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Background: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).Methods: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).Results: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P<0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P<0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis.Conclusions: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer. [ABSTRACT FROM AUTHOR]

Background:To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8+) and regulatory T lymphocytes (FoxP3+) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).Methods:CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8+ and FOXP3+ cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).Results:We found that infiltration of CD8+ T lymphocytes within the tumour epithelium provided the strongest prognostic information (P<0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P<0.001), suggesting FOXP3+ T-lymphocyte infiltration to be a better prognostic tool than CD8+ T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3+ cells at the tumour invasive front, significantly improved prognosis.Conclusions:Analyses of intraepithelial infiltration of CD8+ T lymphocytes, infiltration of FOXP3+ T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer. [ABSTRACT FROM AUTHOR]

BackgroundMutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC.PatientsWe analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n=197) and Colorectal Cancer in Umeå Study (CRUMS; n=414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression.ResultsQuadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P=0.003 and CRUMS; P=0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information.ConclusionsOur results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC. [ABSTRACT FROM AUTHOR]

Background:A most important characteristic feature for poor prognosis in colorectal cancer (CRC) is the presence of lymph node metastasis. Determination of carcinoembryonic antigen (CEA) mRNA levels in lymph nodes has proven powerful for quantification of disseminated tumour cells. Here, we investigate the utility of human tissue kallikrein-related peptidase 6 (KLK6) mRNA as a progression biomarker to complement CEA mRNA, for improved selection of patients in need of adjuvant therapy and intensified follow-up after surgery.Methods:Lymph nodes of pTNM stage I-IV CRC- (166 patients/503 lymph nodes) and control (23/108) patients were collected at surgery and analysed by quantitative RT-PCR.Results:Lymph node KLK6 positivity was an indicator of poor outcome (hazard ratio 3.7). Risk of recurrence and cancer death increased with KLK6 lymph node levels. Patients with KLK6 lymph node levels above the 90th percentile had a hazard ratio of 6.5 and 76 months shorter average survival time compared to patients with KLK6 negative nodes. The KLK6 positivity in lymph nodes with few tumour cells, that is, low CEA mRNA levels, also indicated poor prognosis (hazard ratio 2.8).Conclusion:In CRC patients, lymph node KLK6 positivity indicated presence of aggressive tumour cells associated with poor prognosis and high risk of tumour recurrence. [ABSTRACT FROM AUTHOR]

Objective:To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.Methods:We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m−2), hypertension (blood pressure 140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose 6.1 mmol l−1 or post-load glucose in capillary plasma 8.9 mmol l−1).Results:None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20–5.52; P trend=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1–9 were 1.56 (95% CI 0.93–2.62; P=0.090), 1.83 (95% CI 1.00–3.36; P=0.051) and 1.50 (95% CI 0.83–2.71; P=0.18), respectively.Conclusions:Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.International Journal of Obesity (2008) 32, 304–314; doi:10.1038/sj.ijo.0803713; published online 18 September 2007 [ABSTRACT FROM AUTHOR]

The advent of halogenated pyrimidines (bromodeoxyuridine, BrdU; idoxuridine, IdU) and antibodies to recognize them has opened new horizons for the measurement of proliferation in human tumours. These precursors of DNA can be given to patients and a single biopsy can be taken to measure in a flow cytometer both the fraction of labelled cells and their rate of movement through the S phase. From these two parameters the potential doubling time, T[SUBPOT], can be calculated. To measure both parameters simultaneously a compromise is made in the time of assessing the labelling index (LI). LI should ideally be assessed after a very short interval, e.g. 0.5-1 h, to avoid the contaminating influence of any cells dividing between injection and biopsy. However, an interval of 4-8 h is considered necessary to assess TS from the relative movement of cells through the S phase. Several techniques exist to correct for cell division if the interval is long. The simplest correction, which only corrects for the division of labelled cells, is most widely used. Downward correction factors of at least 10% are commonly applied, reducing the observed LI values. In this paper we illustrate graphically the dependence of the appropriate correction factor on various cell kinetic parameters. The duration of G2 is the most critical parameter for both the size and direction of any correction factor. The G2 phase has previously been shown to be about three times longer in human tumours than in rodents. If G2+M is as long as 6 h, the main artefact of the intervals between injection and biopsy up to 7 h is that the observed LI is too low because of division of unlabelled G2 cells. A correction of up to 10% is needed but in an upward direction. A nomogram of probable correction factors as a function of sampling interval is provided. We show from flow cytometric data that G2+M may be shorter than 4 h for head and neck tumours. It is recommended that the correction factor established by gating the... [ABSTRACT FROM AUTHOR]

The conflicting results about the prognostic impact of tumour cell proliferation in colorectal cancer might be explained by the heterogeneity observed within these tumours. We have investigated whether a systematic spatial heterogeneity exists between different compartments, and whether the presence of such a systematic heterogeneity has any impact on survival. Fifty-six Dukes' stage B colorectal cancers were carefully morphometrically quantified with respect to the immunohistochemical expression of the proliferative marker Ki-67 at both the luminal border and the invasive margin. The proliferative activity was significantly higher at the luminal border compared with the invasive margin (P< 0.001), although the two compartments were also significantly correlated with each other. Tumours with low proliferation at the invasive margin had a significantly poorer prognosis both in univariate (P= 0.014) and in multivariate survival analyses (P= 0.042). We conclude that Dukes' B colorectal cancers exhibit a systematic spatial heterogeneity with respect to proliferation, and tumours with low proliferation at the invasive margin had a poor prognosis. The present data independently confirm recent results from the authors, and provide new insights into the understanding of tumour cell proliferation in colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: To enable the evaluation of locoregional disease in the on-going RECTOPET (REctal Cancer Trial on PET/MRI/CT) study; a methodology to match mesorectal imaging findings to histopathology is presented, along with initial observations., Methods: FDG-PET/MRI examinations were performed in twenty-four consecutively included patients with rectal adenocarcinoma. In nine patients, of whom five received neoadjuvant treatment, a postoperative MRI of the surgical specimen was performed. The pathological cut-out was performed according to clinical routine with the addition of photo documentation of each slice of the surgical specimen, meticulously marking the location, size, and type of pathology of each mesorectal finding. This allowed matching individual nodal structures from preoperative MRI, via the specimen MRI, to histopathology., Results: Preoperative MRI identified 197 mesorectal nodal structures, of which 92 (47%) could be anatomically matched to histopathology. Of the matched nodal structures identified in both MRI and histopathology, 25% were found to be malignant. These malignant structures consisted of lymph nodes (43%), tumour deposits (48%), and extramural venous invasion (9%). One hundred eleven nodal structures (55%) could not be matched anatomically. Of these, 97 (87%) were benign lymph nodes, and 14 (13%) were malignant nodal structures. Five were malignant lymph nodes, and nine were tumour deposits, all of which had a short axis diameter < 5 mm., Conclusions: We designed a method able to anatomically match and study the characteristics of individual mesorectal nodal structures, enabling further research on the impact of each imaging modality. Initial observations suggest that small malignant nodal structures assessed as lymph nodes in MRI often comprise other forms of mesorectal tumour spread., Trial Registration: Clinical Trials Identifier: NCT03846882 .

Purpose: The role of hybrid imaging using 18 F-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study., Methods: This prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Västerbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umeå University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology., Results: Twenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management., Conclusions: The RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI., Trial Registration: NCT03846882 .