Long-Term Survival After Transhiatal Versus Transthoracic Esophagectomy : A Population-Based Nationwide Study in Finland

Background No population-based studies comparing long-term survival after transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE) exist. This study aimed to compare the 5-year survival of esophageal cancer patients undergoing THE or TTE in a population-based nationwide setting. Methods This study included all curatively intended THE and TTE for esophageal cancer in Finland during 1987-2016, with follow-up evaluation until 31 December 2019. Cox proportional hazard models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of 5-year and 90-day mortality. The results were adjusted for age, sex, year of operation, comorbidities, histology, neoadjuvant treatment, and pathologic stage. Results A total of 1338 patients underwent THE (n = 323) or TTE (n = 1015). The observed 5-year survival rate was 39.3% after THE and 45.0% after TTE (p = 0.072). In adjusted model 1, THE was not associated with greater 5-year mortality (HR 0.99; 95% CI 0.82-1.20) than TTE. In adjusted model 2, including T stage instead of pathologic stage, the 5-year mortality hazard rates after THE (HR 0.87, 95% CI 0.72-1.05) and TTE were comparable. The 90-day mortality rate for THE was higher than for TTE (adjusted HR 0.72; 95% CI 0.45-1.14). In subgroup analyses, no differences between THE and TTE were observed in Siewert II gastroesophageal junction cancers, esophageal cancers, or pN0 tumors, nor in the comparison of THE and TTE with two-field lymphadenectomy. The sensitivity analysis, including patients with missing patient records, who underwent surgery during 1996-2016 mirrored the main analysis. Conclusions This Finnish population-based nationwide study suggests no difference in 5-year or 90-day mortality after THE and TTE for esophageal cancer.Peer reviewe

Preoperative hemoglobin count and prognosis of esophageal cancer, a population-based nationwide study in Finland

Publisher Copyright: © 2021Background: 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. Conclusion: In this population-based nationwide study, preoperative hemoglobin count had no independent prognostic significance in esophageal cancer.Peer reviewe

Preoperative Esophageal Stenting and 5-Year Survival in Patients Undergoing Esophagectomy for Esophageal Cancer : a Population-Based Nationwide Study from Finland

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.publishedVersionPeer reviewe

Toll-like receptors in Alimentary tract -special reference to Barrett’s esophagus

Abstract 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 TLR8 ovat mahdollisia terapeuttisia kohteita ruokatorven adenokarsinoomassa

Toll-like receptors 3, 7, 8, and 9 in gastric cancer

Abstract 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

Evolution of pancreatic surgery over time and effects of centralization:a single-center retrospective cohort study

Abstract 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 period. Conclusions: The hospital volume of pancreatectomies has increased substantially, while complications and postoperative mortality have remained at acceptable levels. Long-term survival and resection rate of PDAC patients showed notable improvement over two decades

Risk of progression in Barrett’s esophagus based on diagnoses of general and gastrointestinal pathologists:a retrospective case-control study from Northern and Central Finland

Abstract 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

Localization of nucleic acid-sensing toll-like receptors in human and mouse pancreas

Abstract Nucleic acid‐sensing toll‐like receptors (TLRs) (3, 7, 8, 9) have a role both in antiviral innate immunity and in autoimmune disorders. We assessed the expression of TLR3, 7, 8 and 9 in human and mouse pancreas focusing on the subpopulations of cells in the Langerhans islets. We studied eight human samples with normal pancreatic islets and two samples from patients with type 1 diabetes. Additionally, 10 CD‐1 mouse pancreases were analysed. Immunohistochemical double‐stainings for the TLRs and insulin, glucagon or somatostatin, respectively, were performed along with appropriate controls. In human pancreas, strong immunoreaction of TLR7 and TLR8 was observed in the insulin‐positive beta cells, whereas glucagon‐ or somatostatin‐expressing cells of the islets were weakly stained or negative. In type 1 diabetes, the expression in islets was weak or lost (TLR7: p = 0.014, TLR8: p = 0.053), correlating with loss of beta cells. TLR3 and 9 were expressed only weakly with no correlation with specific cell types. In mouse pancreas, only TLR9 was detected. Intra‐pancreatic nerve ganglia strongly expressed TLR7. The strong expression of TLR7 and TLR8 in the beta cells of normal human islets could be an important piece in the puzzle of type 1 diabetes pathogenesis, and be linked with destruction of this particular subpopulation of the islet cells. In normal mice, only TLR9 can be constantly detected in the islets, highlighting differences between the species