Clinicopathological Factors Associated with Incomplete Excision of Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (SCC) is the second most common type of cancer in Swedish men and women. The incidence of SCC is increasing rapidly. Primary treatment is complete surgical excision with sufficient margins to avoid recurrence and metastasis. The aim of this retrospective study was to identify the clinicopathological factors associated with incomplete excision of SCCs. Clinicopathological data and surgical outcome was obtained for 691 SCCs excised during a 2-year period (2014 to 2015) in Gothenberg, Sweden. Overall, 81 SCCs (11.7%) were incompletely excised. Incomplete excisions were associated with physician specialty and experience, tumour localization in the head and neck region, larger tumour diameter, and lower grade of tumour differentiation. However, multiple regression analysis revealed that large tumour size and excisions carried out by general practitioners were the only factors that significantly negatively affected rates of incomplete excision. These results should be taken into consideration when excising SCCs, in order to avoid multiple excisions.

Enriching social and economic aspects in sustainability assessments of remediation strategies - Methods and implementation.

Over the last decade, there has been rapid development in promoting and implementing sustainable remediation. It is now common to include at least some sustainability considerations in remediation projects. Specific challenges that have been highlighted often relate to economic and social aspects not receiving enough attention: broadening the social aspects, community and meaningful stakeholder engagement, understanding stakeholders' risk perception, and a need for better estimates of site-specific economic costs and benefits. This study presents an application of the Sustainable Choice of REmediation (SCORE) framework with special focus on (1) demonstrating the working process for a broad sustainability assessment and (2) sharing the lessons learned from its application. Specific objectives are to describe (a) the types of stakeholders involved in the assessment, (b) the methods for collection of social and economic sustainability data, (c) residents' perception of risks, (d) the use of the sustainability assessment results in the decision-making process, and (5) possibilities for improving the methods and working process. SCORE was applied and evaluated with input from, and together with, stakeholders at the BT Kemi industrial site in the village of Teckomatorp, south Sweden, a former pesticide production site associated with the most infamous Swedish environmental scandal. A questionnaire (n = 78) was used to collect input from residents regarding local acceptance and economic externalities of the remediation alternatives. Alternatives with a high degree of removal of contaminants received a high ranking in the assessment, primarily due to social and economic effects. The working process can be improved, specifically regarding workshop preparation and workshop structure. A broad representation of stakeholders and early establishment of communication channels to residents is key for robust assessment of social aspects. The information from the sustainability assessment was used in the decision-making process, not least for revising remediation options.

Expression of major histocompatibility complex class I-related chain A/B (MICA/B) in pancreatic carcinoma.

Major histocompatibility complex class I-related chain A and B (MICA/B) are two stress-inducible ligands that bind to the immunoreceptor NKG2D and play an important role in mediating cytotoxicity of NK and T cells. Release of MIC molecules from the cell surface is thought to constitute an immune escape mechanism of tumor cells and thus could be associated with more aggressive course of tumor growth. In this study, we investigated the expression of MICA/B in ductal pancreatic carcinoma and serum in relation to tumor stage, differentiation and survival. MICA/B expression in tumor tissues and sera from patients with pancreatic cancer were analyzed by immunohistochemical staining (IHC), western blotting and ELISA, respectively. MICA/B expression was present in 17 of 22 (77%) of the tumors but not in normal pancreatic ductal epithelial cells. Poorly differentiated tumors showed more pronounced MICA/B expression compared to differentiated tumors, but did not correlate significantly to other tumor characteristics. MICA/B-negative tumors displayed significantly lower incidence of lymph node metastases (p<0.01), and less mortality within 3 years following resection (p<0.02). In conclusion, tissue levels of MICA/B expression were elevated in pancreatic cancer cells without elevated levels in serum, despite well-recognized acute phase reactants in serum. Poorly differentiated tumors showed high MICA/B expression, which was related to extended tumor lymph node metastases and less frequent long-term survival.

EGF receptor and COX-1/COX-2 enzyme proteins as related to corresponding mRNAs in human per-operative biopsies of colorectal cancer.

BACKGROUND: Cyclooxygenase (COX) and epidermal growth factor receptor (EGFR) activities promote progression of colorectal cancer. Combined treatment against these targets has not been more effective than single treatments alone. Therefore, our aim was to analyze relationships between COX and EGFR in peroperative colorectal tumor biopsies. METHOD: Tumor and colon mucosa tissue were collected at primary intended curative operations in patients according to well-recognized statistical distributions of tumor stages in colorectal cancer. COX-1, COX-2 and EGFR content in tumor and colon mucosa tissue were quantified by western blot and Q-PCR. RESULTS: COX-2 protein appeared as two bands, one at 66 kDa in almost all tumor and mucosa samples and one at 74 kDa in 73% of the tumors and in 23% of the mucosa samples. Tumor COX-2 mRNA was not different from the content in mucosa samples, while COX-2 protein was increased in tumor tissue (p < 0.0003). A correlation between 74 kDa COX-2 protein and COX-2 mRNA occurred in tumor tissue, with significantly increasing COX-2 mRNA across tumor stages. EGFR mRNA content was lower in tumor tissue (p < 0.0001), while EGFR protein was similar in tumor and mucosa samples. COX-2 and EGFR proteins showed a positive correlation in mucosa, while a negative correlation occurred in tumor tissue. Tumor tissue with high COX-2 74 kDa protein lacked EGFR protein. CONCLUSION: Our present results are compatible with the theory that COX-2 and EGFR signalling pathways are inversely related in colorectal cancer tissue. This may explain why combinatorial clinical treatments have been less rewarding.

Expression of the chemokine decoy receptor D6 is decreased in colon adenocarcinomas.

Recruitment of immune cells to tumors is a complex process crucial for both inflammation-driven tumor progression and specific anti-tumor cytotoxicity. Chemokines control the directed migration of immune cells, and their actions are partly controlled by nonsignaling chemokine decoy receptors. The role of the receptors such as D6, Duffy antigen receptor for chemokines and ChemoCentryx chemokine receptor in immunity to tumors is still unclear. Using real-time PCR, we detected significantly decreased expression of D6 mRNA in colon tumors compared to unaffected mucosa. D6 protein was expressed by lymphatic endothelium and mononuclear cells in the colon lamina propria and detected by immunohistochemistry in two out of six tissue samples containing high D6 mRNA levels, whereas no staining was observed in any tissue samples expressing low mRNA levels. When examining the density of lymphatic vessels in colon tumors, we detected a marked increase in vessels identified by the lymphatic endothelial marker Lyve-1, excluding passive regulation of D6 due to decreased lymphatic vessel density. In parallel, the Treg-recruiting chemokine CCL22, which is sequestered by D6, was threefold increased in tumor tissue. Furthermore, we could show that low D6 expression correlated to more invasive tumors and that tumor location influences D6 expression, which is lower in the more distal parts of the colon. The data support that regulation of D6 by colon tumors results in altered levels of proinflammatory CC chemokines, thereby shaping the local chemokine network to favor tumor survival. This may have implications for the design of future immunotherapy for colon cancer.

Accumulation of CCR4⁺CTLA-4 FOXP3⁺CD25(hi) regulatory T cells in colon adenocarcinomas correlate to reduced activation of conventional T cells.

BACKGROUND: Colorectal cancer usually gives rise to a specific anti-tumor immune response, but for unknown reasons the resulting immunity is not able to clear the tumor. Recruitment of activated effector lymphocytes to the tumor is important for efficient anti-tumor responses, while the presence of regulatory T cells (Treg) down-modulate tumor-specific immunity. We therefore aimed to determine homing mechanisms and activation stage of Treg and effector T cell infiltrating colon tumors compared to cells from the unaffected mucosa in patients suffering from colon adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: Lymphocytes were isolated from unaffected and tumor mucosa from patients with colon adenocarcinoma, and flow cytometry, immunohistochemistry, and quantitative PCR was used to investigate the homing mechanisms and activation stage of infiltrating Treg and conventional lymphocytes. We detected significantly higher frequencies of CD25(high)FOXP3⁺CD127(low) putative Treg in tumors than unaffected mucosa, which had a complete demethylation in the FOXP3 promotor. Tumor-associated Treg had a high expression of CTLA-4, and some appeared to be antigen experienced effector/memory cells based on their expression of αEß7 (CD103). There were also significantly fewer activated T cells and more CTLA-4⁺ conventional T cells susceptible to immune regulation in the tumor-associated mucosa. In contrast, CD8⁺granzyme B⁺ putative cytotoxic cells were efficiently recruited to the tumors. The frequencies of cells expressing α4ß7 and the Th1 associated chemokine receptor CXCR3 were significantly decreased among CD4⁺ T cells in the tumor, while frequencies of CD4⁺CCR4⁺ lymphocytes were significantly increased. CONCLUSIONS/SIGNIFICANCE: This study shows that CCR4⁺CTLA4(hi) Treg accumulate in colon tumors, while the frequencies of activated conventional Th1 type T cells are decreased. The altered lymphocyte composition in colon tumors will probably diminish the ability of the immune system to effectively attack tumor cells, and reducing the Treg activity is an important challenge for future immunotherapy protocols.

Selective upregulation of endothelial E-selectin in response to Helicobacter pylori-induced gastritis.

Helicobacter pylori is one of the most common bacterial pathogens, infecting up to 50% of the world's population. The host is not able to clear the infection, leading to life-long chronic inflammation with continuous infiltration of lymphocytes and granulocytes. The migration of leukocytes from the blood into inflamed tissue is dependent on adhesion molecules expressed on the vascular endothelium. The aim of this study was to characterize the effect of H. pylori-induced gastritis with regard to the expression of endothelial adhesion molecules in the gastric mucosa and compare this to other types of chronic mucosal inflammations. Our results demonstrate an increased level of expression of the adhesion molecule E-selectin, but not of intracellular adhesion molecule 1, vascular adhesion molecule 1, or vascular adhesion protein 1, in H. pylori-induced gastritis but not in gastritis induced by acetylsalicylic acid or pouchitis. The upregulated E-selectin expression was determined to be localized to the gastric mucosa rather than being a systemic response to the infection. Moreover, the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI) was found to be an important determinant for the upregulation of human endothelial E-selectin expression in vitro, and this process is probably dependent on the CagL protein, mediating binding to alpha5beta1 integrins. Thus, endothelial E-selectin expression induced by H. pylori probably contributes to the large influx of neutrophils and macrophages seen in infected individuals, and our results suggest that this process may be more pronounced in patients infected with cagPAI-positive H. pylori strains and may thereby contribute to tissue damage in these individuals.

CCL28 is increased in human Helicobacter pylori-induced gastritis and mediates recruitment of gastric immunoglobulin A-secreting cells.

Human Helicobacter pylori infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only H. pylori-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosa-associated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in H. pylori-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from H. pylori-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA(+) memory B cells from H. pylori-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from H. pylori-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1alpha). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in H. pylori-infected individuals.

Gastric gelatinase B/matrix metalloproteinase-9 is rapidly increased in Helicobacter felis-induced gastritis.

It has previously been shown that matrix metalloproteinase-9 (MMP-9) levels, originating from macrophages, are considerably increased in human Helicobacter pylori-associated gastritis. Here, the early kinetics of the MMP-9 response resulting from Helicobacter infection in C57BL/6 and MMP-9 knock-out mice using the murine Helicobacter felis model were examined. H. felis infection induced severe gastritis in the murine stomach at just 2 weeks after infection. Before gastritis, an increase was observed in MMP-9-positive cells detected by immunohistochemistry in the basal lamina propria. This finding was corroborated by gelatin zymography of stomach samples. As the gastritis increased so did the concentration of MMP-9 and the incidence of gastric MMP-9-positive cells, their location corresponding to that of macrophages. In contrast, systemic levels of MMP-9 remained unchanged. When MMP-9-deficient mice were infected with H. felis, no significant difference in gastritis development was detected compared with disease development in wild-type animals. We conclude that MMP-9 production is an early event in the response to gastric Helicobacter infection, a feature that may favor the recruitment of immune cells early during infection. At later stages, however, the increased levels of MMP-9 may damage the integrity of the stomach mucosa.

Annoyance due to single and combined sound exposure from railway and road traffic.

Environmental noise is a growing and well recognized health problem. However, in many cases people are exposed not to a single noise source-for example, road, railway, or aircraft noise-but to a combination of noise exposures and there is only limited knowledge of the effects on health of exposure to combined noise sources. A socio-acoustic survey among 1953 persons aged 18-75 years was conducted in residential areas exposed to railway and road traffic noise with sound levels ranging from L(Aeq,24h) 45-72 dB in a municipality east of Gothenburg, Sweden. The objectives were to assess various adverse health effects, including annoyance, and to elucidate the impact of exposure to single and combined noise sources. In areas exposed to both railway and road traffic, the proportion annoyed by the total traffic sound environment (total annoyance) was significantly higher than in areas with one dominant noise source (rail or road traffic) with the same total sound exposure (L(Aeq,24h,tot)). This interaction effect was significant from 59 dB and increased gradually with higher sound levels. Effects of the total sound exposure should be considered in risk assessments and in noise mitigation activities.

Paid and unpaid work, and its relation to low back and neck/shoulder disorders among women.

The aim of the present study was to estimate the influence of total work hours, paid work in the labor market and unpaid work in the family domain, on care-seeking for low back and neck/shoulder disorders in the female population. The exposure assessments considered a typical working' day during the previous twelve months and were assessed by interviews and questionnaires; 704 cases and 984 referents were examined. The cases had sought professional care during the study period; the referents were randomly selected from the same source population. There was no increased relative risk for care-seeking for low back and neck/shoulder disorders for gainfully employed women compared to those not employed, or for full-time compared to part-time working women. At least 60 hours per week of paid work, or at least 40 hours per week of unpaid work, separately, indicated an increased relative risk for care-seeking. The present results did not strengthen the hypothesis that a high amount of hours of work is an independent risk factor for musculoskeletal disorders.

Glass-based radon-exposure assessment and lung cancer risk.

Lung cancer risk estimation in relation to residential radon exposure remains uncertain, partly as a result of imprecision in air-based retrospective radon-exposure assessment in epidemiological studies. A recently developed methodology provides estimates for past radon concentrations and involves measurement of the surface activity of a glass object that has been in a subject's dwellings through the period for exposure assessment. Such glass measurements were performed for 110 lung cancer subjects, diagnosed 1985 to 1995, and for 231 control subjects, recruited in a case-control study of residential radon and lung cancer among never-smokers in Sweden. The relative risks (with 95% confidence intervals) of lung cancer in relation to categories of surface-based average domestic radon concentration during three decades, delimited by cutpoints at 50, 80, and 140 Bq m(-3), were 1.60 (0.8 to 3.4), 1.96 (0.9 to 4.2), and 2.20 (0.9 to 5.6), respectively, with average radon concentrations below 50 Bq m(-3) used as reference category, and with adjustment for other risk factors. These relative risks, and the excess relative risk (ERR) of 75% (-4% to 430%) per 100 Bq m(-3) obtained when using a continuous variable for surface-based average radon concentration estimates, were about twice the size of the corresponding relative risks obtained among these subjects when using air-based average radon concentration estimates. This suggests that surface-based estimates may provide a more relevant exposure proxy than air-based estimates for relating past radon exposure to lung cancer risk.