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Article ; Online: Toll-like receptors 1-9 in small bowel neuroendocrine tumors-Clinical significance and prognosis.

Hiltunen, Niko / Kemi, Niko / Väyrynen, Juha P / Böhm, Jan / Kauppila, Joonas H / Huhta, Heikki / Helminen, Olli

2024 Volume 19, Issue 5, Page(s) e0302813

Abstract: Toll-like receptors (TLRs) are pattern recognition receptors of the innate immunity. TLRs are known to mediate both antitumor effects and tumorigenesis. TLRs are abundant in many cancers, but their expression in small bowel neuroendocrine tumors (SB-NETs) ...

Abstract	Toll-like receptors (TLRs) are pattern recognition receptors of the innate immunity. TLRs are known to mediate both antitumor effects and tumorigenesis. TLRs are abundant in many cancers, but their expression in small bowel neuroendocrine tumors (SB-NETs) is unknown. We aimed to characterize the expression of TLRs 1-9 in SB-NETs and lymph node metastases and evaluate their prognostic relevance. The present study included 125 patients with SB-NETs, of whom 95 had lymph node metastases, from two Finnish hospitals. Tissue samples were stained immunohistochemically for TLR expression, assessed based on cytoplasmic and nucleic staining intensity and percentage of positively stained cells. Statistical methods for survival analysis included Kaplan-Meier method and Cox regression adjusted for confounding factors. Disease-specific survival (DSS) was the primary outcome. TLRs 1-2 and 4-9 were expressed in SB-NETs and lymph node metastases. TLR3 showed no positive staining. In primary SB-NETs, TLRs 1-9 were not associated with survival. For lymph node metastases, high cytoplasmic TLR7 intensity associated with worse DSS compared to low cytoplasmic intensity (26.4% vs. 84.9%, p = 0.028). Adjusted mortality hazard (HR) was 3.90 (95% CI 1.07-14.3). The expression of TLRs 1-6 and 8-9 in lymph node metastases were not associated with survival. SB-NETs and their lymph node metastases express cytoplasmic TLR 1-2 and 4-9 and nucleic TLR5. High TLR7 expression in SB-NET lymph node metastases was associated with worse prognosis. The current research has future perspective, as it can help create base for clinical drug trials to target specific TLRs with agonists or antagonists to treat neuroendocrine tumors.
MeSH term(s)	Humans ; Neuroendocrine Tumors/pathology ; Neuroendocrine Tumors/metabolism ; Female ; Male ; Middle Aged ; Prognosis ; Aged ; Toll-Like Receptors/metabolism ; Intestinal Neoplasms/pathology ; Intestinal Neoplasms/metabolism ; Intestinal Neoplasms/mortality ; Intestine, Small/pathology ; Intestine, Small/metabolism ; Lymphatic Metastasis ; Adult ; Aged, 80 and over ; Clinical Relevance
Chemical Substances	Toll-Like Receptors
Language	English
Publishing date	2024-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0302813
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Article ; Online: Toll-like receptors 1, 2, 4, 5, and 6 in gastric cancer.

Eskuri, Maarit / Kemi, Niko / Helminen, Olli / Huhta, Heikki / Kauppila, Joonas H

Virchows Archiv : an international journal of pathology

2023

Abstract: Toll-like receptors (TLRs) are expressed on both immune cells and tumor cells, triggering both anti-tumor and pro-tumor responses. Therefore, TLRs have potential as prognostic biomarkers and immunotherapeutic targets. The aim of this study was to ... ...

Abstract	Toll-like receptors (TLRs) are expressed on both immune cells and tumor cells, triggering both anti-tumor and pro-tumor responses. Therefore, TLRs have potential as prognostic biomarkers and immunotherapeutic targets. The aim of this study was to investigate TLR1, TLR2, TLR4, TLR5, and TLR6 expression and association with clinicopathological variables and survival in gastric cancer. Immunohistochemical study on cancer specimens from 564 resected gastric cancer patients was performed using tissue microarrays. The association between patient survival and TLR expression was calculated with Cox regression adjusted for confounding factors. Patients with high cytoplasmic TLR2 expression had significantly poorer 5-year survival than the low cytoplasmic TLR2 expression group in multivariate analysis (adjusted HR 1.38, 95% CI 1.11-1.71), and this estimate was similar in intestinal type (adjusted HR 1.33, 95% CI 0.98-1.80) and diffuse type (adjusted HR 1.48, 95% CI 1.06-2.05) histology subgroups. Patients with high cytoplasmic TLR6 expression group had significantly better 5-year survival compared with low cytoplasmic TLR6 expression group in multivariate analysis (adjusted HR 0.74, 95% CI 0.60-0.91). In the subgroup analysis of diffuse type of histology, the 5-year survival was better in high cytoplasmic TLR6 expression group in multivariable analysis (HR 0.62, 95% CI 0.46-0.83). In the intestinal type of histology subgroup, no significant differences between the groups were present. TLR1, TLR4, and TLR5 expression were not associated with 5-year survival. In conclusion, cytoplasmic TLR2 and TLR6 expression seem to have independent prognostic impact in gastric cancer, while TLR1, TLR4, and TLR5 do not.
Language	English
Publishing date	2023-09-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1184867-4
ISSN	1432-2307 ; 0945-6317
ISSN (online)	1432-2307
ISSN	0945-6317
DOI	10.1007/s00428-023-03635-1
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Article ; Online: 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.

Huhta, Heikki / Melkko, Jukka / Kuopio, Teijo / Karttunen, Tuomo J / Helminen, Olli

Scandinavian journal of gastroenterology

2022 Volume 57, Issue 9, Page(s) 1024–1029

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 ...

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 ( 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.
MeSH term(s)	Adenocarcinoma ; Barrett Esophagus/pathology ; Case-Control Studies ; Disease Progression ; Esophageal Neoplasms/pathology ; Finland ; Humans ; Hyperplasia ; Metaplasia ; Pathologists ; Precancerous Conditions/pathology ; Retrospective Studies
Language	English
Publishing date	2022-04-21
Publishing country	England
Document type	Journal Article
ZDB-ID	82042-8
ISSN	1502-7708 ; 0036-5521
ISSN (online)	1502-7708
ISSN	0036-5521
DOI	10.1080/00365521.2022.2063033
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Article ; Online: Toll-like receptors 3, 7, 8, and 9 in gastric cancer.

Eskuri, Maarit / Kemi, Niko / Helminen, Olli / Huhta, Heikki / Kauppila, Joonas H

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica

2022

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, ...

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.
Language	English
Publishing date	2022-10-22
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	93340-5
ISSN	1600-0463 ; 0903-4641
ISSN (online)	1600-0463
ISSN	0903-4641
DOI	10.1111/apm.13281
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Article: Evolution of pancreatic surgery over time and effects of centralization-a single-center retrospective cohort study.

Nortunen, Minna / Meriläinen, Sanna / Ylimartimo, Aura / Peroja, Pekka / Karjula, Heikki / Niemelä, Jarmo / Saarela, Arto / Huhta, Heikki

Journal of gastrointestinal oncology

2023 Volume 14, Issue 1, Page(s) 366–378

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 ...

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.
Language	English
Publishing date	2023-02-24
Publishing country	China
Document type	Journal Article
ZDB-ID	2594644-4
ISSN	2219-679X ; 2078-6891
ISSN (online)	2219-679X
ISSN	2078-6891
DOI	10.21037/jgo-22-649
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Article ; Online: Primary Outcome of Laparoscopic Colorectal Resections in a Northern Finnish Hospital: A Single Center Study.

Huhta, H / Vuolio, S / Typpö, I / Rahko, A / Suokanerva, K / Rintala, J M

Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society

2018 Volume 108, Issue 2, Page(s) 137–143

Abstract: Background and aims: Over the past decades, laparoscopic colorectal surgery has become widely used for various indications. Large multicenter studies have demonstrated that laparoscopy has clear advantages over open surgery. Compared to open procedures, ...

Abstract	Background and aims: Over the past decades, laparoscopic colorectal surgery has become widely used for various indications. Large multicenter studies have demonstrated that laparoscopy has clear advantages over open surgery. Compared to open procedures, laparoscopy decreases perioperative blood loss, post-operative pain, and hospitalization time, but provides equivalent long-term oncological and surgical results. Most studies have been conducted in high-volume institutions with selected patients, which may have influenced the reported outcome of laparoscopy. Here, we investigated the primary outcome of all laparoscopic colorectal resections performed between 2005 and 2015 in a low-volume center. Materials and methods: This retrospective study included bowel resections performed between 2005 and 2015 in the Lapland Central Hospital. Data were retrieved from electronic patient registries, and all operations that began as a laparoscopy were included. Patient records were investigated to determine the primary surgical outcome and possible complications within the first 30 days after surgery. Results: During 2005-2015, 385 laparoscopic colorectal resections were performed. Indications included benign (n = 166 patients, 43.1%) and malignant lesions (n = 219 cases, 56.9%). The median patient age was 68 years, and 50.4% were male. The median American Society of Anesthesiologist score was III, and 48.5% of patients had an American Society of Anesthesiologist class of III or IV. The median hospital stay after surgery was 6 days (interquartile range: 3.8). The conversion rate to open surgery rate was 13%. The total surgical complication rate was 24.2%, and re-operation was required in 11.2% of patients. A total of 26 patients had anastomotic leakage, of which 16 required re-operations. The 30-day mortality was 0.8%. Conclusion: Our results showed that laparoscopic colorectal surgery in a peripheral hospital resulted in primary outcome rates within the range of those reported in previous multicenter trials. Therefore, the routine use of laparoscopic colorectal resections with high-quality outcome is feasible in small and peripheral surgical units.
MeSH term(s)	Aged ; Aged, 80 and over ; Colectomy/adverse effects ; Colonic Diseases/mortality ; Colonic Diseases/surgery ; Conversion to Open Surgery ; Female ; Finland ; Humans ; Laparoscopy/adverse effects ; Length of Stay ; Male ; Middle Aged ; Postoperative Complications/epidemiology ; Proctectomy/adverse effects ; Rectal Diseases/mortality ; Rectal Diseases/surgery ; Reoperation ; Retrospective Studies ; Treatment Outcome
Language	English
Publishing date	2018-09-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2077691-3
ISSN	1799-7267 ; 1457-4969
ISSN (online)	1799-7267
ISSN	1457-4969
DOI	10.1177/1457496918798196
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Article ; Online: Hospital volume and outcomes of pancreatic cancer: a Finnish population-based nationwide study.

Huhta, Heikki / Nortunen, Minna / Meriläinen, Sanna / Helminen, Olli / Kauppila, Joonas H

HPB : the official journal of the International Hepato Pancreato Biliary Association

2021 Volume 24, Issue 6, Page(s) 841–847

Abstract: Background: Pancreatic cancer surgery is associated with high incidence of short- and long-term morbidity and mortality. The aim of this study was to assess whether the hospital volume of pancreatic surgery is associated with better survival in a ... ...

Abstract	Background: Pancreatic cancer surgery is associated with high incidence of short- and long-term morbidity and mortality. The aim of this study was to assess whether the hospital volume of pancreatic surgery is associated with better survival in a population-based setting. Methods: All patients who underwent pancreatic resection for cancer in Finland during 1997-2016 were identified from nationwide registries. The follow-up ended on 31 December 2019. Patients were divided into quintiles based on annual hospital volume (4-year moving average): ≤4, 5-9, 10-18, 19-36 and ≥ 37 resections per year. Cox regression provided hazard ratios (HR) and 95% confidence intervals (CI), adjusted for age, sex, comorbidity and year of surgery. Results: The number of diagnosed pancreatic cancers was 22,724. Of these, 1514 underwent pancreatic surgery due to pancreatic ductal adenocarcinoma. The 5-year survival ranged from 12% to 28%, increasing with higher annual operative volume. Adjusted 5-year mortality was higher in all other quintiles compared to the highest annual volume quintile (HR 1.43, 95% CI 1.16-1.75). Thirty and 90-day mortality were higher in the three lowest volume, compared to the highest quintile. Conclusion: Higher annual hospital volume of pancreatic surgery for pancreatic ductal adenocarcinoma is associated with improved short- and long-term survival.
MeSH term(s)	Carcinoma, Pancreatic Ductal/surgery ; Finland/epidemiology ; Hospitals, High-Volume ; Humans ; Pancreatic Neoplasms/epidemiology ; Pancreatic Neoplasms/surgery ; Pancreatic Neoplasms
Language	English
Publishing date	2021-10-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2131251-5
ISSN	1477-2574 ; 1365-182X
ISSN (online)	1477-2574
ISSN	1365-182X
DOI	10.1016/j.hpb.2021.10.011
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Article ; Online: Prognostic role of TLR4 and TLR2 in hepatocellular carcinoma.

Kairaluoma, Valtteri / Kemi, Niko / Huhta, Heikki / Pohjanen, Vesa-Matti / Helminen, Olli

Acta oncologica (Stockholm, Sweden)

2021 Volume 60, Issue 4, Page(s) 554–558

MeSH term(s)	Carcinoma, Hepatocellular ; Humans ; Liver Neoplasms ; Prognosis ; Toll-Like Receptor 2 ; Toll-Like Receptor 4
Chemical Substances	TLR2 protein, human ; TLR4 protein, human ; Toll-Like Receptor 2 ; Toll-Like Receptor 4
Language	English
Publishing date	2021-01-27
Publishing country	England
Document type	Letter
ZDB-ID	896449-x
ISSN	1651-226X ; 0349-652X ; 0284-186X ; 1100-1704
ISSN (online)	1651-226X
ISSN	0349-652X ; 0284-186X ; 1100-1704
DOI	10.1080/0284186X.2021.1877346
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Article ; Online: Carbonic Anhydrases II and IX in Non-ampullary Duodenal Adenomas and Adenocarcinoma.

Nortunen, Minna / Parkkila, Seppo / Saarnio, Juha / Huhta, Heikki / Karttunen, Tuomo J

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society

2021 Volume 69, Issue 11, Page(s) 677–690

Abstract: Non-ampullary duodenal adenocarcinoma (DAC) is a rare malignancy. Little information is available concerning the histopathological prognostic factors associated with DAC. Carbonic anhydrases (CAs) are metalloenzymes catalyzing the universal reaction of ... ...

Abstract	Non-ampullary duodenal adenocarcinoma (DAC) is a rare malignancy. Little information is available concerning the histopathological prognostic factors associated with DAC. Carbonic anhydrases (CAs) are metalloenzymes catalyzing the universal reaction of CO
MeSH term(s)	Adenocarcinoma/enzymology ; Adenocarcinoma/pathology ; Adult ; Aged ; Antigens, Neoplasm/genetics ; Antigens, Neoplasm/metabolism ; Carbonic Anhydrase II/genetics ; Carbonic Anhydrase II/metabolism ; Carbonic Anhydrase IX/genetics ; Carbonic Anhydrase IX/metabolism ; Cell Differentiation ; Cohort Studies ; Duodenal Neoplasms/enzymology ; Duodenal Neoplasms/pathology ; Female ; Humans ; Male ; Middle Aged
Chemical Substances	Antigens, Neoplasm ; Carbonic Anhydrase II (EC 4.2.1.-) ; CA9 protein, human (EC 4.2.1.1) ; Carbonic Anhydrase IX (EC 4.2.1.1)
Language	English
Publishing date	2021-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218208-7
ISSN	1551-5044 ; 0022-1554
ISSN (online)	1551-5044
ISSN	0022-1554
DOI	10.1369/00221554211050133
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Article ; Online: Carbonic Anhydrases II, IX, and XII in Reflux Esophagitis.

Nortunen, Minna / Väkiparta, Nina / Parkkila, Seppo / Saarnio, Juha / Huhta, Heikki / Karttunen, Tuomo J

Digestive diseases and sciences

2021 Volume 67, Issue 5, Page(s) 1761–1772

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Bicarbonates ; Carbonic Anhydrase II/metabolism ; Carbonic Anhydrases/metabolism ; Carcinoma, Squamous Cell ; Esophagitis ; Esophagitis, Peptic ; Gastroesophageal Reflux ; Humans ; Isoenzymes
Chemical Substances	Bicarbonates ; Isoenzymes ; Carbonic Anhydrase II (EC 4.2.1.-) ; Carbonic Anhydrases (EC 4.2.1.1)
Language	English
Publishing date	2021-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	304250-9
ISSN	1573-2568 ; 0163-2116
ISSN (online)	1573-2568
ISSN	0163-2116
DOI	10.1007/s10620-021-06985-5
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