-one-patient-out cross-validation scheme, three different outlier identification methods were investigated to decrease the influence of systematic errors, like a residual risk in misplacement of the sample and spectral dilution of marker bands (esp. cancerous tissue) and therewith optimize the experimental design. Furthermore other validations methods like leave-one-sample-out and leave-one-spectrum-out cross-validation schemes were compared with leave-one-patient-out cross-validation. High-risk lesions were differentiated from low-risk lesions with a sensitivity of 79%, specificity of 74% and an accuracy of 77%, cancer and normal tissue with a sensitivity of 79%, specificity of 83% and an accuracy of 81%. Additionally applied outlier identification enabled us to improve the recognition of neoplastic biopsy samples.
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•A Raman fiber-optical approach was applied to differentiate between colonic lesions.•Cancer, tubular adenoma, hyperplastic polyps and normal tissue were classified by SVM.•A classifier was build up for an automatic recognition of colonic lesions.•Detection of spectral outlier allows improved classification of endoscopic samples.•LOPO-CV should be applied for improved classification of endoscopic samples.
Several randomised trials have consistently shown that FOLFOX therapy results in superior response rates and time to disease progression in comparison with fluorouracil-leucovorin given as first- or ...secondline therapy in metastatic colorectal cancer. 49- 51 Irinotecan and oxaliplatin, each in combination with fluorouracil, are the new standard in the palliative treatment of colorectal cancer. Because of their superior effectiveness, triplet therapies consisting of either irinotecan or oxaliplatin in combination with infusional fluorouracil-leucovorin have become the standard treatment in the palliative situation. First results of interim efficacy and safety analysis from a study comparing FUFOX (weekly fluorouracil 2000 mg/m2 24 hour infusion, leucovorin 500 mg/m2, oxaliplatin 50 mg/m2) with CAPOX (capecitabine 1000 mg/m2 twice daily for days 1-14, oxaliplatin 70 mg/m2 on days 1 and 8; every three weeks) in 399 patients showed that CAPOX had a comparable efficacy and toxicity profile to FUFOX in the firstline treatment of advanced colorectal cancer. 60 Time to progression was eight months in the FUFOX group and 7.5 months in the CAPOX group. ...329 patients showing positive EGFR expression were randomly assigned to receive either cetuximab alone or in combination with irinotecan.). ...progress is on the horizon but can only take place through interdisciplinary cooperation and careful design, and completion of randomised clinical trials.
The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting ...outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC.
Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification.
Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05).
Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.
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