Toll-like receptor 4 and interleukin 6 gene polymorphisms in Helicobacter pylori related diseases

Abstract Helicobacter pylori is a Gram-negative bacterium, which infects the stomach of more than 50% of the population worldwide. In addition to being the most important risk factor for gastric cancer and peptic ulcers, H. pylori infection is a risk factor for several extra-digestive diseases including dyslipidemia. The consequences of having an H. pylori infection are significantly influenced by the inflammatory response of the host. The pattern recognition receptor Toll-like receptor 4 (TLR4) and the cytokine interleukin 6 (IL6) are important mediators of inflammation in H. pylori related diseases. We have analyzed a series of control subjects and patients with dyspepsia, peptic ulcers or gastric cancer for frequent genetic polymorphisms of the TLR4 and IL6 genes. The prevalence of H. pylori infection, the histologic features of gastritis and cancer and serum endocrine markers and lipid concentrations were also analyzed. Furthermore, the expression of TLR4 was analyzed in specific cell types of gastric mucosa by immunohistochemistry. The TLR4 wild type genotypes of polymorphisms +896 and +1196 were associated with an increased risk of peptic ulcers. The same genotypes also associated with higher serum gastrin levels, but not with atrophy or other features of gastritis. The TLR4 expression was seen in the gastrin and somatostatin secreting cells of gastric mucosa. These results suggest a regulatory link between TLR4 and gastrin secretion. Such a link indicates the presence of a novel effector mechanism for innate immunity in modifying the host endocrine function. The IL6 -174 polymorphism associated significantly with a risk of the diffuse type of gastric carcinoma but not with the intestinal type or its precursor conditions. Finally, we demonstrated that H. pylori infections modify HDL serum levels significantly only in IL6 -174 CC genotype patients, which suggests that the detrimental effects of H. pylori infections on HDL levels are transmitted through IL6. These results clarify the mechanisms of H. pylori related diseases and open new possibilities for research on peptic ulcer disease, gastric cancer and dyslipidemia.Tiivistelmä Helicobacter pylori on yleinen ihmisen mahalaukussa esiintyvä Gram-negatiivinen bakteeri. Helikobakteeri on tärkein mahasyövän ja maha- ja pohjukaissuolihaavan riskitekijä ja se on myös muun muassa rasva-aineenvaihdunnan häiriöiden riskitekijä. Ihmisen tulehdusvaste vaikuttaa merkittävästi helikobakteeri-infektion seurauksiin. Tollin kaltainen reseptori 4 (TLR4), joka on hahmontunnistusreseptori ja tulehduksenvälittäjäaine interleukiini 6 (IL6) ovat tärkeitä ihmisen tulehdusvasteeseen osallistuvia proteiineja. Olemme tutkineet dyspepsiaa, maha- ja pohjukaissuolihaavaa ja mahasyöpää sairastavilta potilailta sekä kontrollihenkilöiltä TLR4:n ja IL6:n geenien yleisiä emäsjärjestyksen polymorfioita. Tutkimme myös helikobakteeri-infektion yleisyyttä ja histologisia piirteitä, mahasyövän histologisia piirteitä ja seerumin merkkiaineita ja lipidipitoisuuksia. Lisäksi tutkimme TLR4:n ilmenemistä mahan limakalvolla immunohistokemiallisesti. TLR4:n polymorfismien +896 ja +1196 villin tyypin genotyypit liittyivät kohonneeseen maha- ja pohjukaissuolihaavan riskiin. Samat genotyypit liittyivät myös korkeampiin gastriinitasoihin. TLR4:ä esiintyi mahalaukun limakalvolla gastriinia tai somatostatiinia ilmentävissä soluissa. Täten TLR4:n ja maha- pohjukaissuolihaavariskin yhteys näyttää välittyvän gastriinin erityksen kautta, mikä viittaa uuteen säätely-yhteyteen luontaisen immuniteetin ja mahalaukun umpieritysjärjestelmän välillä. IL6 -174 -polymorfismi yhdistyi diffuusin tyypin mahakarsinooman riskiin mutta ei intestinaalisen tyypin karsinooman riskiin. Helikobakteeri-infektio yhdistyi pienentyneisiin HDL-kolesterolipitoisuuksiin vain potilailla, joilla oli IL6 -174 CC genotyyppi, mikä viittaa helikobakteerin kolesterolitasoille haitallisen vaikutuksen välittyvän IL6:n kautta. Nämä tulokset antavat lisätietoa helikobakteerin aiheuttamien sairauksien mekanismeista ja avaavat uusia tutkimuspolkuja myös mahahaavan, mahasyövän ja rasva-aineenvaihdunnan häiriöiden kliiniseen tutkimukseen

Tumour budding and tumour–stroma ratio in hepatocellular carcinoma

Abstract Background: Tumour budding and low tumour–stroma ratio (TSR) are associated with poor prognosis in some cancers, but their value in Western hepatocellular carcinoma is unclear. The prognostic value of tumour budding and TSR in hepatocellular carcinoma was examined. Methods: Some 259 hepatocellular carcinoma patients treated in Oulu University Hospital 1983–2018 were included in this retrospective cohort study. Tumour budding and TSR were analysed from the haematoxylin- and eosin-stained original diagnostic slides, by dividing patients into bud-negative (0 bud) or bud-positive (≥1 bud) groups, and into high TSR (<50%) and low TSR (≥50%) groups. Surgically treated patients (n = 47) and other treatments (n = 212) were analysed separately. Primary outcomes were overall, and disease-specific 5-year mortality was adjusted for confounding factors. Results: Surgically treated patients with positive tumour budding had increased 5-year overall (adjusted HR 3.87, 95% CI 1.10–13.61) and disease-specific (adjusted HR 6.17, 95% CI 1.19–31.90) mortality compared with bud-negative patients. In surgically treated patients, TSR had no effect on 5-year overall (adjusted HR 2.03, 95% CI 0.57–7.21) or disease-specific (adjusted HR 3.23, 95% CI 0.78–13.37) mortality. No difference in survival related to tumour budding and TSR in non-surgically treated patients was observed. Conclusions: Tumour budding is a prognostic factor in surgically treated hepatocellular carcinoma

Ruoansulatuskanavan yläosan neuroendokriiniset kasvaimet ovat harvinaisia

Tiivistelmä Ruoansulatuskanavan yläosassa äärimmäisen harvinaiset neuroendokriiniset kasvaimet ovat yleensä hormonaalisesti toimimattomia. Ruokatorvessa yleisin tyyppi on huonoennusteinen neuroendokriininen karsinooma. Mahalaukussa yleisin on atrofiseen gastriittiin liittyvä tyypin 1 neuroendokriininen kasvain. Siinä ennuste on parempi kuin tyypin 2 ja 3 kasvaimissa ja neuroendokriinisessä karsinoomassa. Pohjukaissuolen neuroendokriiniset kasvaimet ovat yleensä toimimattomia. Yleisin hormonaalisesti aktiivinen kasvain on yleensä MEN1-oireyhtymään liittyvä gastrinooma

Treatment trends and outcomes of hepatocellular carcinoma in a single center for 35 years

Abstract Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The aim of this study was to examine the trends of HCC treatment and the outcomes in a single tertiary center for 35 years. Methods: Two hundred seventy–three consecutive HCC patients between 1983–2018 were identified from Oulu University Hospital records. Primary outcomes of the study were postoperative complications within 30 days after the operation, and short– (30–and 90–day) and long-term (1, 3 and 5–year) survival. Results: Of the 273 patients, 49 underwent surgical resection, 25 local ablation, 48 angiological treatment and 151 had palliative treatment. The rate of surgery declined over time, while other invasive treatments increased. Major complications occurred in 14 (28.6%) patients after surgical resection, in 2 (8.0%) patients after local ablation and in 13 (27.1%) patients after angiological treatment (P=0.022). Recurrence and local recidives were observed especially in local ablation group and in angiological treatment group (P<0.001). Overall survival rates in surgical resection group were at 30 and 90 days, 1–, 3– and 5–years 95.9%, 95.9%, 85.1%, 59.0% and 51.2%. In local ablation group, respective overall survival rates were 100.0%, 100.0%, 86.1%, 43.1% and 18.8%, and in angiological group 95.8%, 93.6%, 56.1%, 26.3% and 6.6%. In cox regression model adjusted for confounding factors, mortality hazard was lowest after surgical resection. Prognosis was poor in palliative group. Conclusions: Based on this Northern Finland population, the surgical resection of HCC has acceptable complication rate compared to other treatments; and yields the best long-term survival. Overall prognosis of HCC remains poor

Histological assessment of stromal maturity as a prognostic factor in surgically treated gastric adenocarcinoma

Abstract Aims: Histological assessment of stromal maturity is a potential prognostic factor in colorectal cancer, but its applicability in gastric adenocarcinoma is completely unknown. The aim of this study was to evaluate the feasibility and prognostic significance of assessing stromal maturity in gastric adenocarcinoma. Methods and results: This study was conducted retrospectively in a cohort of 583 gastric adenocarcinoma patients treated surgically in Oulu University Hospital, Finland between 1983 and 2016. The original diagnostic slides were used for assessment of stromal maturity. Patients were divided into mature stroma and immature stroma groups, and stromal maturity was analysed in relation to 5‐year and overall survival (OS). The primary outcome of the study was 5‐year survival, and the secondary outcome was OS. The kappa‐coefficient for interobserver agreement was 0.609. Patients with immature stroma had worse 5‐year survival compared to patients with mature stroma [adjusted hazard ratio (HR) = 1.32, 95% confidence interval (CI) = 1.06–1.64]. Stromal maturity was significantly associated with 5‐year survival in intestinal‐type subgroup (adjusted HR = 0.63, 95% CI = 1.20–2.21), but not in the diffuse‐type subgroup (adjusted HR = 1.21, 95% CI = 0.87–1.70). Conclusions: Stromal maturity is an independent prognostic factor in gastric adenocarcinoma, and it can be analysed with moderate reproducibility

Virtual monochromatic imaging reduces beam hardening artefacts in cardiac interior photon counting computed tomography:a phantom study with cadaveric specimens

Abstract In interior cardiac computed tomography (CT) imaging, the x-ray beam is collimated to a limited field-of-view covering the heart volume, which decreases the radiation exposure to surrounding tissues. Spectral CT enables the creation of virtual monochromatic images (VMIs) through a computational material decomposition process. This study investigates the utility of VMIs for beam hardening (BH) reduction in interior cardiac CT, and further, the suitability of VMIs for coronary artery calcium (CAC) scoring and volume assessment is studied using spectral photon counting detector CT (PCD-CT). Ex vivo coronary artery samples (N = 18) were inserted in an epoxy rod phantom. The rod was scanned in the conventional CT geometry, and subsequently, the rod was positioned in a torso phantom and re-measured in the interior PCD-CT geometry. The total energy (TE) 10–100 keV reconstructions from PCD-CT were used as a reference. The low energy 10–60 keV and high energy 60–100 keV data were used to perform projection domain material decomposition to polymethyl methacrylate and calcium hydroxylapatite basis. The truncated basis-material sinograms were extended using the adaptive detruncation method. VMIs from 30–180 keV range were computed from the detruncated virtual monochromatic sinograms using filtered back projection. Detrending was applied as a post-processing method prior to CAC scoring. The results showed that BH artefacts from the exterior structures can be suppressed with high (≥100 keV) VMIs. With appropriate selection of the monoenergy (46 keV), the underestimation trend of CAC scores and volumes shown in Bland-Altman (BA) plots for TE interior PCD-CT was mitigated, as the BA slope values were −0.02 for the 46 keV VMI compared to −0.21 the conventional TE image. To conclude, spectral PCD-CT imaging using VMIs could be applied to reduce BH artefacts interior CT geometry, and further, optimal selection of VMI may improve the accuracy of CAC scoring assessment in interior PCD-CT

Optimized detection and segmentation of nuclei in gastric cancer images using stain normalization and blurred artifact removal

Abstract Histological analysis with microscopy is the gold standard to diagnose and stage cancer, where slides or whole slide images are analyzed for cell morphological and spatial features by pathologists. The nuclei of cancerous cells are characterized by nonuniform chromatin distribution, irregular shapes, and varying size. As nucleus area and shape alone carry prognostic value, detection and segmentation of nuclei are among the most important steps in disease grading. However, evaluation of nuclei is a laborious, time-consuming, and subjective process with large variation among pathologists. Recent advances in digital pathology have allowed significant applications in nuclei detection, segmentation, and classification, but automated image analysis is greatly affected by staining factors, scanner variability, and imaging artifacts, requiring robust image preprocessing, normalization, and segmentation methods for clinically satisfactory results. In this paper, we aimed to evaluate and compare the digital image analysis techniques used in clinical pathology and research in the setting of gastric cancer. A literature review was conducted to evaluate potential methods of improving nuclei detection. Digitized images of 35 patients from a retrospective cohort of gastric adenocarcinoma at Oulu University Hospital in 1987–2016 were annotated for nuclei (n = 9085) by expert pathologists and 14 images of different cancer types from public TCGA dataset with annotated nuclei (n = 7000) were used as a comparison to evaluate applicability in other cancer types. The detection and segmentation accuracy with the selected color normalization and stain separation techniques were compared between the methods. The extracted information can be supplemented by patient’s medical data and fed to the existing statistical clinical tools or subjected to subsequent AI-assisted classification and prediction models. The performance of each method is evaluated by several metrics against the annotations done by expert pathologists. The F1-measure of 0.854 ± 0.068 is achieved with color normalization for the gastric cancer dataset, and 0.907 ± 0.044 with color deconvolution for the public dataset, showing comparable results to the earlier state-of-the-art works. The developed techniques serve as a basis for further research on application and interpretability of AI-assisted tools for gastric cancer diagnosis

Interior photon counting computed tomography for quantification of coronary artery calcium:pre-clinical phantom study

Abstract Computed tomography (CT) is the reference method for cardiac imaging, but concerns have been raised regarding the radiation dose of CT examinations. Recently, photon counting detectors (PCDs) and interior tomography, in which the radiation beam is limited to the organ-of-interest, have been suggested for patient dose reduction. In this study, we investigated interior PCD-CT (iPCD-CT) for non-enhanced quantification of coronary artery calcium (CAC) using an anthropomorphic torso phantom and ex vivo coronary artery samples. We reconstructed the iPCD-CT measurements with filtered back projection (FBP), iterative total variation (TV) regularization, padded FBP, and adaptively detruncated FBP and adaptively detruncated TV. We compared the organ doses between conventional CT and iPCD-CT geometries, assessed the truncation and cupping artifacts with iPCD-CT, and evaluated the CAC quantification performance of iPCD-CT. With approximately the same effective dose between conventional CT geometry (0.30 mSv) and interior PCD-CT with 10.2 cm field-of-view (0.27 mSv), the organ dose of the heart was increased by 52.3% with interior PCD-CT when compared to CT. Conversely, the organ doses to peripheral and radiosensitive organs, such as the stomach (55.0% reduction), were often reduced with interior PCD-CT. FBP and TV did not sufficiently reduce the truncation artifact, whereas padded FBP and adaptively detruncated FBP and TV yielded satisfactory truncation artifact reduction. Notably, the adaptive detruncation algorithm reduced truncation artifacts effectively when it was combined with reconstruction detrending. With this approach, the CAC quantification accuracy was good, and the coronary artery disease grade reclassification rate was particularly low (5.6%). Thus, our results confirm that CAC quantification can be performed with the interior CT geometry, that the artifacts are effectively reduced with suitable interior reconstruction methods, and that interior tomography provides efficient patient dose reduction

Increased n-6 polyunsaturated fatty acids indicate pro- and anti-inflammatory lipid modifications in synovial membranes with rheumatoid arthritis

Abstract Emerging evidence suggests that fatty acids (FAs) and their lipid mediator derivatives can induce both beneficial and detrimental effects on inflammatory processes and joint degradation in osteoarthritis (OA) and autoimmune-driven rheumatoid arthritis (RA). The present study characterized the detailed FA signatures of synovial membranes collected during knee replacement surgery of age- and gender-matched OA and RA patients (n = 8/diagnosis). The FA composition of total lipids was determined by gas chromatography and analyzed with univariate and multivariate methods supplemented with hierarchical clustering (HC), random forest (RF)-based classification of FA signatures, and FA metabolism pathway analysis. RA synovium lipids were characterized by reduced proportions of shorter-chain saturated FAs (SFAs) and elevated percentages of longer-chain SFAs and monounsaturated FAs, alkenyl chains, and C20 n-6 polyunsaturated FAs compared to OA synovium lipids. In HC, FAs and FA-derived variables clustered into distinct groups, which preserved the discriminatory power of the individual variables in predicting the RA and OA inflammatory states. In RF classification, SFAs and 20:3n-6 were among the most important FAs distinguishing RA and OA. Pathway analysis suggested that elongation reactions of particular long-chain FAs would have increased relevance in RA. The present study was able to determine the individual FAs, FA groups, and pathways that distinguished the more inflammatory RA from OA. The findings suggest modifications of FA elongation and metabolism of 20:4n-6, glycerophospholipids, sphingolipids, and plasmalogens in the chronically inflamed RA synovium. These FA alterations could have implications in lipid mediator synthesis and potential as novel diagnostic and therapeutic tools