Kai Klintrup

Stage-dependent alterations of the serum cytokine pattern in colorectal carcinoma

Background:Inflammation contributes to the pathogenesis of colorectal cancer (CRC), and cytokine levels are altered during colorectal carcinogenesis.Methods:The serum levels of 13 cytokines and their relation to clinical and pathological parameters, and systemic inflammatory response (mGPS, CRP and neutrophil–lymphocyte ratio), were analysed from a prospective series of 148 CRC patients and 86 healthy age- and sex-matched controls.Results:CRC patients had higher serum platelet-derived growth factor, interleukin (IL)-6, IL-7, and IL-8 levels and lower monocyte chemotactic protein-1 (MCP-1) levels than the controls. A logistic regression model for discriminating the patients from the controls – including the five most predictive cytokines (high IL-8, high IL-6, low MCP-1, low IL-1ra, and low IP-10) – yielded an area under curve value of 0.890 in receiver operating characteristics analysis. Serum cytokines showed distinct correlation with other markers of systemic inflammatory response, and advanced CRCs were associated with higher levels of IL-8, IL-1ra, and IL-6. A metastasised disease was accompanied by an orientation towards Th2 cytokine milieu.Conclusion:CRC is associated with extensive alterations in serum cytokine environment, highlighting the importance of studying relative cytokine level alterations. Serum cytokine profile shows promise in separating CRC patients from healthy controls but its clinical value is yet to be confirmed.

Detailed analysis of inflammatory cell infiltration in colorectal cancer

Background:Higher-grade inflammatory infiltrate is a promising marker for better prognosis in colorectal cancer (CRC). However, the knowledge on the interrelationships between different inflammatory cells and classifications is fragmentary.Methods:We analysed the densities of eight types of inflammatory cells in a prospectively recruited group of 117 CRC patients and determined their interrelationships and contributions to Klintrup–Mäkinen (K–M) score of overall peritumoural inflammation. We characterised the inflammatory infiltrate in relation to stage and recurrences in 24-month follow-up.Results:There were high positive correlations between the inflammatory cell densities, with the exception of mast cells and CD1a+ immature dendritic cells. High K–M score associated with high peri- and intratumoural densities of CD3+, CD8+, CD68+, CD83+, and FoxP3+ cells and neutrophils. Advanced stage associated with low K–M score, as well as low CD3+, CD8+, CD83+, and FoxP3+ cell counts, of which low K–M score, low CD3+ T-cell count, and low FoxP3+ T-cell count were linked to higher recurrence rate.Conclusion:The density of CRC inflammatory infiltrate declines as stage advances. Especially, low K–M score and low T-cell counts predict higher recurrence rate. The high positive correlations between the individual inflammatory markers support the value of overall inflammatory reaction scoring.

Characteristics and significance of colorectal cancer associated lymphoid reaction.

A subset of colorectal cancers (CRCs) exhibits so‐called Crohns like lymphoid reaction (CLR), an inflammatory reaction pattern that consists of numerous transmural lymphoid aggregates. However, the composition of these aggregates, their biological mechanisms and their prognostic significance are not well‐defined. We analyzed two CRC cohorts (418 and 149 patients) and determined clinicopathological features including survival. A new method for evaluating CLR based on counting the areal density of the lymphoid follicles (CLR density) was adopted. Immune cell densities at intratumoral and peritumoral regions, as well as the composition of the lymphoid follicles, were studied by immunohistochemistry. We found that CLR comprised of lymphoid aggregates with no evidence of granuloma formation. High CLR density associated with lower tumor stage, lack of preoperative radiotherapy or chemoradiotherapy and deficient mismatch repair enzyme expression. CLR density had positive correlations with peritumoral and intratumoral densities of CD83+ mature dendritic cells and T cells. High CLR density associated with better survival and had prognostic value that was independent of stage, Klintrup‐Mäkinen score for peritumoral inflammation and the numbers of tumor infiltrating T cells. CLR density evaluation had excellent intraobserver and interobserver agreement. In conclusion, the results suggest that CLR contributes to the adaptive antitumor immunity. Quantitative evaluation of CLR density is a relevant prognostic indicator in CRC.

Serum endostatin levels are elevated in colorectal cancer and correlate with invasion and systemic inflammatory markers.

Background:Endostatin, a fragment of collagen XVIII, is an endogenous angiogenesis inhibitor with anti-tumour functions. However, elevated circulating endostatin concentrations have been found in several human cancers including colorectal cancer (CRC).Methods:Serum endostatin levels were measured by enzyme-linked immunoassay from a series of 143 patients with CRC and from 84 controls, and correlated with detailed clinicopathological features of CRC, serum leukocyte differential count and C-reactive protein (CRP) levels.Results:Patients with CRC had higher serum endostatin levels than the controls (P=0.005), and high levels associated with age, tumour invasion through the muscularis propria and poor differentiation, but not with metastases. Endostatin levels showed a positive correlation with the markers of systemic inflammatory response and a negative correlation with the densities of tumour-infiltrating mast cells and dendritic cells. Collagen XVIII was expressed in tumour stroma most strikingly in blood vessels and capillaries, and in the muscle layer of the bowel wall.Conclusions:Elevated endostatin levels in CRC correlate with systemic inflammation and invasion through the muscularis propria. Increased endostatin level may be a result of invasion-related cleavage of collagen XVIII expressed in the bowel wall. The negative correlations between serum endostatin and intratumoural mast cells and immature dendritic cells may reflect angiogenesis inhibition by endostatin.

The relationships between serum cytokine levels and tumor infiltrating immune cells and their clinical significance in colorectal cancer

Increased inflammatory cell infiltration correlates to improved survival in colorectal cancer (CRC). Development and progression of CRC is associated with alterations in serum cytokine levels but their significance is not well defined. In this study, we investigated the relationships between the serum levels of 13 cytokines and the densities of eight types of tumor infiltrating inflammatory cells and their impact on disease‐free survival (DFS), cancer‐specific survival (CSS) and overall survival (OS) in a prospectively recruited group of 147 CRC patients. There were strong positive correlations between the serum concentrations of different cytokines, as well as between the different types of tumor infiltrating immune cells, whereas the associations between serum cytokines and tumor infiltrating immune cells were generally weak. High serum IL‐12 levels associated with increased densities of peritumoral CD8+ T cells, intraepithelial CD3+ T cells and intratumoral neutrophils, while high serum CCL4 levels associated with increased densities of peritumoral CD68+ cells. In multivariate survival models, increased infiltration of intraepithelial CD3+ T cells and increased serum CCL4 associated with improved DFS, whereas higher intratumoral CD83+ dendritic cell density and increased serum interferon gamma levels associated with improved CSS and OS. Also high density of peritumoral CD3+ T cells associated with improved CSS. In conclusion, serum cytokines and tumor infiltrating immune cells in CRC represent entities with high intragroup correlations but relatively weak intergroup correlations. The results suggest that tumor infiltrating CD3+ T cells, CD83+ dendritic cells, serum CCL4 and serum interferon gamma represent relevant markers of disease outcome.

Annexin A10 is a marker for the serrated pathway of colorectal carcinoma

Serrated adenocarcinoma (SAC), representing at least 10xa0% of colorectal carcinomas (CRC), differs from conventional carcinomas not only by its histology, but also by its molecular basis. However, the diagnosis of SAC in poorly differentiated cases and without an adjacent serrated adenoma can be challenging. In this study, we utilized previously described expression data and identified annexin A10 (ANXA10) as a potential marker for SAC. We conducted ANXA10 immunohistochemistry in groups of 146 CRC patients and 131 serrated and conventional polyps. In CRC cases, ANXA10 expression associated with serrated histology (sensitivity 42xa0% and specificity 98xa0%). BRAF V600E mutation correlated with ANXA10 expression but also seven BRAF wild-type tumors (5xa0%) were positive for ANXA10. Immunoreactivity for either ANXA10 or BRAF V600E was an accurate predictor of serrated histology (sensitivity 55xa0% and specificity 97xa0%). ANXA10 expression did not associate with tumor stage or grade. Of the 131 colorectal polyps, 30/30 of sessile serrated adenomas, 6/11 traditional serrated adenomas, 20/32 hyperplastic polyps, and 2/27 tubulovillous adenomas were positive for ANXA10, while 31/31 tubular adenomas were negative. In conclusion, the results suggest that ANXA10 is a marker with high specificity for the serrated pathway of CRC.

The role of low CRP values in the prediction of the development of acute diverticulitis

PurposeComputed tomography (CT) is the most appropriate imaging modality for the assessment of acute diverticulitis at the emergency unit. The aim of this study was to determine the clinical outcome of the patients presented first time with symptoms of acute diverticulitis and low CRP values.MethodsTwo-hundred patients, who presented with the symptoms of acute diverticulitis and had CRP values under 150xa0mg/L, underwent abdominal CT examination on admission to Oulu University Hospital. The clinical parameters and radiological findings were compared in relation to clinical outcome both by means of univariate and multivariate analyses.ResultsSeventy-one (35.5xa0%) of the 200 patients presented on admission with complicated diverticulitis. CRP values between 100 and 150xa0mg/L predicted complicated disease, but the mean values of CRP between uncomplicated disease, 89xa0mg/Lu2009±u200939, and complicated disease, 101xa0mg/Lu2009±u200939, did not differ significantly. Free intra-abdominal fluid in CT was the only independent risk factor of the need for interventional therapy and treatment in the intensive care unit. Longevity of the patients and free fluid in CT predicted significantly prolonged hospitalization. Mortality was 1xa0% and older patients were significantly affected. The recurrence rate of acute diverticulitis was 24xa0% (43/177) in the whole group and 18xa0% (23/129) after uncomplicated diverticulitis.ConclusionsLow CRP values do not reliably predict uncomplicated disease in patients presented first time at the emergency unit with acute diverticulitis. We recommend that the need for abdominal CT is carefully evaluated according to the patient’s clinical status, always even when the CRP value is under 150xa0mg/L.

Decreased serum apolipoprotein A1 levels are associated with poor survival and systemic inflammatory response in colorectal cancer

Recent studies have reported of an association between high serum apolipoprotein A1 (APOA1) levels and favorable prognosis in several malignancies, while the significance of apolipoprotein B (APOB) in cancer is less well-known. In this study, we analyzed the correlation between serum APOA1 and APOB levels, and APOB/APOA1 ratio, and their associations with clinicopathologic parameters, the levels of twenty systemic inflammatory markers, and survival in 144 colorectal cancer (CRC) patients. We demonstrated that low serum APOA1 levels associated with advanced T-class and TNM-stage but low serum APOB levels did not significantly correlate with tumor characteristics. Serum APOA1 levels showed strong negative correlation with the markers of systemic inflammation including serum CRP and interleukin (IL)-8 levels and blood neutrophil count, whereas high serum APOB levels associated with high serum CCL2 levels. High APOA1 and APOB levels and low APOB/APOA1 ratio associated with improved cancer specific and overall survival. APOA1 had independent prognostic value in Cox regression analysis. In conclusion, low serum APOA1 levels are associated with advanced stage and systemic inflammation, while serum APOB does not significantly correlate with tumor stage. Serum APOA1 represents a promising additional prognostic parameter in CRC.

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Preoperative anemia in colorectal cancer: relationships with tumor characteristics, systemic inflammation, and survival

Anemia is common in colorectal cancer (CRC) but its relationships with tumor characteristics, systemic inflammation, and survival have not been well characterized. In this study, blood hemoglobin levels and erythrocyte mean corpuscular volume (MCV) levels were measured in two independent cohorts of 148 CRC patients and 208 CRC patients, and their correlation with patient and tumor characteristics, systemic inflammatory markers (modified Glasgow Prognostic Score: mGPS; serum levels of thirteen cytokines, C-reactive protein, albumin), and survival were analyzed. We found that anemia, most frequently normocytic, followed by microcytic, was present in 43% of the patients. Microcytic anemia was most commonly associated with proximal colon tumor location. Average MCV and blood hemoglobin levels were lower in tumors with high T-class. Low blood hemoglobin associated with systemic inflammation, including high mGPS and high serum levels of C-reactive protein and IL-8. Particularly, normocytic anemia associated with higher mGPS. Normocytic anemia associated with a tendency towards worse overall survival (multivariate hazard ratio 1.61, 95% confidence interval 1.07–2.42, pu2009=u20090.023; borderline statistical significance considering multiple hypothesis testing). In conclusion, anemia in CRC patients is most frequently normocytic. Proximal tumor location is associated with predominantly microcytic anemia and systemic inflammation is associated with normocytic anemia.