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Aim: We compared variability in number of examined lymph nodes between pathologists and analyzed survival implications in lung and esophageal cancer after standardized lymphadenectomy. Methods: Outcomes of 294 N2 dissected lung cancer patients and 132 2-field dissected esophageal cancer patients were retrospectively examined. The primary outcome was difference in reported lymph node count among pathologists. Secondary outcomes were overall and disease-specific survival related to this count and survival related to the 50% probability cut-off value of detecting metastasis based on the number of examined lymph nodes. Results: The median number of examined lymph nodes in lung cancer was 13 (IQR 9–17) and in esophageal cancer it was 22 (18–29). The pathologist with the highest median number of examined nodes had > 50% higher lymph node yield compared with the pathologist with the lowest median number of nodes in lung (15 vs. 9.5, p = 0.003), and esophageal cancer (28 vs. 17, p = 0.003). Survival in patients stratified by median reported lymph node count in both lung (adjusted RMST ratio < 14 vs. ≥ 14 lymph nodes 0.99, 95% CI 0.88–1.10; p = 0.810) and esophageal cancer (adjusted RMST ratio < 25 vs. ≥ 25 lymph nodes 0.95, 95% CI 0.79–1.15, p = 0.612) was similar. The cut-off value for 50% probability of detecting metastasis by number of examined lymph nodes in lung cancer was 15.7 and in esophageal cancer 21.8. When stratified by this cut-off, no survival differences were seen. Conclusion: The quality of lymphadenectomy based on lymph node yield is susceptible to error due to detected variability between pathologists in the number of examined lymph nodes. This variability in yield did not have any survival effect after standardized lymphadenectomy.

Background: The CD274 (PD-L1)/PDCD1 (PD-1) immune checkpoint interaction may promote cancer progression, but the expression patterns and prognostic significance of PD-L1 and PD-1 in the colorectal cancer microenvironment are inadequately characterised. Methods: We used a custom 9-plex immunohistochemistry assay to quantify the expression patterns of PD-L1 and PD-1 in macrophages, T cells, and tumour cells in 910 colorectal cancer patients. We evaluated cancer-specific mortality according to immune cell subset densities using multivariable Cox regression models. Results: Compared to PD-L1⁻ macrophages, PD-L1⁺ macrophages were more likely M1-polarised than M2-polarised and located closer to tumour cells. PD-L1⁺ macrophage density in the invasive margin associated with longer cancer-specific survival [Ptrend= 0.0004, HR for the highest vs. lowest quartile, 0.52; 95% CI: 0.34–0.78]. T cell densities associated with longer cancer-specific survival regardless of PD-1 expression (Ptrend < 0.005 for both PD-1⁺ and PD-1⁻ subsets). Higher densities of PD-1⁺ T cell/PD-L1⁺ macrophage clusters associated with longer cancer-specific survival (Ptrend < 0.005). Conclusions: PD-L1⁺ macrophages show distinct polarisation profiles (more M1-like), spatial features (greater co-localisation with tumour cells and PD-1⁺ T cells), and associations with favourable clinical outcome. Our comprehensive multimarker assessment could enhance the understanding of immune checkpoints in the tumour microenvironment and promote the development of improved immunotherapies.

Tiivistelmä JOHDANTO: Tutkimuksessamme arvioitiin porrastestin hyötyjä vakavien komplikaatioiden ja kuolleisuuden ennustajana vaativassa syöpäkirurgiassa. POTILAAT JA MENETELMÄT: Aineiston muodostivat Keski-Suomen keskussairaalassa vuosina 2012–2021 leikatut 495 ruokatorvi- ja keuhkosyöpäpotilasta. Porrastestistä muodostettiin kolme ryhmää: yli 14 metriä (neljä kerrosta), 10–14 metriä (3–4 kerrosta) ja alle kymmenen metriä (alle kolme kerrosta) nousevat. Potilaat vastasivat myös suorituskykykyselyyn. Päätemuuttujat olivat vakavat komplikaatiot, kuolleisuus 90 vuorokauden kuluessa, viiden vuoden kokonaiskuolleisuus sekä kuolemat muuhun kuin syöpään. TULOKSET: Vakavia komplikaatioita ilmaantui eniten huonon (alle 10 m) suorituskyvyn ryhmässä (23 %) verrattuna 10–14 metrin (12 %) ja yli 14 metrin (11 %) ryhmiin (p = 0,037). Yhdeksänkymmenen vuorokauden kuolleisuus oli vastaavasti 10 %, 4,1 % ja 0,7 % (p < 0,001), ja viiden vuoden elossaolo-osuudet olivat 45 %, 36 % ja 69 % (p < 0,001). Kun tarkasteltiin muita kuin syövästä johtuvia kuolemia, elossaolo-osuudet olivat 47 %, 66 % ja 88 % (p < 0,001). Monimuuttujamallissa porrastestitulos oli kuolleisuuden lisääntymisen itsenäinen riskitekijä. PÄÄTELMÄT: Suorituskyky vaikuttaa ruokatorvi- ja keuhkosyöpäkirurgiassa potilaan hoitolinjaukseen, leikkauskomplikaatioihin ja pitkän ajan tuloksiin.

Background: Colorectal cancer (CRC) causes the second most cancer deaths worldwide, but the disease course varies according to tumour characteristics and immunological factors. Our objective was to examine the associations of tumour necrosis with tumour characteristics, immune cell infiltrates, serum cytokine concentrations, as well as prognosis in CRC. Methods: Three independent CRC cohorts, including 1413 patients, were analysed. Associations of the areal percentage of tumour necrosis with clinicopathologic parameters, tumour infiltrating immune cells, cytokine concentrations in systemic and mesenteric vein blood, and survival were examined. Results: Higher tumour necrosis percentage associated with shorter colorectal cancer-specific survival independent of tumour grade, T, N or M-class, mismatch repair status, BRAF status, and other possible confounding factors. In the largest cohort (N = 1100), the HR for high tumour necrosis percentage (≥40% vs. <3%) was 3.22 (95% CI 1.68–6.17, Ptrend < 0.0001). Tumour necrosis percentage positively correlated with peripheral serum levels of CXCL8, a proinflammatory chemokine, and negatively correlated with mesenteric serum levels of CXCL10 and mast cell densities in the invasive margin of the tumour. Conclusions: Our results support the value of tumour necrosis as a prognostic factor in colorectal cancer. CXCL8 may have a role in the systemic effects of tumour necrosis.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates located at sites of chronic inflammation and recognized as prognosticators in several cancers. We aimed to analyse the prognostic effect of TLSs in colorectal cancer (CRC) pulmonary metastases and primary tumours, with a comparison to the CD3+ and CD8+ cell density-based immune cell score (ICS). For TLS density and TLS maximum diameter analysis, 67 pulmonary metastases and 63 primary tumours were stained with haematoxylin and eosin. For ICS scoring and analysis, CD3 and CD8 immunohistochemistry was performed. Excellent interobserver agreement was achieved in all TLS measurements. Of all patients, 36 patients had low TLS density (< 0.222 follicles/mm) and 31 patients had high TLS density (≥ 0.222 follicles/mm) in the first resected pulmonary metastases. TLS density (adjusted HR 0.91, 0.48–1.73) or maximum diameter (adjusted HR 0.78, 0.40–1.51) did not have prognostic value in pulmonary metastases. In primary tumours, higher TLS density (adjusted HR 0.39, 0.18–0.87) and maximum diameter (adjusted HR 0.28, 0.11–0.73) were associated with lower mortality. In the pulmonary metastases, ICS had superior prognostic value to TLSs; however, TLSs and ICS were significantly associated. In conclusion, TLSs in CRC pulmonary metastases had no prognostic value but correlated with the ICS. TLSs in primary tumours associated with favourable prognosis.

Background: A considerable proportion of intended pulmonary metastasectomies is known to turn out as new incidental primary lung cancers in final pathology. We aimed to analyse the trends and results of pulmonary metastasectomies using the intention-to-treat approach with an emphasis on final histopathological findings. Methods: All intention-to-treat pulmonary metastasectomies performed in Oulu University Hospital between 2000 and 2020 were included in the study. Long term survival was analysed with the Kaplan-Meier method and log-rank tests. A binary logistic regression analysis was performed to calculate odds ratios for incidental primary lung cancer in final histology. Results: A total of 154 intended pulmonary metastasectomies were performed to 127 individual patients. There was an increasing trend in pulmonary metastasectomies during the study period. Despite the increasing trend in comorbidities of the operated patients, the length of hospital stays decreased, and the postoperative complication rates remained stable. In final pathology reports, 9.7% were new primary lung cancers and 13.0% were benign nodules. A long disease-free interval (≥24 months) and smoking history were associated with incidental primary lung cancer in final histology. The short-term 30- and 90-day mortalities after pulmonary metastasectomy were 0.7%. The 5-year survival after pulmonary metastasectomy from all histologies was 52.8%, and from colorectal cancer metastasectomies (n=34) it was 73.5%. Conclusions: The significant amount of new primary lung cancer lesions in pulmonary metastasectomy specimens highlight the diagnostic importance of pulmonary metastasectomy. A segmentectomy could be considered as a primary procedure in pulmonary metastasectomy in patients with a long disease-free interval and a heavy smoking history.

Objective: To evaluate the prognostic value of tumor budding and tumor-stroma ratio (TSR) in resected pulmonary metastases of colorectal carcinoma (CRC). Methods: In total, 106 pulmonary metastasectomies were performed to 74 patients in two study hospitals during 2000–2020. All relevant clinical data were retrospectively collected. Tumor budding based on the International Tumor Budding Consensus Conference recommendations and TSR in the first resected pulmonary metastases and primary tumors were evaluated from diagnostic hematoxylin-eosin-stained histopathological slides. Results: 60 patients (85.7%) had low tumor budding (≤5 buds/field) and 10 patients (14.3%) had high tumor budding (>5 buds/field) in their first pulmonary metastases of CRC. 5-year overall survival rates of pulmonary metastasectomy in low and high total tumor budding were 28.3% and 37.3% (p = 0.387), respectively. 19 patients (27.1%) had low TSR and 51 patients (72.9%) had high TSR. The 5-year overall survival rates were 32.9% in low and 28.6% in high TSR of first pulmonary metastases (p = 0.746). Tumor budding and TSR did not provide prognostic value in Cox multivariate analysis. Tumor budding and TSR in resected pulmonary metastases were not associated with those of the primary tumor. Conclusion: Tumor budding and TSR in the resected pulmonary metastases of CRC showed no statistically significant prognostic value, however, additional well-powered confirmatory studies are needed.

Background: Preoperative esophageal stenting is proposed to have a negative effect on outcomes. The aim was to compare a 5-year survival in patients undergoing esophagectomy for esophageal cancer with and without preoperative esophageal stent in a population-based nationwide cohort from Finland. The secondary outcome was 90-day mortality. Methods: This study included curatively intended esophagectomies for esophageal cancer in Finland between 1999 and 2016, with follow-up until December 31, 2019. Cox proportional hazards models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of overall 5-year and 90-day mortality. Model 1 was adjusted for age, sex, year of the surgery, comorbidities, histology, pathological stage, and neoadjuvant therapy. Model 2 included also albumin level and BMI. Result: Of 1064 patients, a total of 134 patients underwent preoperative stenting and 930 did not. In both adjusted models 1 and 2, higher 5-year mortality was seen in patients with preoperative stent with HRs of 1.29 (95% CI 1.00–1.65) and 1.25 (95% CI 0.97–1.62), respectively, compared to no stenting. The adjusted HR of 90-day mortality was 2.49 (95% CI 1.27–4.87) in model 1 and 2.49 (95% CI 1.25–4.99) in model 2. When including only neoadjuvant-treated patients, those with preoperative stent had a 5-year survival of 39.2% compared to 46.4% without stent (adjusted HR 1.34, 95% CI 1.00–1.80), and a 90-day mortality rate of 8.5% and 2.5% (adjusted HR 3.99, 95% CI 1.51–10.50). Discussion: This nationwide study reports worse 5-year and 90-day outcomes in patients with preoperative esophageal stent. Since residual confounding remains possible, observed difference could be only an association rather than the cause.

Tiivistelmä Myrkytystietokeskukseen tulee vuosittain noin 30 puhelua, joissa syövyttävää happoa tai emästä on otettu suun kautta, ja noin 200 puhelua, joissa tiedetään tai epäillään, että henkilö on niellyt pariston. Oireettomissa ja lievissä happo- ja emäsaltistuksissa päivystyskäynti ei usein ole tarpeellinen tai potilas voidaan kotiuttaa lyhyen seurannan jälkeen. Merkittävissä altistuksissa päivystyksellinen tietokonekuvantaminen on tarkin keino vamman laajuuden arvioinnissa. Pinnalliset nekroosit aiheuttavat parantuessaan ruokatorven ahtaumia. Jos ruokatorvi puhkeaa korroosiovamman seurauksena, joudutaan päivystykselliseen leikkaushoitoon. Merkittäviin ruokatorven korroosiovammoihin liittyy kohonnut syöpäriski, joskin latenssiaika on yli 20 vuotta. Vaikeiden korroosiovammojen akuuttivaiheen ja myöhäiskomplikaatioiden hoito kuuluu ruokatorvikirurgian keskuksiin.

Background: Multimodal treatment of gastric cancer includes careful preoperative staging, perioperative oncological treatment, and selective minimally invasive approach. The aim was to evaluate whether this approach improves short- and long-term outcomes in operable gastric cancer. Methods: This study included 181 gastric cancer patients who underwent curative intent surgery in Central Finland Central Hospital between years 2005 and 2021 for gastric or esophagogastric junction adenocarcinoma. Those 65 patients in group 1 operated between years 2005–2010 had open surgery with possible adjuvant therapy. During the second period including 58 patients (2011–2015), perioperative chemotherapy and minimally invasive surgery were implemented. The period, when these treatments were standard practise, was years 2016–2021 including 58 patients (group 3). Outcomes were lymph node yield, major complications and 1- and 3-year survival rates. Results: Median lymph node yield increased from 17 in group 1 and 20 in group 2 to 23 in group 3 (p < 0.001). Major complication rates in groups 1–3 were 12.3%, 32.8%, and 15.5% (group 1 vs. group 2, p = 0.007; group 2 vs. group 3, p = 0.018), respectively. Overall 1-year survival rates between study groups 1–3 were 78.5% vs. 69.0% vs. 90.2% (p = 0.018) and 3-year rates 44.6% vs. 44.8% vs. 68.1% (p = 0.016), respectively. For overall 3-year mortality, adjusted hazard ratio (HR) was 1.02 (95%CI 0.63–1.66) in group 2 and HR 0.37 (95%CI 0.20–0.68) in group 3 compared to group 1. Conclusions: In medium-volume center, modern multimodal therapy in operable gastric cancer combined with minimally invasive surgery increased lymph node yield and improved long-term survival without increasing postoperative morbidity.

Objectives: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3–12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n = 143), GAD antibody (GADA) multiple (n = 126) and islet antigen 2 antibody (IA-2A) multiple (n = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n = 87), GADA only (n = 114) and IA-2A only (n = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

Background: Anatomic variation or early differences in glucose metabolism have been linked to the development of type 1 diabetes. We aimed to describe early glucose metabolism based on HbA1c, oral glucose tolerance test (OGTT), and random plasma glucose years before the presentation of type 1 diabetes in five risk groups based on autoantibody combinations. For the first time, we were able to include for comparison children with very low risk of progression to type 1 diabetes. Methods: The Finnish Diabetes Prediction and Prevention birth cohort study screened newborn infants for HLA susceptibility to type 1 diabetes since 1994. Those carrying a risk genotype were prospectively followed up with islet autoantibody testing. Glucose parameters were obtained starting from the time of seroconversion. By 31 August 2014, 1162 children had developed at least one islet autoantibody and were included in the current study. Type 1 diabetes was diagnosed in 335 children (progressors). In the non-progressor groups, 207 developed multiple (≥2) biochemical islet autoantibodies, 229 a single biochemical autoantibody, 370 ICA only, and 64 transient autoantibodies. Children were divided into five risk groups. Glucose metabolism was evaluated. Results: We observed lower HbA1c values in early follow-up 4.5 to 6.0 years before diagnosis in the progressors when compared to the same time in children with a single biochemical autoantibody or low-risk (ICA only and transient) participants, who did not progress to clinical type 1 diabetes. However, no such differences were observed in OGTTs or random plasma glucose. The variation was minimal in glucose values in the low-risk groups. Conclusion: We report the possibility of early alteration in glucose metabolism in future progressors. This could suggest early defects in multiple glucose-regulating hormones.

The objective of this study was to evaluate the prognostic value of CD3⁺ and CD8⁺ based immune cell score (ICS), programmed death -1 (PD-1) and programmed death ligand -1 (PD-L1) in pulmonary metastases of proficient mismatch repair colorectal cancer (CRC) patients. A total of 101 pulmonary metastases and 62 primary CRC tumours were stained for CD3⁺, CD8⁺, PD-1 and PD-L1 expression. The prognostic value of ICS, PD-1/PD-L1 expression in 67 first pulmonary metastases and 61 primary CRC tumour was analysed. Comparative analysis was also performed between primary tumours and pulmonary metastases, as well as between T-cell densities and PD-1/PD-L1 expression. The 5-year overall survival rates of low, intermediate, and high ICS in pulmonary metastases were 10.0%, 25.5% and 47.0% (p = 0.046), respectively. Patients with high vs. low ICS in pulmonary metastases had a significantly better 5-year survival (adjusted HR 0.25, 95% CI 0.09–0.75, p = 0.013). High tumour cell PD-L1 expression in the pulmonary metastases was associated with improved survival (p = 0.024). Primary tumour CD8⁺ expression was significantly correlated with all T-cell densities in pulmonary metastases. Conclusion: The ICS evaluated from the resected pulmonary metastases of CRC showed significant prognostic value. High PD-L1 expression in pulmonary metastases is associated with favourable prognosis.

Barrett’s esophagus progresses to high-grade dysplasia or cancer along the well-established metaplasia-dysplasia-adenocarcinoma sequence. The aim of this study was to evaluate the value of p53, Ki67, and toll-like receptor 5 (TLR5) in prediction of malignant progression of Barrett’s metaplasia and low-grade dysplasia. This was a retrospective matched case–control study based on Northern and Central Finland population. Patients diagnosed with esophageal high-grade dysplasia or adenocarcinoma were included. From these patients, all previous endoscopy samples were obtained along with original diagnostic HE-slides and clinical data. Age- and sex-matched patients with non-progressing Barrett’s metaplasia and low-grade dysplasia confirmed with follow-up endoscopies were used as controls. Two gastrointestinal pathologist re-reviewed all original HE-slides, and newly made sections to confirm representative tissue material blinded from clinical data. p53, Ki67, and TLR5 were immunohistochemically stained. Final cohort included 45 patients with progressive Barrett’s metaplasia (n = 21) or low-grade dysplasia (n = 24), and 92 patients with non-progressive Barrett’s metaplasia (n = 52) or low-grade dysplasia (n = 40). In Barrett’s metaplasia, aberrant p53 expression was observed in 6% of samples in progressors and 0% in non-progressors. In low-grade dysplasia, aberrant p53 was seen in 56% of samples in progressors and 17% in non-progressors (Odd’s ratio 6.7, 95% CI 1.8–24.6). Ki67 or TLR5 showed no association with disease progression. In this matched case–control study, p53 expression associated with a high risk of malignant progression in Barrett’s low-grade dysplasia. Routine staining of p53 is indicated in expert confirmed low-grade dysplasia.

Background: The prognostic value of preoperative hemoglobin in patients undergoing esophagectomy is unknown. The aim of this study was to examine whether preoperative hemoglobin is associated with prognosis in patients undergoing esophagectomy for cancer. Materials and methods: This was a population-based nationwide retrospective cohort study in Finland, using Finnish National Esophago-Gastric Cancer Cohort (FINEGO). Esophagectomy patients with available preoperative hemoglobin measurement were included. Multivariable cox regression provided hazard ratios (HR) with 95% confidence intervals (CI), adjusted for calendar period of surgery, age at surgery, sex, comorbidity (Charlson Comorbidity Index), tumor histology, tumor stage, neoadjuvant therapy, type of surgery (minimally invasive or open) and annual hospital volume. Results: Of the 1313 patients, 932 (71.0%) were men and 799 (60.9%) had esophageal adenocarcinoma. Overall all-cause mortality was significantly higher in the lowest hemoglobin count tertile (HR 1.26 (1.07–1.47)) compared to the highest tertile, but this association was attenuated after adjustment for confounding. No differences were found between the preoperative hemoglobin groups in the adjusted analyses of 90-day all-cause, 5-year all-cause, and 5-year cancer-specific mortality. Conclusions: In this population-based nationwide study, preoperative hemoglobin count had no independent prognostic significance in esophageal cancer.

Background: Esophageal adenocarcinoma (EAC) is the sixth leading cause of cancer-related death worldwide. It develops through Barrett’s metaplasia — dysplasia sequence. However, the effectiveness of endoscopic surveillance is limited, since diagnosis of low-grade dysplasia (LGD) is known to be challenging for pathologists. Our aim was to compare the risk of Barrett’s progression based on diagnoses of general and expert gastrointestinal (GI) pathologists in a population-based cohort. Methods: A total of 60 patients with non-dysplastic metaplasia (BE) or LGD progressing to high grade dysplasia (HGD) or EAC during follow-up could be identified in the population. For comparison, series representing non-progressive BE (n = 56) and LGD cases (n = 54), matched for age, gender, and length of follow-up were collected. All available original HE stained slides (n = 292) were blindly re-evaluated by two experienced GI pathologists and patient groups of progressive non-progressive BE and LGD were formed according to revised diagnoses. Results: Original diagnosis for each sample was changed in 25% of BE, 59% of LGD, and 33% of HGD diagnoses. Of the original LGD diagnoses, 53% were downgraded to BE or indefinite for dysplasia (ID). Of LGD diagnoses made by an expert GI pathologist, 61% were in the progressive LGD group, whereas only 42% of general pathologists’ LGD diagnoses were in the progressive LGD group. Conclusion: Based on this retrospective case-control study, LGD is strongly over-diagnosed among general pathologists. LGD diagnosed by expert GI pathologists predicts progressive disease. Recommendation for consensus diagnosis by expert GI pathologists is justified also in the Finnish population-based setting.

Tertiary lymphoid structures (TLSs) are part of immune response against cancer. Their high density and high diameter have been shown to be associated with prognosis in different cancer types. The aim of this study was to examine the prognostic significance of TLS density and diameter in gastric cancer and reproducibility of their assessments. TLS densities and maximal TLS diameter were assessed from hematoxylin–eosin (HE) stained slides of 721 surgically treated gastric cancer patients from two hospitals in Finland. Mortality hazard ratios (HRs) for TLS densities and maximal TLS diameter were analyzed. TLS densities and maximal TLS diameter were assessed with moderate interobserver agreement (Cohen’s kappa 0.50–0.62). Maximal TLS density was not associated with survival (adjusted HR 0.85, 95% CI 0.70–1.02) and neither was hotspot TLS density (adjusted HR 0.85, 95% CI 0.70–1.02). High maximal TLS diameter was associated with longer survival in overall study population (adjusted HR 0.74, 95% CI 0.61–0.89) and in diffuse type subgroup (adjusted HR 0.65, 95% CI 0.50–0.85). In conclusion, high maximal TLS diameter is associated with improved survival in gastric cancer and can be assessed from HE-stained slides. Its prognostic value might be limited to diffuse histological type.

Background: Although high T cell density is a strong favourable prognostic factor in colorectal cancer, the significance of the spatial distribution of T cells is incompletely understood. We aimed to evaluate the prognostic significance of tumour cell-T cell co-localisation and T cell densities. Methods: We analysed CD3 and CD8 immunohistochemistry in a study cohort of 983 colorectal cancer patients and a validation cohort (N = 246). Individual immune and tumour cells were identified to calculate T cell densities (to derive T cell density score) and G-cross function values, estimating the likelihood of tumour cells being co-located with T cells within 20 µm radius (to derive T cell proximity score). Results: High T cell proximity score associated with longer cancer-specific survival in both the study cohort [adjusted HR for high (vs. low) 0.33, 95% CI 0.20–0.52, Ptrend < 0.0001] and the validation cohort [adjusted HR for high (vs. low) 0.15, 95% CI 0.05–0.45, Ptrend < 0.0001] and its prognostic value was independent of T cell density score. Conclusions: The spatial point pattern analysis of tumour cell-T cell co-localisation could provide detailed information on colorectal cancer prognosis, supporting the value of spatial measurement of T cell infiltrates as a novel, robust tumour-immune biomarker.

Monocarboxylate transporters (MCTs) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies across the plasma membrane. The prognostic role of MCTs in neuroendocrine tumors is unknown. We aimed to analyze MCT1 and MCT4 expression in small bowel neuroendocrine tumors (SB-NETs). The cohort included 109 SB-NETs and 61 SB-NET lymph node metastases from two Finnish hospitals. Tumor samples were immunohistochemically stained with MCT1 and MCT4 monoclonal antibodies. The staining intensity, percentage of positive cells, and stromal staining were assessed. MCT1 and MCT4 scores (0, 1 or 2) were composed based on the staining intensity and the percentage of positive cells. Survival analyses were performed with the Kaplan–Meier method and Cox regression, adjusted for confounders. The primary outcome was disease-specific survival (DSS). A high MCT4 intensity in SB-NETs was associated with better DSS when compared to low intensity (85.7 vs. 56.6%, p = 0.020). A high MCT4 percentage of positive cells resulted in better DSS when compared to a low percentage (77.4 vs. 49.1%, p = 0.059). MCT4 scores 0, 1, and 2 showed DSS of 52.8 vs. 58.8 vs. 100% (p = 0.025), respectively. After adjusting for confounders, the mortality hazard was lowest in the patients with a high MCT4 score. MCT1 showed no association with survival. According to our study, a high MCT4 expression is associated with an improved prognosis in SB-NETs.

Toll-like receptors (TLRs) have been shown to have anti-tumor, pro-tumor, or even dual effects in cancer, and are thus potential prognostic biomarkers and immunotherapeutic targets. The present study aimed to evaluate associations between endosomal TLRs, namely TLR3, TLR7, TLR8, and TLR9, expression and clinicopathological variables and survival in gastric cancer. A total of 564 gastric adenocarcinoma patients were included in this retrospective cohort study. Samples and clinicopathological data were retrieved and organized into tissue microarray blocks. Protein expressions were detected by immunohistochemical staining. The patients were divided into low expression and high expression groups by median values of expression. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI), adjusted for confounders. Patients with high nuclear TLR3 expression had significantly poorer 5-year survival than the low nuclear TLR3 expression group in the univariable analysis (crude HR 1.31, 95% CI 1.07–1.60). With radically resected patients, poor prognosis was also seen in the multivariable analysis (adjusted HR 1.38, 95% CI 1.08–1.77). Cytoplasmic TLR3, TLR7, TLR8, and TLR9 were not associated with 5-year survival. In conclusion, high nuclear TLR3 expression seems to have prognostic impact in gastric cancer, while TLR7, TLR8, and TLR9 do not.

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.

Background: Minimally invasive esophagectomy (MIE) is a complex procedure with learning associated morbidity. The aim was to evaluate the learning curve for MIE focusing on short-term outcomes in two settings: (I) experienced MIE surgeon in new hospital (Hospital 1); (II) surgeons experienced with open esophagectomy and minimally invasive surrogate surgery (Hospital 2). Methods: In Hospital 1 and Hospital 2, on intent-to-treat basis number of MIEs were 132 and 57, respectively. The primary outcomes were major complications and anastomosis leaks. Secondary outcomes were operative time, blood loss, lymph node yield, hospital stay and 1-year mortality. Length of learning curves were analyzed with risk-adjusted cumulative sum (RA-CUSUM) method. Results: In Hospital 1, major complication and anastomosis leak rates were 9.8% and 4.5%, 22.8% and 12.3% in Hospital 2, respectively. In Hospital 1, complication and leak rates remained stable. In Hospital 2, improvement occurred after 34 cases in major complications and 29 cases in leaks. Of secondary outcomes, improvements were seen in Hospital 1 in operative time after 61, blood loss after 86, lymph node yield after 52, hospital stay after 19 and 1-year mortality after 24 cases. In Hospital 2, improvement occurred in operative time after 30, blood loss after 15, lymph node yield after 45, hospital stay after 50 and 1-year mortality after 15 cases. Conclusions: According to this study, learning phase of the individual surgeon determines the outcomes of MIE, not the institutional learning phase.

Background: Esophagectomy is the mainstay of surgical treatment of esophageal cancer, but involves high operative risk. The aim of this study was to review the evolution surgical treatment of esophageal cancer in Northern Finland, with introduction of minimally invasive techniques. Methods: All elective esophagectomies performed in Oulu University Hospital between years 1987 and 2020 were included. Treatment strategies were compared to current guidelines including staging and use of neoadjuvant therapy, and benchmark values including postoperative morbidity, hospital stay, readmissions and 90-day mortality. Long-term survival was compared to previous national studies. Results: Between years 1987 and 2020 a total of 341 underwent an esophagectomy. Transhiatal resection was performed to 167 (49.3%), Ivor Lewis to 129 (38.1%) and McKeown to 42 (12.4%) patients. MIE was performed to 49 (14.5%) patients. During the past four years 83.7% of locally advanced diseases received neoadjuvant treatment. Since 1987, gradual improvements have occurred especially in incidence of pleural effusion requiring additional drainage procedure (highest in 2011–2013 and in last four years 14.0%), recurrent nerve injuries (highest in 2008–2010 29.4% and lowest in 2017–2020 1.8%) and in 1-year survival rate (1987–1998 68.4% vs. 2017–2020 82.1%). No major changes in comorbidity, complication rate, anastomosis leaks, hospital stay or postoperative mortality were seen. Conclusions: Esophageal cancer surgery has gone through major changes over three decades. Current guideline-based treatment has resulted with progressive improvement in mid- and long-term survival. However, despite modern protocol, no major improvement has occurred for example in major complications, anastomosis leak rates or hospital stay.

The role of inflammation in neuroendocrine tumors is poorly known. The purpose of this study was to characterize the densities of CD3⁺, CD8⁺, CD4⁺ and FOXP3⁺ T cells in small bowel neuroendocrine tumors (SB-NETs), SB-NET lymph node metastases and gastric neuroendocrine tumors (G-NETs) to assess the prognostic role of immune cell infiltrates in SB-NETs. The final cohort included 113 SB-NETs, 75 SB-NET lymph node metastases and 19 G-NETs from two Finnish hospitals. CD3⁺- and CD8⁺-based immune cell score (ICS), and other T cell densities were evaluated. Survival analyses of SB-NETs and SB-NET lymph node metastases were performed with the Kaplan-Meier method and Cox regression adjusted for confounders. The primary outcome was disease-specific survival (DSS). No significant difference in DSS was seen between low and high ICS groups in SB-NETs at 5 years (92.6% vs. 87.8%) or 10 years (53.8% vs. 79.4%), p = 0.507, or in SB-NET lymph node metastases at 5 years (88.9% vs. 90.4%) or 10 years (71.1% vs. 59.8%), p = 0.466. Individual densities of the examined T cell types showed no correlation with prognosis either. SB-NETs and lymph node metastases had similar inflammatory cell profiles, whereas in G-NETs CD3⁺ and CD8⁺ T cells were particularly more abundant. In SB-NETs, ICS or T cell densities showed no correlation with prognosis.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Overall prognosis for survival in HCC is poor. Risk factors for HCC include hepatitis viruses, especially in Eastern countries. In Western countries, heavy alcohol consumption and metabolic liver disease are major causes of liver cirrhosis and cancer. The detection of HCC is challenging because the symptoms often appear at later stages of the cancer. The tumoral microenvironment plays an important role in tumor progression, growth and metastasis. Tumor budding, defined as a single tumor cell or a cell cluster of up to four tumor cells at the invasive front of carcinomas, is associated with poor prognosis in several cancer types. Tumor-Stroma Ratio (TSR) is defined as the percentage of tumor cell component relative to the surrounding stroma. Low TSR (high proportion of stroma) in tumor tissue has been recognized as an important factor for tumor prognosis in gastric cancer, breast cancer, lung cancer and esophageal cancer, for example. Toll-like receptors (TLRs) are innate immunity receptors that are involved in bacterial and viral recognition but also have a role in diverse vital functions, adaptive immunity, and carcinogenesis. This thesis examined the treatment trends and results of HCC patients treated in Oulu University hospital in 1983–2018. Tumor-Stroma ratio and tumor budding were examined from Hematoxylin and Eosin-stained (HE) histological samples that were originally used for diagnostic purposes. The prognostic value of tumor budding, TSR, TLR2, TLR4, TLR5 and TLR8 staining in HCC was evaluated. Based on our study on the Northern Finland population, the rate of surgical treatment has decreased significantly since the introduction of local treatments and TACE. Compared to other treatments, the surgical resection of HCC has an acceptable complication rate and best long-term survival. We observed that tumor budding, TLR4 and TLR5 are independent factors o, Tiivistelmä Hepatosellulaarinen karsinooma (HCC) on maailmanlaajuisesti neljänneksi yleisin syöpäkuolemien syy. HCC-potilaiden ennuste on huono. Suurimpiin riskitekijöihin kuuluvat etenkin itäisissä maissa hepatiittivirukset, kun taas länsimaissa suurimpina riskeinä ovat runsas alkoholin käyttö ja maksan rasvoittuminen, jotka voivat johtaa maksakirroosiin ja syöpään. HCC:n havaitseminen on haasteellista, koska syöpä ei aiheuta juurikaan oireita, kuin vasta taudin myöhäisvaiheissa. Syövän mikroympäristö ja sitä ympäröivä sidekudos (strooma) ovat tärkeässä roolissa syövän koon kehityksessä, kasvussa ja metastasoinnissa. Kasvaimen silmuilu (tumor budding) määritellään laskemalla tuumorisilmut (tumor buds). Tuumorisilmu on yhdestä neljään syöpäsolua kattava solurypäs syövän invasiivisella alueella. Tuumorisilmujen esiintymisen on havaittu olevan huonon ennusteen merkki useissa eri syövissä. Kasvain-stroomasuhde (Tumor-Stroma Ratio, TSR) on tuumorin syöpäsolukomponentin prosenttiosuus verrattuna ympäröivän strooman määrään. Matalan kasvain-stroomasuhteen (korkean stroomaosuuden) on havaittu olevan huonon ennusteen merkki esimerkiksi maha-, rinta-, keuhko- ja ruokatorvisyövässä. Tollin kaltaiset reseptorit (TLR:t) toimivat osana luontaista immuniteettia tunnistaen virusten ja bakteerien osia, mutta niillä on havaittu olevan rooli myös muissa elimistön tapahtumissa, kuten hankinnaisessa immuniteetissa ja karsinogeneesissä. Tämä väitöstutkimus kuvaa OYS:ssa hoidettujen HCC-potilaiden hoidon muuttumisen ja tulokset vuosilta 1983–2018. Väitöstutkimuksessa tutkitaan alun perin diagnostisiin tarkoituksiin kerätyistä hematoksyliini-eosiini- värjätyistä näytteistä tuumorisilmujen määrä ja kasvain-stroomasuhde sekä niiden merkitys HCC-potilaan ennusteelle. Väitöstutkimuksessa analysoidaan myös TLR2:n, TLR4:n, TLR5:n ja TLR8:n esiintyminen ja värjäytyminen maksasyöpäsoluissa ja niiden merkitys HCC-potilaiden ennusteelle. Tuloksemme osoittavat, että kirurgiset hoidot ovat vähentynee

Purpose: To examine and compare the prognostic value of immune cell score (ICS) and Klintrup–Mäkinen (KM) grade in gastric cancer. Methods: Gastric adenocarcinoma tissues from samples of 741 patients surgically treated in two hospitals in Finland were assessed for ICS and KM grade. Cox regression with adjustment for confounders provided hazard ratios (HRs) and 95% CIs. Subgroup analyses were performed in intestinal and diffuse type subgroups. The primary outcome was 5-year overall survival. Results: High ICS was associated to longer 5-year survival (adjusted HR 0.70, 95% CI 0.52–0.94), compared to low ICS. The difference was significant in intestinal type subgroup (adjusted HR 0.54, 95% CI 0.36–0.81) but not in diffuse type subgroup (adjusted HR 0.92, 95% CI 0.58–1.46). High KM grade was an independent prognostic factor for longer 5-year overall survival (adjusted HR 0.59, 95% CI 0.45–0.77) in both intestinal (adjusted HR 0.61, 95% CI 0.44–0.85) and diffuse subgroups (adjusted HR 0.52, 95% CI 0.31–0.86). ICS and KM grade were moderately correlated (ρ = 0.425). When both immune cell score and KM grade were included in the regression analysis, only KM grade remained prognostic. Conclusions: Both ICS and KM grade are prognostic factors in gastric adenocarcinoma, but immunohistochemistry-based ICS might not have additional prognostic value over hematoxylin–eosin-based KM grade.

Background: Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1). Methods: After exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival. Results: The 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26–0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis. Conclusions: High ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.

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.

Background: A recent study concluded that most findings reported as significant in sports medicine and arthroscopic surgery are not “robust” when evaluated with the Fragility Index (FI). A secondary analysis of data from a previous study was performed to investigate (1) the correctness of the findings, (2) the association between FI, p-value and post hoc power, (3) median power to detect a medium effect size, and (4) the implementation of sample size analysis in these randomized controlled trials (RCTs). Methods: In addition to the 48 studies listed in the appendix accompanying the original study by Khan et al. (2017) we did a follow-up literature search and 18 additional studies were found. In total 66 studies were included in the analysis. We calculated post hoc power, p-values and confidence intervals associated with the main outcome variable. Use of a priori power analysis was recorded. The median power to detect small (h > 0.2), medium (h > 0.5), or large effect (h > 0.8) with a baseline proportion of events of 10% and 30% in each study included was calculated. Three simulation data sets were used to validate our findings. Results: Inconsistencies were found in eight studies. A priori power analysis was missing in one-fourth of studies (16/66). The median power to detect a medium effect size with a baseline proportion of events of 10% and 30% was 42% and 43%, respectively. The FI was inherently associated with the achieved p-value and post hoc power. Discussion: A relatively high proportion of studies had inconsistencies. The FI is a surrogate measure for p-value and post hoc power. Based on these studies, the median power in this field of research is suboptimal. There is an urgent need to investigate how well research claims in orthopedics hold in a replicated setting and the validity of research findings.

Objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma with increased expression of tenascin C and fibronectin. Their role and tumor-stroma ratio in PDAC are not well known. The aim of this study was to evaluate tenascin C and fibronectin expression and tumor-stroma ratio and their prognostic relevance in PDAC. Methods: Ninety-five resected PDACs were immunohistochemically stained for tenascin C and fibronectin, and the expression was separately assessed in tumor bulk and front. Tumor-stroma ratio was determined with sections stained with hematoxylin-eosin. Results: Tenascin C and fibronectin were abundantly expressed in the stroma of PDAC, but absent in adjacent normal pancreatic tissue. Fibronectin expression of the bulk was associated with high T class (P = 0.045). In the main analysis, tenascin C and fibronectin expression and tumor-stroma ratio were not associated with patient survival. In a subgroup analysis of early-stage PDAC (T1–T2 tumors), high tenascin C expression in the tumor bulk was associated with poor prognosis (hazard ratio, 8.23; 95% confidence interval, 2.71–24.96). Conclusions: Tenascin C and fibronectin are abundantly expressed in PDAC, but they seem to have no major association with patient survival. However, in early-stage PDAC, tenascin C expression of the tumor bulk may have prognostic impact. Tumor-stroma ratio has no prognostic value in PDAC.

An immune cell score (ICS) was introduced for predicting survival in pancreatic ductal adenocarcinoma (PDAC). Few studies have compared different methods of evaluating immune infiltrate. This study compared ICSs determined in whole sections or tissue microarray-like hotspots for predicting survival after PDAC surgery. We included in 79 consecutive patients from a single geographical area that underwent surgery for PDAC (R0/R1, stages I–III). We performed digital image analyses to evaluate CD3 and CD8 staining. ICSs were classified as low, moderate, or high, based on the numbers of immune cells in the tumour core and invasive margin. We compared ICS groups determined with the hotspot and whole-section techniques. Associations between ICS and survival were analysed with Cox regression models, adjusted for sex, age, tumour stage, differentiation grade, perineural invasion, and resection radicality. In hotspot ICS analysis, 5-year overall survival rates for low, moderate, and high groups were 12.1%, 26.3%, and 26.8%, respectively (p = 0.193). In whole-section analyses, overall survival rates were 5.3%, 26.4%, and 43.8%, respectively (p = 0.030). In the adjusted Cox model, whole-section ICS groups were inversely associated with the overall mortality hazard ratio (HR): low, moderate, and high ICS groups had HRs of 1.00, 0.42 (95% CI 0.20–0.88), and 0.27 (95% CI 0.11–0.67), respectively. The number of immune cells per square millimetre in the tumour core and the invasive margin were significantly higher and had a wider range in hotspots than in whole-tissue sections. Accordingly, ICS could predict survival in patients with PDAC after surgery. Whole tissue section ICSs exhibited better prognostic value than hotspot ICSs.

Background: HIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities. Methods: We investigated the expression and prognostic role of HIF-1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry. Results: In our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216–3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival. Conclusions: Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia-related prognostic factor should be addressed with caution.

Background: Tenascin-C and fibronectin are adhesive glycoproteins modulating the structure of the extracellular matrix and cellular functions. Their expression and function in esophageal adenocarcinoma is poorly known. The aim of this study was to evaluate the expression of tenascin-C and fibronectin in esophageal adenocarcinoma and its precursor stages. Results: Stromal tenascin-C and fibronectin expression were found in all evaluated lesion types. Expression of both molecules increased from gastric metaplasia towards adenocarcinoma (p<0.05). In carcinomas, tenascin-C expression in the bulk was associated with T-stage (p=0.006), presence of lymph node (p=0.004) and distant organ metastases (p=0.007). Abundant tenascin-C expression associated with poor survival (p=0.034) in univariate analysis. Fibronectin expression associated to T-stage (p=0.030). Expression of tenascin-C or fibronectin in the tumor invasive front was not associated to clinicopathological variables or survival. No significant correlation with tumor/stroma percentage, cancer-associated fibroblasts or mean vascular density was observed with either tenascin-C or fibronectin. Methods: Tenascin-C and fibronectin were stained immunohistochemically and assessed in esophageal specimens from patients with esophageal adenocarcinoma (n=90) or dysplasia (n=30). Structures and lesion were evaluated including normal esophagus (n=77), gastric (n=61) or intestinal (n=51) metaplasia without dysplasia, and low-grade (n=42) or high-grade (n=34) dysplasia, and esophageal adenocarcinoma (n=90). In carcinomas, both bulk and invasive front were separately evaluated. In addition, tumor/stroma percentage, cancer-associated fibroblasts and mean vascular density were evaluated. Conclusions: Tenascin-C and fibronectin are upregulated in esophageal adenocarcinoma when compared to Barrett’s esophagus and dysplasia. Increased tenascin-C expression is associated with metastasis and poor prognosis in esophageal adenoc

Type 1 diabetes is considered to be a T cell-mediated autoimmune disease characterized by destruction of the pancreatic beta cells. Its prediction is currently based on diabetes-associated autoantibodies, giving a cumulative risk of 84% during 15 years of follow-up since seroconversion. Prediction of the timing of clinical onset has remained challenging, however. This thesis examines glucose metabolism in autoantibody-positive children with a high risk of developing type 1 diabetes. Out of a total of 14,876 children with an increased genetic risk followed up from birth in the Finnish DIPP study, 567 developed ≥2 autoantibodies during the follow-up and 255 of these (45%) were diagnosed with type 1 diabetes until the end of December 2011. The glucose parameters measured were HbA1c, OGTT and random plasma glucose with 3 to 12 months interval. Seven-day continuous glucose monitoring (CGM) was performed on an age and sex-matched cohort. We showed that rising HbA1c, impaired glucose tolerance in OGTT, random plasma glucose values of ≥7.8mmol/l and potentially CGM can predict type 1 diabetes with a median time to diagnosis of approximately one year. Our results suggest that especially HbA1c and random plasma glucose are cost-effective and improve the prediction of diabetes. These markers may be useful for monitoring the response to treatment in prevention studies., Tiivistelmä Tyypin 1 diabetesta pidetään T-soluvälitteisenä autoimmuunitautina, joka johtaa haiman beetasolujen tuhoutumiseen. Tyypin 1 diabeteksen ennustaminen perustuu tällä hetkellä diabetekseen assosioituviin vasta-aineisiin, jotka antavat 84% kumulatiivisen riskin 15 vuoden seurannassa. Taudin puhkeamisen ajankohdan ennustaminen on kuitenkin edelleen vaikeaa. Tämä väitöskirja käsittelee glukoosiaineenvaihduntaa vasta-ainepositiivisilla lapsilla, joilla on suurentunut riski sairastua tyypin 1 diabetekseen. Suomalaisessa DIPP-tutkimuksessa vasta-aineiden kehittymistä on seurattu yhteensä 14876 lapselta. Seurannan aikana 567 lasta kehitti ≥2 autovasta-ainetta ja näistä 255 (45%) sairastui tyypin 1 diabetekseen joulukuun loppuun 2011 mennessä. Glukoosiaineenvaihduntaa seurattiin tutkimalla HbA1c, OGTT ja satunnaisia verensokeriarvoja 3–12 kuukauden välein. Ikä ja sukupuolivakioidussa kohortissa tehtiin jatkuvan sokeripitoisuuden seuranta (CGM). Tutkimuksessamme nouseva HbA1c, heikentynyt sokerin sieto OGTT-kokeessa, satunnainen verensokeri ≥7.8 mmol/l ja mahdollisesti CGM ennustavat tyypin 1 diabeteksen puhkeamista. Tulostemme perusteella erityisesti kustannustehokkaat HbA1c ja satunnainen verensokeri parantavat diabeteksen ennustamista. Nämä parametrit saattavat olla hyödyllisiä myös preventiotutkimuksissa hoitovasteen seurannassa.