TLR2 and TLR4 in colorectal cancer: relationship to tumor necrosis and markers of systemic inflammation.

In colorectal cancer (CRC), systemic inflammation is associated with poor prognosis, but the underlying mechanisms are not fully characterized. Tumor necrosis may contribute to systemic inflammation by inducing interleukin (IL)-6 signaling, and proinflammatory cytokines such as IL-6 and IL-8, and matrix metalloproteinase (MMP)-8 also are linked to adverse CRC outcomes. Because Toll-like receptors (TLRs) are important mediators of inflammatory responses, we investigated the roles of TLR2 and TLR4 in CRC-associated systemic inflammatory responses, especially tumor necrosis. In 118 patients with CRC, extensive tumor necrosis was associated with low TLR4 expression in tumor cells. Tumor cell TLR4 expression was inversely correlated with serum IL-6 and MMP-8 levels, blood total leukocyte and neutrophil counts, and serum C-reactive protein levels. Tumor cell TLR2 expression was not significantly associated with necrosis or systemic inflammation, but low expression in normal mucosa was linked to high serum MMP-8 and IL-8. These findings indicate that tumor necrosis is associated with low TLR4 expression in cancer cells and that low TLR4 expression correlates with a strong systemic inflammatory response. The low TLR2 expression in normal mucosa and its association with systemic inflammation suggest that the normal mucosa may reflect or contribute to the systemic inflammatory response.

Putative anoikis resistant subpopulations are enriched in lymph node metastases and indicate adverse prognosis in colorectal carcinoma.

Anoikis refers to apoptosis induced by the loss of contact with the extracellular matrix. Anoikis resistance is essential for metastasis. We have recently shown that it is possible to quantitatively evaluate putative anoikis resistant (AR) subpopulations in colorectal carcinoma (CRC). Abundance of these multi-cell structures is an independent marker of adverse prognosis. Here, we have quantified putative AR subpopulations in lymph node (LN) metastases of CRC and evaluated their prognostic value and relationship with the characteristics of primary tumors. A case series included 137 unselected CRC patients, 54 with LN metastases. Areal densities (structures/mm2) of putative AR structures in primary tumors had been analyzed previously and now were determined from all nodal metastases (n = 183). Areal density of putative AR structures was higher in LN metastases than in primary tumors. Variation of the areal density within different LN metastases of a single patient was lower than between metastases of different patients. Abundance of putative AR structures in LN metastases was associated with shorter cancer specific survival (p = 0.013), and this association was independent of T and N stages. Abundance of putative AR structures in primary tumors and LN metastases had a cumulative adverse effect on prognosis. Enrichment of putative AR subpopulations in LN metastases suggest that in metastasis formation, there is a selection favoring cells capable of forming these structures. Higher intra-case constancy relative to inter-case variation suggests that such selection is stable in metastasis development. Our findings indirectly support the biological validity of our concept of putative AR structures.

Sarcopenia and Myosteatosis Are Associated with Neutrophil to Lymphocyte Ratio but Not Glasgow Prognostic Score in Colorectal Cancer Patients.

Cancer patients commonly present sarcopenia, myosteatosis, and systemic inflammation, which are risk factors of poor survival. In this study, sarcopenia and myosteatosis were defined from preoperative body computed tomography scans of 222 colorectal cancer (CRC) patients and analyzed in relation to tumor and patient characteristics, markers of systemic inflammation (modified Glasgow prognostic score (mGPS), neutrophil−lymphocyte ratio (NLR), serum levels of C-reactive protein (CRP), albumin, and 13 cytokines, and survival. Of the systemic inflammation markers, sarcopenia and/or myosteatosis associated with elevated NLR (p = 0.005) and low albumin levels (≤35 g/L) (p = 0.018), but not with mGPS or serum cytokine levels. In addition, myosteatosis was associated with a proximal tumor location (p = 0.039), serrated tumor subtype (p < 0.001), and severe comorbidities (p = 0.004). Multivariable analyses revealed that severe comorbidities and serrated histology were independent predictors of myosteatosis, and older age and elevated NLR were independent indicators of sarcopenia. Myosteatosis associated with shorter overall survival in univariable analysis (HR 1.959, 95% CI 1.24−3.10, p = 0.004) but not in multivariable analysis (p = 0.075). We conclude that sarcopenia and myosteatosis were associated with inflammatory marker NLR, but not with mGPS. Moreover, patients with serrated CRC may have an increased risk of myosteatosis. Myosteatosis or sarcopenia were not independent predictors of patient survival.

Annual hospital volume and colorectal cancer survival in a population-based nationwide cohort study in Finland.

PURPOSE: To examine the annual hospital volume of surgery in relation to survival in colorectal cancer. Previous studies on hospital volume and survival following colorectal cancer surgery are conflicting. METHODS: All 49 032 patients who underwent resection for colorectal cancer in 1987-2016 in Finland were included, with complete follow-up until December 31, 2019. Primary outcome was 5-year mortality. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI) for quartiles of annual hospital volume for colorectal surgery, adjusted for calendar period, age, sex, comorbidity, stage, tumor location and oncological therapy. Additionally, colon and rectal cancer surgery were assessed separately. Sensitivity analysis of patients with confirmed curative intent was conducted. RESULTS: Compared to highest quartile (≥108 resections annually), lowest hospital volume (≤37 resections annually) was associated with slightly increased 5-year all-cause mortality (adjusted HR 1.07, 95% CI 1.02-1.12). A pre-planned subgroup-analysis suggested a slightly improved 5-year survival in high-volume institutions for rectal cancer, but not colon cancer surgery. Sensitivity analysis including only those operated with confirmed curative intent suggested no differences between hospital volume groups in colorectal, colon or rectal cancer for 5-year all-cause mortality. CONCLUSION: Higher hospital volume is associated with slightly improved all-cause 5-year mortality in colorectal cancer surgery, but this effect may be limited to rectal cancer surgery only. Volume-outcome relationship in rectal cancer surgery should be investigated further using large datasets. These results do not support centralization of colon cancer surgery based on hospital volume only.

Systemic inflammation is associated with circulating cell death released keratin 18 fragments in colorectal cancer.

Systemic inflammation is a stage-independent marker of poor prognosis in colorectal cancer (CRC), activated in a complex, multifactorial process. It has been proposed that one of the main factors driving systemic inflammation may be tumor necrosis. Keratin 18 (KRT18) fragments are released from dead cells and their serum levels are markers for apoptotic and necrotic cell death. In CRC, high KRT18 levels associate with advanced disease, but their relationship with tumor necrosis and systemic inflammation is unknown. In this study, serum total soluble KRT18 (tKRT18) and apoptosis-related, caspase-cleaved fragment (aKRT18) levels were measured preoperatively from 328 CRC patients, and their difference was calculated to assess necrosis related KRT18 (nKRT18) levels. The relationships of these markers with tumor necrosis, clinicopathologic features, systemic inflammation markers (C-reactive protein, albumin, and 13 cytokines), and survival were analyzed. High serum tKRT18, aKRT18, and nKRT18 levels showed association with a higher extent of tumor necrosis, distant metastasis, and increased levels of several markers of systemic inflammation, including CXCL8. High serum tKRT18 (multivariable HR 1.94, 95% CI 1.28-2.95, p = .002) and nKRT18 (multivariable HR 1.87, 95% CI 1.24-2.82, p = .003) levels were associated with poor overall survival independent of potential confounding factors. Our results show that tumor necrosis in CRC contributes to serum levels of KRT18 fragments, and both necrosis and KRT18 levels associate with systemic inflammation. Moreover, we show that serum tKRT18 and nKRT18 levels have independent prognostic value in CRC. Our observations confirm the link between cell death and systemic inflammation.

Putative anoikis-resistant subpopulations in colorectal carcinoma: a marker of adverse prognosis.

Anoikis is a form of apoptosis induced when a cell loses contact with the extracellular matrix (ECM). Anoikis resistance is essential for metastasis formation, yet only detectable by in vitro experiments. We present a method for quantitation of putative anoikis-resistant (AR) subpopulations in colorectal carcinoma (CRC) and evaluate their prognostic significance. We studied 137 CRC cases and identified cell subpopulations with and without stromal or extracellular matrix (ECM) contact with hematoxylin-and-eosin-stained sections and immunohistochemistry for laminin and type IV collagen. Suprabasal cells of micropapillary structures and inner cells of cribriform and solid structures lacked both stromal contact and contact with ECM proteins. Apoptosis rate (M30) was lower in these subpopulations than in the other carcinoma cells, consistent with putative AR subpopulation. We determined the areal density of these subpopulations (number/mm2 tumor tissue), and their high areal density independently indicates low cancer-specific survival. In conclusion, we show evidence that subpopulations of carcinoma cells in micropapillary, cribriform, and solid structures are resistant to anoikis as shown by lack of ECM contact and low apoptosis rate. Abundance of these subpopulations is a new independent indicator of poor prognosis in CRC, consistent with the importance of anoikis resistance in the formation of metastasis.

Prospective, Randomized Study on the Use of Prosthetic Mesh to Prevent a Parastomal Hernia in a Permanent Colostomy: Results of a Long-term Follow-up.

BACKGROUND: Parastomal hernias are common with permanent colostomies and prone to complications. The short-term results of trials of parastomal hernia prevention are widely published, but long-term results are scarce. OBJECTIVE: The aim of the study is to detect the long-term effects and safety of preventive intra-abdominal parastomal mesh. DESIGN: This is a long-term follow-up of a previous prospective randomized, controlled multicenter trial. SETTINGS: This study was conducted at 2 university hospitals and 3 central hospitals in Finland. PATIENTS: Patients who had a laparoscopic abdominoperineal resection for rectal cancer between 2010 and 2013 were included in the study and invited for a follow-up visit. MAIN OUTCOME MEASURES: The primary outcomes measured were clinical and radiological parastomal hernias. RESULTS: Twenty subjects in the mesh group and 15 in the control group attended the follow-up visit with a median follow-up period of 65 (25th-75th percentiles, 49-91) months. A clinically detectable parastomal hernia was present in 4 of 20 (20.0%) and 5 of 15 (33.3%) subjects in the mesh and control groups (p = 0.45). A radiological parastomal hernia was present in 9 of 19 (45.0%) subjects in the mesh group and 7 of 12 (58.3%) subjects in the control group (p = 0.72). However, when all subjects (n = 70, 1:1) who attended the 12-month follow-up were screened for long-term results according to register data, 9 of 35 (25.9%) subjects in the mesh group and 16 of 35 (45.6%) subjects in control group were diagnosed with a parastomal hernia during the follow-up period (p = 0.10). In addition, only 1 of 35 (2.7%) subjects in the mesh group but 6 of 35 (17.1%) subjects in the control group underwent a parastomal hernia operation during the long-term follow-up (p = 0.030). LIMITATIONS: The study is limited by the small number of patients. CONCLUSION: Prophylactic intra-abdominal keyhole mesh did not decrease the rate of clinically detectable hernias but reduced the need for the surgical repair of parastomal hernias. Further trials are needed to identify a more efficient method to prevent parastomal hernias. See Video Abstract at http://links.lww.com/DCR/B171. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov. Identifier: NCT02368873. ESTUDIO PROSPECTIVO ALEATORIZADO SOBRE EL USO DE MALLA PROTÉSICA PARA PREVENIR UNA HERNIA PARAESTOMAL EN UNA COLOSTOMÍA PERMANENTE: RESULTADOS DE UN SEGUIMIENTO A LARGO PLAZO: PREVENCIÓN DE HERNIA PARAESTOMAL, NEOPLASIA COLORRECTAL/ANAL: Las hernias paraestomales son comunes con colostomías permanentes y son propensas a complicaciones. Los resultados a corto plazo de los ensayos sobre la prevención de la hernia parastomal se publican ampliamente, pero los resultados a largo plazo son escasos.El objetivo del estudio es detectar los efectos a largo plazo y la seguridad de la malla parastomal intraabdominal preventiva.Este es un seguimiento a largo plazo de un estudio aleatorizado prospectivo, controlado y multicentrico previo.Este estudio se realizó en dos hospitales universitarios y tres hospitales centrales en Finlandia.Los pacientes que se sometieron a una resección abdominoperineal laparoscópica por cáncer de recto 2010-2013 fueron incluidos en el estudio e invitados a una visita de seguimiento.Hernias parastomales clínicas y radiológicas.Veinte sujetos en el grupo de malla y 15 en el grupo control asistieron a la visita de seguimiento con una mediana de seguimiento de 65 meses (25-75 ° percentil 49-91). Una hernia paraestomal clínicamente detectable estuvo presente en 4/20 (20.0%) y 5/15 (33.3%) en los grupos de malla y control, respectivamente (p = 0.45). Una hernia parastomal radiológica estuvo presente en 9/19 (45.0%) en el grupo de malla y 7/12 (58.3%) en el grupo de control (p = 0.72). Sin embargo, cuando todos los sujetos (n = 70, 1: 1) que asistieron a los 12 meses de seguimiento fueron evaluados para obtener resultados a largo plazo de acuerdo con los datos del registro, 9/35 (25.9%) sujetos en el grupo de malla y 16/35 (45,6%) sujetos en el grupo control fueron diagnosticados con una hernia paraestomal durante el período de seguimiento (p = 0,10). Además, solo 1/35 (2.7%) en el grupo de malla pero 6/35 (17.1%) en el grupo control se sometieron a una operación de hernia paraestomal durante el seguimiento a largo plazo (p = 0.030).El estudio está limitado por un pequeño número de pacientes.La malla intra-abdominal profiláctica en ojo de cerradura no disminuyó la tasa de hernias clínicamente detectables, pero redujo la necesidad de la reparación quirúrgica de las hernias paraestomales. Se necesitan ensayos adicionales para identificar un método más eficiente para prevenir las hernias parastomales. Vea el resumen del video en http://links.lww.com/DCR/B171. (Traducción-Dr. Gonzalo Hagerman).NCT02368873.

Serum enterolactone concentrations are low in colon but not in rectal cancer patients.

The dietary lignan metabolite, enterolactone, has been suggested to have anti-cancer functions, and high serum enterolactone concentrations have been associated with decreased risk of breast and prostate cancers. We hypothesized that serum enterolactone concentrations as a marker of plant-based foods are associated with decreased risk in colorectal cancer (CRC). We measured serum enterolactone glucuronide and sulfate concentrations by liquid chromatography-tandem mass spectrometry in 115 CRC patients and 76 sex- and age-matched controls and analyzed the results with respect to tumor parameters, clinical parameters, and systemic inflammatory markers. Patients with colon cancer had significant lower serum enterolactone glucuronide and sulfate concentrations than controls (glucuronide: median 3.14 nM vs. 6.32 nM, P < 0.001; sulfate: median 0.13 nM vs. 0.17 nM, P = 0.002), whereas rectal cancer patients had similar enterolactone levels as controls (glucuronide: median 5.39 nM vs. 6.32 nM, P = 0.357; sulfate: median 0.19 nM vs. 0.17 nM, P = 0.452). High serum enterolactone concentrations were associated with low tumor grade, high serum creatinine levels, and concomitant diabetes. In summary, our results suggest that serum enterolactone concentrations are decreased in colon but not in rectal cancer. Further investigations are required to assess whether this reflects an altered lignan metabolism by the colon microbiome.

Mechanical and oral antibiotic bowel preparation versus no bowel preparation for elective colectomy (MOBILE): a multicentre, randomised, parallel, single-blinded trial.

BACKGROUND: Decreased surgical site infections (SSIs) and morbidity have been reported with mechanical and oral antibiotic bowel preparation (MOABP) compared with no bowel preparation (NBP) in colonic surgery. Several societies have recommended routine use of MOABP in patients undergoing colon resection on the basis of these data. Our aim was to investigate this recommendation in a prospective randomised context. METHODS: In this multicentre, parallel, single-blinded trial, patients undergoing colon resection were randomly assigned (1:1) to either MOABP or NBP in four hospitals in Finland, using a web-based randomisation technique. Randomly varying block sizes (four, six, and eight) were used for randomisation, and stratification was done according to centre. The recruiters, treating physicians, operating surgeons, data collectors, and analysts were masked to the allocated treatment. Key exclusion criteria were need for emergency surgery; bowel obstruction; colonoscopy planned during surgery; allergy to polyethylene glycol, neomycin, or metronidazole; and age younger than 18 years or older than 95 years. Study nurses opened numbered opaque envelopes containing the patient allocated group, and instructed the patients according to the allocation group to either prepare the bowel, or not prepare the bowel. Patients allocated to MOABP prepared their bowel by drinking 2 L of polyethylene glycol and 1 L of clear fluid before 6 pm on the day before surgery and took 2 g of neomycin orally at 7 pm and 2 g of metronidazole orally at 11 pm the day before surgery. The primary outcome was SSI within 30 days after surgery, analysed in the modified intention-to-treat population (all patients who were randomly allocated to and underwent elective colon resection with an anastomosis) along with safety analyses. The trial is registered with ClinicalTrials.gov, NCT02652637, and EudraCT, 2015-004559-38, and is closed to new participants. FINDINGS: Between March 17, 2016, and Aug 20, 2018, 738 patients were assessed for eligibility. Of the 417 patients who were randomised (209 to MOABP and 208 to NBP), 13 in the MOABP group and eight in the NBP were excluded before undergoing colonic resection; therefore, the modified intention-to-treat analysis included 396 patients (196 for MOABP and 200 for NBP). SSI was detected in 13 (7%) of 196 patients randomised to MOABP, and in 21 (11%) of 200 patients randomised to NBP (odds ratio 1·65, 95% CI 0·80-3·40; p=0·17). Anastomotic dehiscence was reported in 7 (4%) of 196 patients in the MOABP group and in 8 (4%) of 200 in the NBP group, and reoperations were necessary in 16 (8%) of 196 compared with 13 (7%) of 200 patients. Two patients died in the NBP group and none in the MOABP group within 30 days. INTERPRETATION: MOABP does not reduce SSIs or the overall morbidity of colon surgery compared with NBP. We therefore propose that the current recommendations of using MOABP for colectomies to reduce SSIs or morbidity should be reconsidered. FUNDING: Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, and Helsinki University Hospital research funds.

Platelet count, aspirin use, and characteristics of host inflammatory responses in colorectal cancer.

BACKGROUND: Platelets not only contribute to hemostasis but also to the regulation of inflammatory reactions and cancer pathogenesis. We hypothesized that blood platelet count would be associated with systemic inflammation, the densities of tumor infiltrating immune cells, and survival in colorectal cancer (CRC), and these relationships could be altered by aspirin use. METHODS: We measured blood platelet count in a cohort of 356 CRC patients and analyzed its relationships with tumor and patient characteristics including aspirin use, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of CRP, albumin, and 13 cytokines), blood hemoglobin levels, five types of tumor infiltrating immune cells (CD3, CD8, FoxP3, Neutrophil elastase, mast cell tryptase), and survival. RESULTS: Platelet count inversely correlated with blood hemoglobin levels (p < 0.001) and positively correlated with serum levels of CRP and multiple cytokines including IL-1RA, IL-4, IL-6, IL-7, IL-8, IL-12, IFNγ, and PDGF-BB (p < 0.001 for all), while aspirin use was not associated with the levels of systemic inflammatory markers. High platelet count was also associated with high mGPS (p < 0.001) but did not show statistically significant multivariable adjusted associations with the densities of tumor infiltrating immune cells. Higher platelet counts were observed in higher tumor stage (p < 0.001), but platelet count or aspirin use were not associated with patient survival. CONCLUSIONS: High platelet count is associated with systemic inflammation in CRC. This study could not demonstrate statistically significant associations between platelet count, aspirin use, and the densities of tumor infiltrating immune cells.

Serum TLR2 and TLR4 levels in colorectal cancer and their association with systemic inflammatory markers, tumor characteristics, and disease outcome.

Toll-like receptors (TLRs) are involved in colorectal cancer (CRC) pathogenesis. However, the significance of serum TLR concentrations in CRC is unknown. We analyzed serum TLR2 and TLR4 concentrations with ELISA in preoperative samples from 118 patients with CRC and 88 matched controls. We also assessed tissue TLR expression with immunohistochemistry and by detecting serum determinants of systemic inflammation. Most participants (>70%) had undetectable serum TLR2. The mean serum TLR4 levels were lower in patients than in controls (1.1 vs 1.8 ng/mL; p = 0.015). Undetectable TLR4 was more common in stage I (39%) than in stages II-IV (11%, p < 0.001). TLR2 or TLR4 expression in tumor cells did not correlate with serum levels, but abundant TLR2 expression in normal colon epithelium was associated with detectable serum TLR2 (p = 0.034). Undetectable serum TLR2 was linked to high modified Glasgow prognostic scores (p = 0.010), high CRP levels (p = 0.013), blood vessel invasion (p = 0.013), and tended to be associated with worse 5-year survival (p = 0.052). In conclusion, serum TLR2 levels were inversely associated with systemic inflammation in patients with CRC. Moreover, serum TLR2 levels might depend more on normal colorectal mucosa contributions than on tumor tissue contributions. Further studies are required to assess the prognostic value of serum TLR2.

Alterations in serum amino-acid profile in the progression of colorectal cancer: associations with systemic inflammation, tumour stage and patient survival.

BACKGROUND: Cancer cachexia is a complex wasting syndrome affecting patients with advanced cancer, with systemic inflammation as a key component in pathogenesis. Protein degradation and release of amino acids (AAs) in skeletal muscle are stimulated in cachexia. Here, we define factors contributing to serum AA levels in colorectal cancer (CRC). METHODS: Serum levels of nine AAs were characterised in 336 CRC patients and their relationships with 20 markers of systemic inflammatory reaction, clinicopathological features of cancers and patient survival were analysed. RESULTS: Low serum glutamine and histidine levels and high phenylalanine levels associated with indicators of systemic inflammation, including high modified Glasgow Prognostic Score, high blood neutrophil/lymphocyte ratio and high serum levels of CRP, IL-6 and IL-8. Low levels of serum glutamine, histidine, alanine and high glycine levels also associated with advanced cancer stage and with poor cancer-specific survival in univariate analysis. CONCLUSIONS: In CRC, serum AA levels are associated with systemic inflammation and disease stage. These findings may reflect muscle catabolism induced by systemic inflammation in CRC.

High-serum MMP-8 levels are associated with decreased survival and systemic inflammation in colorectal cancer.

BACKGROUND: Matrix metalloproteinase-8 (MMP-8) is a protease mainly expressed by neutrophils that cleaves numerous substrates, including collagens and cytokines. We have previously shown that serum MMP-8 levels increase in colorectal cancer (CRC) and correlate with distant metastasis. However, short follow-up in our prospective cohort did not enable survival analyses at the time of the first publication. METHODS: Preoperative serum MMP-8 levels were measured by immunofluorometric assay in 271 CRC patients and related to clinicopathological parameters, markers of systemic inflammation (modified Glasgow Prognostic Score, mGPS; serum levels of C-reactive protein (CRP), albumin and 13 cytokines), the density of six types of tumour-infiltrating immune cells and survival. RESULTS: Increased MMP-8 levels associated with higher mGPS and higher serum levels of CRP and several cytokines, including IL-1ra, IL-7 and IL-8 (p < 0.001 for all). Serum MMP-8 negatively correlated with tumour-infiltrating mast cells (invasive margin: p = 0.005, tumour centre: p = 0.010). The patients with high-serum MMP-8 levels (>100 ng/mL) had poor cancer-specific survival, independent of tumour stage, grade, lymphatic invasion, patient age, BRAF VE1 immunohistochemistry, mismatch repair deficiency, Immunoscore and mGPS (multivariate HR 2.12, 95% CI 1.21-3.71, p = 0.009). CONCLUSIONS: High-serum MMP-8 levels are associated with systemic inflammation and adverse outcome in CRC.

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, p = 0.023; 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.

Mortality and Survival after Surgical Treatment of Colorectal Cancer in Patients Aged over 80 Years.

OBJECTIVE: The purpose of this study was to identify the clinical factors and tumor characteristics that predict the outcome of colorectal cancer patients aged >80 years. MATERIALS AND METHODS: The data of 186 patients aged >80 years with colorectal cancer were collected from a computer database, and the variables were analyzed by both uni- and multivariate analyses. RESULTS: The 30-day mortality was 4% and the 90-day mortality 10%. The 1-year survival was 76%, and 27 (61%) of the 44 deaths were unrelated to cancer. The overall 5-year survival was 36%, the median survival 38 months, and the cancer-specific survival 40%. The recurrence rate after radical surgery was 22% and it was not affected by age. Kaplan-Meier estimates indicated that age, number of underlying diseases, radical operation, Union for International Cancer Control stage of the tumor, tumor size, number of lymph nodes involved, venous invasion, and recurrent disease were significant predictors of survival, but in the Cox regression model, only radical operation and venous invasion were independent prognostic factors for survival. CONCLUSIONS: After good surgical selection, low early mortality and acceptable long-term survival can be achieved even in the oldest old patients with colorectal cancer. However, low early mortality seems to underestimate the effects of surgery during the first postoperative year.

Divergent expression of bacterial wall sensing Toll-like receptors 2 and 4 in colorectal cancer.

AIM: To characterize the expression of toll-like receptors (TLR) 2 and 4 in colorectal cancer (CRC) and in normal colorectal mucosa. METHODS: We analysed tissue samples from a prospective series of 118 unselected surgically treated patients with CRC. Sections from formalin fixed, paraffin embedded specimens were analysed for TLR2 and TLR4 expression by immunohistochemistry. Two independent assessors evaluated separately expression at the normal mucosa, at the invasive front and the bulk of the carcinoma, and in the lymph node metastases when present. Expression levels in different locations were compared and their associations with clinicopathological features including TNM-stage and the grade of the tumour and 5-year follow-up observations were analysed. RESULTS: Normal colorectal epithelium showed a gradient of expression of both TLR2 and TLR4 with low levels in the crypt bases and high levels in the surface. In CRC, expression of both TLRs was present in all cases and in the major proportion of tumour cells. Compared to normal epithelium, TLR4 expression was significantly weaker but TLR2 expression stronger in carcinoma cells. Weak TLR4 expression in the invasive front was associated with distant metastases and worse cancer-specific survival at 5 years. In tumours of the proximal colon the cancer-specific survival at 5 years was 36.9% better with strong TLR4 expression as compared with those with weak expression (P = 0.044). In contrast, TLR2 expression levels were not associated with prognosis. Tumour cells in the lymph node metastases showed higher TLR4 expression and lower TLR2 expression than cells in primary tumours. CONCLUSION: Tumour cells in CRC show downregulation of TLR4 and upregulation of TLR2. Low expression of TLR4 in the invasive front predicts poor prognosis and metastatic disease.

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.

Predictors of quality-of-life after ileal pouch-anal anastomosis in patients with ulcerative colitis.

OBJECTIVES: Predictors of the postoperative quality of life (QoL) following ileal pouch anal anastomosis (IPAA) have not been thoroughly investigated. This study was planned to assess the postoperative QoL following IPAA and to identify its predictors using the 15D instrument. MATERIALS AND METHODS: A retrospective cohort study was conducted on IPAA-operated patients with ulcerative colitis in two Finnish tertiary hospitals during the period 1985-2014 (n = 485). Medical records were examined to collect data on baseline, operative and postoperative characteristics. Patients were surveyed using the 15D-instrument to assess their postoperative QoL. Linear regression analyses and receiver operating characteristic curve were applied to identify the predictors of postoperative QoL. RESULTS AND CONCLUSIONS: Of all patients, 61.5% experienced worse postoperative QoL, with significantly lower QoL level than that of an age and sex-standardized general population in 12 dimensions of the 15D-instrument, with the highest mean difference QoL scores calculated for excretion, sexual activity and sleeping dimensions. Older age and preoperative hypertension were the only significant predictors of lower overall QoL (p = .003 and p = .03, respectively). A preoperative age of ≥35 years was the most valid predictor of lower postoperative QoL (Sensitivity = 62.4% and Specificity = 49.6%, p = .04). In conclusion, postoperative QoL is generally low using the 15D-instrument after IPAA. Worse postoperative QoL is predicted after the age of 35.

Decreased preoperative serum 25-Hydroxyvitamin D levels in colorectal cancer are associated with systemic inflammation and serrated morphology.

Deficiency of vitamin D is associated with increased risk of several types of cancer including colorectal cancer (CRC). However, factors contributing to low levels of 25-hydroxyvitamin D [25(OH)D] in CRC are not clear. Therefore, in this study serum 25(OH)D levels in 117 CRC patients and 86 controls were analyzed and correlated with the clinicopathological data including morphological subtype (serrated or conventional), quantity of tumor infiltrating immune cells, levels of systemic inflammatory markers, and disease outcome. We found that the patients had lower serum 25(OH)D levels compared to the controls. Interestingly, among the patients mismatch repair deficiency, serrated morphology, and high body mass index associated with lowest serum 25(OH)D levels. In addition, patients operated in summer or autumn had higher serum 25(OH)D levels. Furthermore, serum 25(OH)D levels inversely correlated with several systemic inflammatory markers, e.g. serum C reactive protein, but did not associate with prognosis. Mechanism leading to vitamin D deficiency in these patients are not clear but could be related to the effects of systemic inflammation. Longitudinal studies are warranted to assess vitamin D deficiency as a potential risk factor for serrated colorectal polyps and adenocarcinoma.

Ectopic crypt foci in conventional and serrated colorectal polyps.

AIMS: Despite almost pathognomonic status of ectopic crypt foci (ECF) in the diagnosis of traditional serrated adenoma (TSA), there are few systematic studies on their prevalence in other types of colon polyps or in adenomas adjacent to colorectal cancer (CRC). METHODS: We calculated ECF in all the polyps (n=922) removed in the colonoscopy in Oulu University Hospital in 2001. Moreover, to study ECF in precursor lesions next to CRCs, we re-examined a previously described cohort of 148 CRCs. RESULTS: ECF were seen in 53 (5.7%) polyps representing 28 (6.5%) tubular adenomas (TAs), 14 (53.8%) tubulovillous adenomas (TVAs), 2 (100.0%) villous adenomas (VAs) and 9 (100.0%) TSAs. In all TSAs and VAs, the density of ECF was higher than in TVAs and TAs. An adjacent precursor lesion was recognised in 28 of 148 (18.9%) CRCs. Twenty-four (85.7%) of these contained ECF. CONCLUSIONS: ECF can most frequently be observed in TSAs but also in many TVAs, VAs and TAs, reflecting a histological overlap between serrated and conventional polyps. Especially, precursor lesions adjacent to CRC frequently contain ECF.