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Background: Short-term outcomes of pancreatic surgery have improved globally during the last two decades. Long-term survival of resectable pancreatic ductal adenocarcinoma (PDAC) has also shown slight improvement. We describe a cohort of 566 consecutive pancreatectomies performed at a Northern Finnish tertiary center. We analyze the trends in short-term outcomes of all-cause pancreatic surgery and long-term survival of PDAC patients. Methods: All pancreatic resections performed at the Oulu University Hospital during years 2000–2020 were included. Patient data was analyzed in four time periods (2000–2005, 2006–2010, 2011–2015 and 2016–2020). Clinicopathological parameters of patients and tumors, complication data and short-term mortality were recorded for all patients and compared between time quartiles. Long-term survival and administration rates of neo-, and/or adjuvant therapy of PDAC patients were analyzed. Results: A total of 566 pancreatectomies were performed during the study period: 359 (63%) pancreatoduodenectomies (PDs), 130 (23.0%) open left pancreatectomies (LPs), 45 (8.0%) laparoscopic LPs, 26 (5.1%) total pancreatectomies (TPs), and 6 (1.1%) enucleations. Median age of patients was 63 [57–71] years, and 49% [267] of patients were men. Number of pancreatectomies per time period increased from 67 in 2000–2005 to 266 in 2016–2020. American Society of Anesthesiologists (ASA) Physical Classification III patients and T3 tumors were more frequently operated on in later time periods. Complication rates remained at constant low levels throughout the study period, but reoperation rate increased from 9.4% in 2000–2010 to 16.2% in 2011–2020. Short-term (90-day) mortality after pancreatectomy decreased from 3.1% to 0.74%, while 5-year survival improved from 14.3% in 2006–2011 to 21.4% in 2011–2015. Resection rate of diagnosed PDAC cases, as reported by the Finnish Cancer Registry (FCR) for the catchment area, increased from 3.2% to 14.9% over the study peri

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.

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.

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.

Background: The pathogenesis of gastroesophageal reflux disease (GERD) has not been resolved in detail. Esophageal epithelial cells provide resistance to acidic reflux via several mechanisms, many of which involve buffering acid with bicarbonate and transporting protons. Carbonic anhydrases (CAs) are enzymes that control the acid–base balance by catalyzing the reversible hydration of carbon dioxide to produce bicarbonate and hydrogen ions. Aims: We aimed to determine the immunohistochemical expression patterns of CAII, CAIX, and CAXII in the normal esophageal squamous epithelium and in patients with GERD. Methods: We evaluated 82 biopsy samples, including 26 with a histologically normal esophagus, 26 with histologically mild esophagitis, and 30 with severe esophagitis. Expression patterns of CAII, CAIX, and CAXII in the esophageal squamous epithelium were determined by immunohistochemical staining. Results: Cytoplasmic CAII expression was predominantly detected in the upper luminal part of the squamous epithelium and was significantly (p < 0.01) increased in GERD. Expression of CAIX was essentially membranous. The isozyme was constantly present in the peripapillary cells. In the interpapillary areas, clustered expression was observed to emerge and increase significantly (p < 0.01) in esophagitis. CAXII expression was the most abundant of the isozymes and was mainly membranous. In the normal squamous epithelium, CAXII expression was confined to the basal layer; in severe esophagitis, CAXII expression increased significantly in both basal (p < 0.05) and superficial (p < 0.01) halves of the epithelium. Conclusions: We demonstrate upregulated expression of CAII, CAIX, and CAXII in GERD. The increase in expression likely contributes to esophageal epithelial resistance to acidic reflux.

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.

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheralvasoconstriction and redistribution of bloodflow to protect the brain, myocardium, and adrenal glands. By using a chronicallyinstrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship betweenperipheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetusesat 115–128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascu-lar hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baselinewere collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation levelof 70%–80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher inthe descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aortaincreased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased,and the diastolic component in the aortic isthmus bloodflow velocity waveform became more retrograde, thus decreasing theaortic isthmus antegrade/retrograde bloodflow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained evenduring prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hy-poxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO)or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure.

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: Nifedipine is a widely used drug in pregnancies complicated by maternal hypertensive disorders that can be associated with placental insufficiency and fetal hypoxemia. The evidence regarding fetal myocardial responses to nifedipine in hypoxemia is limited. Objective: We hypothesized that nifedipine would not impair fetal sheep cardiac function under hypoxemic environment. In particular, we investigated the effects of nifedipine on fetal ventricular functional parameters and cardiac output. Study design: A total of 21 chronically instrumented fetal sheep at 122 to 134 gestational days (term, 145 days) were included in this study. Fetal cardiac function was evaluated by measuring global longitudinal strain, indices describing ventricular systolic and diastolic function, and cardiac outputs using two-dimensional speckle tracking and tissue and spectral pulsed-wave Doppler echocardiography. Fetal carotid artery blood pressure and blood gas values were invasively monitored. After baseline data collection, fetal hypoxemia was induced by maternal hyperoxygenation. After hypoxemia phase data collection, 9 fetuses received nifedipine infusion, and 12 fetuses received saline infusion. Data were collected 30 and 120 minutes after the infusion was started. After 120 minutes of data collection, maternal and fetal oxygenation were normalized, and normoxemia phase data were collected, while infusion was continued. Results: Hypoxemia decreased fetal carotid artery mean arterial pressure from 40 (8) mm Hg to 35 (8) mm Hg (P<.007), and left ventricular global longitudinal strain showed less deformation than at baseline(P=0.001). Under hypoxemia, nifedipine caused a reduction in right ventricular global longitudinal strain (P<0.05), a decrease in right ventricular isovolumic relaxation velocity and its deceleration (P<0.01) indicating diastolic dysfunction, and a drop in right ventricular cardiac output (P<0.05). Nifedipine did not alter fetal left ven

Inflammatory and neoplastic diseases of the esophagus and duodenum cause a significant burden to healthcare and economies worldwide. Their etiology is multifactorial, but precursor lesions and risk factors are identifiable. Gastroesophageal reflux disease (GERD) is exceedingly common in western countries and causes the most medical health care expenses of all gastrointestinal diseases. GERD is the main risk factor for esophageal adenocarcinoma (EAC)––it can complicate into Barrett’s esophagus (BE) and further into esophageal adenocarcinoma. EAC has a poor overall prognosis still today, despite evolving management. High-quality prognostic biomarkers for EAC and progression of BE into cancer are lacking. Unlike esophageal diseases, nonampullary duodenal adenomas and adenocarcinoma (DAC) are rare neoplasias, although their incidence is slowly rising. In these rare diseases, the molecular pathological profiling is still incomplete, and the range of applicable prognostic biomarkers is very limited. Carbonic anhydrases (CA) are highly active, pH-controlling enzymes of the body. They participate in various physiological processes, but their primary function is to preserve optimal intra- and extracellular pH conditions in normal tissues. In cancer, CAII, CAIX, and CAXII seem to contribute to the development of malignant pH arrangement. The malignant pH gradient––slightly alkaline intracellular pH and extracellular acidosis––is in many ways critical to cancer progression, by benefiting cancer cell abilities to grow, migrate, invade, and metastasize. This study’s aim was to investigate the immunohistochemical expression patterns and potential roles of CAII, CAIX, and CAXII in the predisposing, premalignant and malignant conditions of distal esophagus and nonampullary duodenum. CA expression was evaluated in normal esophagus, GERD, Barrett’s esophagus, esophageal adenocarcinoma, normal duodenum, nonampullary duodenal adenomas and duodenal adenocarcinoma. The patient c, Tiivistelmä Ruokatorven ja pohjukaissuolen tulehdukselliset sairaudet ja kasvaimet aiheuttavat merkittäviä kustannuksia ja kuormittavat terveydenhuoltoa kaikkialla maailmassa. Näiden sairauksien etiologia on monitekijäinen, mutta hoidettavia esiasteita ja riskitekijöitä on tunnistettu ja niiden tutkiminen on potilaan hoidon ja ennusteen kannalta tärkeää. Ruokatorven refluksitauti on yleistynyt pitkään maailmanlaajuisesti. Sen hoito aiheuttaa nykyään suurimmat lääkehoidolliset kustannukset kaikista ruuansulatuskanavan sairauksista. Refluksitauti on myös ruokatorven adenokarsinooman merkittävin riskitekijä — Barrettin ruokatorvi on refluksitaudin komplikaatio ja ruokatorven adenokarsinooman esiaste. Ruokatorven adenokarsinooman ennuste on edelleen huono. Biomerkkiaineita ruokatorvisyövän ennusteen ja Barrettin ruokatorven muuntumisriskin selventämiseksi on etsitty pitkään, mutta käyttökelpoisia merkkiaineita ei ole juurikaan kliinisessä käytössä. Ei-ampullaarisen pohjukaissuolen adenoomat ja adenokarsinooma ovat sen sijaan hyvin harvinaisia kasvaimia. Tämän vuoksi niiden molekyylipatologisten ennustetekijöiden ja biomerkkiaineiden määritystyö on vielä epätäydellistä verrattuna yleisempiin syöpätyyppeihin. Hiilihappoanhydraasit (CA) ovat korkean aktiviteetin entsyymejä, jotka kontrolloivat pH:n muutoksia elimistössä. Ne osallistuvat lukuisiin kehon fysiologisiin prosesseihin, mutta niiden pääasiallinen tehtävä on säilyttää optimaaliset pH-olosuhteet soluissa ja niiden ulkopuolella. Syöpäsoluissa CAII, IX ja XII kuitenkin näyttävät olevan osallisina nk. pahanlaatuisen pH-gradientin syntymisessä. Tässä suhteessa niiden liiallinen tai liian vähäinen toiminta vaikuttaa olevan hyödyllistä syöpäsoluille. Tämän tutkimuksen tavoitteena oli selvittää CAII, IX ja XII:n immunohistokemiallinen ilmentyminen ja potentiaalinen merkitys ruokatorven ja pohjukaissuolen syövissä sekä niille altistavissa muutoksissa. Hiilihappoanhydraasien ilmentyminen määritettiin normaalissa ruokatorves

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.

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.

Introduction: We hypothesized that nifedipine and sildenafil would have no detrimental effects on placental hemodynamics and gas exchange under fetal hypoxemia. Methods: In 33 chronically instrumented fetal sheep, placental volume blood flow (QPlac) and umbilical artery (UA) vascular impedance were measured by Doppler ultrasonography. Fetal carotid artery blood pressure and blood gas values were monitored. After baseline data collection, maternal and fetal hypoxemia were induced. Following hypoxemia phase data collection, 12 fetuses received sildenafil and 9 fetuses nifedipine infusion, and 12 fetuses served as controls receiving saline infusion. Data were collected 30 and 120 min after infusion was started. Then maternal oxygenation was normalized and normoxemia phase data were collected, while infusion was continued. Results: Hypoxemia significantly decreased fetal pO2 and blood pressure. In the sildenafil group at 30- and 120-min hypoxemia + infusion phases, fetal blood pressure and QPlac were significantly lower and pCO2 higher than at baseline without returning to baseline level at normoxemia + infusion phase. In hypoxemia, nifedipine did not affect fetal blood pressure or placental hemodynamics. Both in the sildenafil and nifedipine groups, fetal pO2 remained significantly lower at normoxemia + infusion phase than in the control group. Umbilical artery vascular impedance did not change during the experiment. Discussion: In fetal hypoxemia, sildenafil had detrimental effects on placental hemodynamics that disturbed placental gas exchange. Nifedipine did not alter placental hemodynamics in hypoxemia but disturbed placental gas exchange upon returning to normoxemia. Umbilical artery vascular impedance did not reflect alterations in placental hemodynamics.

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.

The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near‐term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P < 0.05) from [mean (SD)] 158 (7) to 188 (23) beats min⁻¹ and LV cardiac output (P < 0.0001) from 629 (198) to 776 (283) ml min⁻¹. Combined cardiac output fell (P < 0.0001) from 1524 (341) to 720 (273) ml min⁻¹. During main pulmonary artery occlusion, FO volume blood flow increased (P < 0.001) from 507 (181) to 776 (283) ml min⁻¹. This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P < 0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and PCO₂ increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near‐term gestation.

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

Incidence of esophageal adenocarcinoma is rising rapidly in Western countries. The main risk factor for esophageal adenocarcinoma is Barrett’s esophagus. Barrett’s esophagus results from long-term gastroesophageal reflux disease. The gastrointestinal tract is colonized by bacteria, fungi and viruses forming the alimentary tract microbiome. Microbiome transformation is involved in pathogenesis of alimentary tract cancer and also in the development of Barrett’s metaplasia. Toll-like receptors (TLR) are molecules of the innate immune system and they are involved in bacterial and viral recognition and regulation of immune functions in the host and cancer cells. This thesis examined the effect of alimentary tract microbiome and cancer- on the function of TLRs in normal gastrointestinal epithelial cells. An additional focus of the thesis was also to assess the carcinogenetic effect of TLRs 1–9 in Barrett’s esophagus metaplasia – dysplasia – carcinoma sequence. Study material consisted of: a patient cohort, organ donors, conventional and germ-free mice. TLRs are expressed also in a “microbe-free” gut. There were significant differences in all TLRs between small- and large intestine of conventional mice and in humans. In germ-free mice that difference was not observed. Normal tissue sampled adjacent to the tumors of cancer patients can be used as controls in immunohistochemical TLR studies in gastrointestinal cancer Clinical data indicate that TLRs linearly increase toward dysplasia in Barrett’s esophagus. High cytoplasmic and nuclear TLR4 expression and TLR1 and 8 nuclear immunoreactivity in esophageal adenocarcinoma are associated with metastatic disease and poor prognosis. Based on our results, bacteria seem to downregulate TLR expression of the intestine. TLRs 1–9 apparently have a role in malignant progression of Barrett’s dysplasia. TLR1, TLR4 and TLR8 may represent a novel therapeutic target in esophageal adenocarcinoma., Tiivistelmä Ruokatorven adenokarsinooma on länsimaissa nopeasti yleistyvä syöpätyyppi. Tämän syöpätyypin tärkein riskitekijä on Barrettin ruokatorvi, joka kehittyy pitkään jatkuneen gastroesofageaalisen refluksitaudin pohjalta. Ruuansulatuskanavassa on suuri määrä bakteereja, sieniä ja viruksia, jotka muodostavat yhdessä ruuansulatuskanavan mikrobiomin. Normaalin mikrobiomin muutokset ovat yhteydessä usean eri ruuansulatuskanavan syövän patogeneesiin ja myös Barrettin ruokatorven muodostumiseen. Tollin kaltaiset reseptorit ovat luontaisen immuniteetin molekyylejä, jotka osallistuvat bakteerien ja virusten tunnistukseen ja sääntelevät immuunivastetta sekä normaalitilanteessa että syövissä. Väitöskirjassa tutkitaan ruuansulatuskanavan mikrobiomin ja syövän vaikutuksia normaalien epiteelisolujen TLR:ien toimintaan. Lisäksi selvitetään TLR:ien karsinogeneettisiä vaikutuksia Barrettin ruokatorven metaplasia- dysplasia -adenokarsinoomasekvenssissä. Tutkimusmateriaalina käytetään potilaskohortista ja elinluovutuksista peräisin olevia potilasnäytteitä sekä normaalien ja bakteerittomien hiirien näytteitä. Tuloksemme osoittavat, että TLR:t ilmentyvät myös bakteerittomassa ruuansulatuskanavassa, ja TLR:en ilmentyminen oli merkittävästi voimakkaampaa ohutsuolessa kuin paksusuolessa normaaleilla hiirillä ja ihmisillä. Tätä eroa ei havaittu bakteerittomilla hiirillä. Ruuansulatuskanavan syöpien viereistä ja sen altistamaa tervettä kudosta voidaan käyttää terveenä kontrollina immunohistokemiallisissa TLR- tutkimuksissa. Kliinisessä aineistossa TLR:ien ilmentyminen kasvaa lineaarisesti kohti dysplasiaa Barrettin ruokatorvessa. TLR4:n korkea ilmentyminen solulimassa ja tumassa sekä TLR8:n ilmentyminen tumassa ovat yhteydessä metastaattiseen tautiin ja huonoon ennusteeseen. Tulosten perusteella bakteerit näyttävät heikentävän TLR:ien toimintaa suolistossa. Lisäksi kaikilla tutkituilla TLR:illä (1–9) näyttää olevan osuutta Barrettin dysplasian etenemisessä kohti syöpää. TLR1, TLR4 ja