Publications
-
-
Holm, Maia Blomhoff; Dorg, Linda Trobe; Rootwelt-Revheim, Mona-Elisabeth; Labori, Knut Jørgen & Verbeke, Caroline Sophie
(2026).
Expression of glycolytic markers in cancer and stromal cells of treatment-naïve and neoadjuvantly treated pancreatic ductal adenocarcinoma.
Virchows Archiv.
ISSN 0945-6317.
doi:
10.1007/s00428-026-04478-2.
Full text in Research Archive
-
Hilal, Mohammad Abu; Uijterwijk, Bas A.; Lemmers, Daniël H.L.; Janssen, Boris V.; Besselink, Marc G. & Bianchi, Denise
[Show all 56 contributors for this article]
(2025).
The Brescia International Multidisciplinary Consensus Guidelines on the Optimal Pathology Assessment and Multidisciplinary Pathways of Non-Pancreatic Neoplasms in and Around the Ampulla of Vater (PERIPAN).
United European Gastroenterology Journal (UEG Journal).
ISSN 2050-6406.
13(7),
p. 1048–1068.
doi:
10.1002/ueg2.70074.
Full text in Research Archive
Show summary
Importance
The lack of multidisciplinary workflow guidelines and clear definitions and classifications for neoplasms in and around the ampulla of Vater results in inconsistencies affecting patient care and research.
Objective
The PERIPAN international multidisciplinary consensus group aimed to standardize the multidisciplinary diagnostic workflow and achieve consensus on definitions and classifications in order to ensure proper classification and optimal diagnostic assessment and consequently to improve patient care and future research.
Design
An international team of 43 experts (pathologists, surgeons, radiologists, gastroenterologists, oncologists) from 12 countries identified knowledge gaps, reviewed 37061 articles, and proposed recommendations using the Scottish Intercollegiate Guidelines Network methodology (SIGN), including the Delphi methodology and the AGREEII tool for quality assessment and external validation.
Results
The 38 consensus questions and 51 recommendations provide guidance on the following key aspects: I. More specific anatomic criteria for the definition of what qualifies as “ampullary” neoplasms, their distinction from duodenal and common bile duct tumors, and clinicopathologic characteristics of anatomic subsets; II. Avoidance of the confusing term “periampullary” for final classification; III. Refined definitions of intestinal, pancreatobiliary and mixed subtypes, and introduction of rare histologic subtypes; IV. The use and limitations of immunohistochemical and molecular profiling; V. Biopsy acquisition; VI. Clinical information required for accurate pathology assessment of biopsies and ampullectomy specimens; VII. Key items to be included in pathology reports of endoscopic specimens.
Conclusions and Relevance
Recognition of the Brescia PERIPAN guidelines will allow a more accurate classification of true ampullary cancers and their differentiation from other “periampullary” tumors. This will have significant implications for endoscopic interpretation and management, staging, pathologic diagnosis and therapeutic evaluation as well as oncologic treatment of various anatomic and histologic subsets of ampullary tumors. This will enhance the quality of both clinical care and future research in this complex medical field.
-
Alver, Tine Norman; Bergholtz, Helga; Holm, Maia Blomhoff; Dorg, Linda Trobe; Skrede, Martina & Kure, Elin Wenche Hegland
[Show all 7 contributors for this article]
(2025).
Spatial Transcriptomics Reveals Cancer and Stromal Cell Heterogeneity Between Center and Invasive Front of Pancreatic Cancer.
Modern Pathology.
ISSN 0893-3952.
38(6),
p. 1–12.
doi:
10.1016/j.modpat.2025.100726.
Full text in Research Archive
Show summary
Intratumor heterogeneity is considered a major cause of treatment failure in pancreatic ductal adenocarcinoma (PDAC). In recent years, marked heterogeneity at the genomic and transcriptional level has been revealed, but the spatial distribution of the heterogeneous cell populations has not been considered. Yet, it is assumed that cancer cells at the invasive front are endowed with enhanced migratory and invasive properties, although evidence is scanty, and cancer-associated fibroblasts (CAFs) in this location have not been characterized. In this study, digital spatial profiling was used to compare the transcriptional profiles of cancer cells and CAFs in the tumor center versus the invasive front of human PDAC. Four well-differentiated PDACs with conventional morphology were investigated with the GeoMx system (Nanostring). Regions of interest were analyzed in the tumor center and at the invasive front using a whole transcriptome assay in the cancer cell and CAF segments separately. Three of the PDACs harbored mutated KRAS, whereas the fourth case was confirmed wild-type KRAS. Substantial inter-regional heterogeneity was identified, with increased activity of pathways associated with cellular stress (including TNFa-signaling via NFkB, hypoxia, P53 pathway), proliferation (MYC targets, mitotic spindle), glycolysis, and epithelialemesenchymal transition (EMT) at the invasive front in both the cancer cell and CAF segments compared with the center of the tumor. Immunohistochemical validation on 17 PDACs of well, moderate, and poor differentiation confirmed significant inter-regional heterogeneity in the expression level of markers of EMT and glycolysis. The results of this study show that in PDAC, transcriptional profiles of both cancer cells and CAFs differ between the center of the tumor and the invasive front.
-
Holm, Maia Blomhoff; Lenggenhager, Daniela; Detlefsen, Sönke; Santha, Petra & Verbeke, Caroline Sophie
(2024).
Identification of tumour regression in neoadjuvantly treated pancreatic cancer is based on divergent and nonspecific criteria.
Histopathology.
ISSN 0309-0167.
85(1),
p. 171–181.
doi:
10.1111/his.15190.
Full text in Research Archive
Show summary
Aims Following the increased use of neoadjuvant therapy for pancreatic cancer, grading of tumour regression (TR) has become part of routine diagnostics. However, it suffers from marked interobserver variation, which is mainly ascribed to the subjectivity of the defining criteria of the categories in TR grading systems. We hypothesized that a further cause for the interobserver variation is the use of divergent and nonspecific morphological criteria to identify tumour regression. Methods and Results Twenty treatment-naïve pancreatic cancers and 20 pancreatic cancers treated with neoadjuvant chemotherapy were reviewed by three experienced pancreatic pathologists who, blinded for treatment status, categorized each tumour as treatment-naïve or neoadjuvantly treated, and annotated all tissue areas they considered showing tumour regression. Only 50%–65% of the cases were categorized correctly, and the annotated tissue areas were highly discrepant (only 3%–41% overlap). When the prevalence of various morphological features deemed to indicate TR was compared between treatment-naïve and neoadjuvantly treated tumours, only one pattern, characterized by reduced cancer cell density and prominent stroma affecting a large area of the tumour bed, occurred significantly more frequently, but not exclusively, in the neoadjuvantly treated group. Finally, stromal features, both morphological and biological, were investigated as possible markers for tumour regression, but failed to distinguish TR from native tumour stroma. Conclusion There is considerable divergence in opinion between pathologists when it comes to the identification of tumour regression. Reliable identification of TR is only possible if it is extensive, while lesser degrees of treatment effect cannot be recognized with certainty.
-
Holm, Maia Blomhoff & Verbeke, Caroline Sophie
(2022).
Prognostic Impact of Resection Margin Status on Distal Pancreatectomy for Ductal Adenocarcinoma.
Current Oncology.
ISSN 1198-0052.
29(9),
p. 6551–6563.
doi:
10.3390/curroncol29090515.
Full text in Research Archive
Show summary
Pancreatic cancer is associated with a poor prognosis. While surgical resection is the only treatment option with curative intent, most patients die of locoregional and/or distant recurrence. The prognostic impact of the resection margin status has received much attention. However, the evidence is almost exclusively related to pancreatoduodenectomies, while corresponding data for distal pancreatectomy specimens are limited. The key data, such as the rate of microscopic margin involvement (“R1”), the site of margin involvement, and the impact of R1 on patient outcome, are divergent between studies and do not currently allow any general conclusions. The main reasons for the variability in the published data are the small size of the study cohorts and their heterogeneity, as well as the marked divergence in pathology examination practices. The latter is a consequence of the lack of concrete guidance, both for grossing and microscopic examination. The increasing administration of neoadjuvant chemo(radio)therapy introduces a further factor of uncertainty as the conventional definition of a tumour-free margin (“R0”) based on 1 mm clearance is inadequate for these specimens. This review discusses the published data regarding the prognostic impact of margin status in distal pancreatectomy specimens along with the challenges and uncertainties that are related to the assessment of the margins.
-
Tran, My Linh; Holm, Maia Blomhoff & Verbeke, Caroline Sophie
(2022).
Tumour Size and T-Stage in Pancreatic Cancer Resection Specimens Depend on the Pathology Examination Approach.
Cancers.
14(10),
p. 1–17.
doi:
10.3390/cancers14102471.
Full text in Research Archive
Show summary
In the eighth edition of the TNM classification for pancreatic ductal adenocarcinoma (PDAC), stages T1 to T3 are defined by tumour size, size measurement being deemed objective and accurate. This study investigated whether various, currently used approaches to tumour measurement result in different tumour sizes and differences in T-stage assignment. In a series of 315 resected PDAC, tumour sizes were measured as follows: macroscopically in a single or in two perpendicular planes and with or without microscopic corroboration. Comparison of the resulting tumour sizes showed that both macroscopic measurement in two planes and microscopic corroboration gave significantly different results (p < 0.001). Compared to the most simple approach (macroscopic measurement in one plane), the comprehensive approach (macroscopic measurement in two planes with microscopic corroboration) resulted in a larger tumour size in 263 (83%) cases (mean absolute size difference: 10 mm; mean relative size change: 36%). T-stage assignment differed in 142 (45%) cases between the simple and comprehensive approach and affected 87%, 38% and 48% of the cases deemed to be stage T1, T2 and T3, respectively. In conclusion, tumour size and T-stage are highly approach-dependent. Consensus on an accurate method is required to ensure comparability of these basic data.
-
Opheim, Gun Lisbeth; Holme, Ane Moe; Holm, Maia Blomhoff; Michelsen, Trond Melbye; Zahid, Saba Muneer & Roland, Marie Cecilie
[Show all 8 contributors for this article]
(2020).
The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies.
The FASEB Journal.
ISSN 0892-6638.
34(9),
p. 12481–12491.
doi:
10.1096/fj.202000766R.
Full text in Research Archive
Show summary
Glucose is a major energy substrate for the fetus, including liver, heart, and brain metabolism. The umbilical vein (UV) blood flow supplies the fetal liver directly from the placenta, whereas a fraction is shunted via ductus venosus (DV) to the fetal systemic circulation bypassing the fetal liver. We hypothesized UV glucose concentration to be a major regulator of the distribution of glucose supply between the fetal liver and DV, and explored the influence of maternal metabolic status on this distribution. We included 124 healthy women with normal singleton pregnancies, scheduled for elective cesarean section. UV and DV blood flow measurements were performed by Doppler ultrasound immediately before, and blood samples were obtained during surgery. UV blood flow was significantly correlated with DV blood flow, liver blood flow, and the DV shunting fraction, while UV glucose concentration was not. For normal‐weight mothers, the maternal‐fetal glucose gradient was positively correlated with DV shunting fraction, and negatively with liver blood flow. For the fetuses of the overweight mothers no such correlation was found. This indicates that within the normal physiological range the human fetus makes adaptations of blood flow to ensure individual needs related to the offered maternal energy supply.
-
Michelsen, Trond Melbye; Holme, Ane Moe; Holm, Maia Blomhoff; Roland, Marie Cecilie; Haugen, Guttorm & Powell, Theresa L.
[Show all 8 contributors for this article]
(2019).
Uteroplacental glucose uptake and fetal glucose consumption: A quantitative study in human pregnancies.
Journal of Clinical Endocrinology and Metabolism (JCEM).
ISSN 0021-972X.
104(3),
p. 873–882.
doi:
10.1210/jc.2018-01154.
Full text in Research Archive
Show summary
Context
Maternal glucose levels and body mass index (BMI) are determinants of fetal overgrowth, but their relation to fetal glucose consumption is not well characterized in human pregnancy.
Objectives
To quantify uteroplacental glucose uptake and the allocation of glucose between the placenta and fetus and to identify factors that affect fetal glucose consumption.
Design
Human in vivo study in term pregnancies.
Setting
Oslo University Hospital, Norway.
Participants
One hundred seventy-nine healthy women with elective cesarean section.
Interventions
Uterine and umbilical blood flow was determined using Doppler ultrasonography. Glucose and insulin were measured in the maternal radial artery and uterine vein and the umbilical artery and vein. In a subcohort (n = 33), GLUT1 expression was determined in isolated syncytiotrophoblast basal and microvillous plasma membranes.
Main Outcome Measures
Uteroplacental glucose uptake and placental and fetal glucose consumption quantified by the Fick principle.
Results
Median (Q1, Q3) uteroplacental glucose uptake was 117.1 (59.1, 224.9) μmol⋅min−1, and fetal and placental glucose consumptions were 28.9 (15.4, 41.8) µmol⋅min−1⋅kg fetus−1 and 51.4 (−65.8, 185.4) µmol⋅min−1⋅kg placenta−1, respectively. Fetal glucose consumption correlated with birth weight (ρ: 0.34; P < 0.001) and maternal–fetal glucose gradient (ρ: 0.60; P < 0.001), but not with maternal BMI or uteroplacental glucose uptake. Uteroplacental glucose uptake was correlated to placental glucose consumption (ρ: 0.77; P < 0.001). Fetal and placental glucose consumptions were inversely correlated (ρ: −0.47; P < 0.001), but neither was correlated with placental GLUT1 expression.
Conclusion
These findings suggest that fetal glucose consumption is balanced against the placental needs for glucose and that placental glucose consumption is a key modulator of maternal–fetal glucose transfer in women.
-
-
Holm, Maia Blomhoff; Kristiansen, Oddrun; Holme, Ane Moe; Bastani, Nasser Ezzatkhah; Horne, Hildegunn & Blomhoff, Rune
[Show all 9 contributors for this article]
(2018).
Placental release of taurine to both the maternal and fetal circulations in human term pregnancies.
Amino Acids.
ISSN 0939-4451.
50(9),
p. 1205–1214.
doi:
10.1007/s00726-018-2576-9.
Full text in Research Archive
Show summary
Taurine is regarded as an essential amino acid in utero, and fetal taurine supply is believed to rely solely on placental transfer from maternal plasma. Despite its potential role in intrauterine growth restriction and other developmental disturbances, human in vivo studies of taurine transfer between the maternal, placental, and fetal compartments are scarce. We studied placental transfer of taurine in uncomplicated human term pregnancies in vivo in a cross-sectional study of 179 mother-fetus pairs. During cesarean section, we obtained placental tissue and plasma from incoming and outgoing vessels on the maternal and fetal sides of the placenta. Taurine was measured by liquid chromatography–tandem mass spectrometry. We calculated paired arteriovenous differences, and measured placental expression of the taurine biosynthetic enzyme cysteine sulfinic acid decarboxylase (CSAD) with quantitative real-time polymerase chain reaction and western blot. We observed a fetal uptake (p < 0.001), an uteroplacental release (p < 0.001), and a negative placental consumption of taurine (p = 0.001), demonstrating a bilateral placental release to the maternal and fetal compartments. Increasing umbilical vein concentrations and fetal uptake was associated with the uteroplacental release to the maternal circulation (rs = − 0.19, p = 0.01/rs = − 0.24, p = 0.003), but not with taurine concentrations in placental tissue. CSAD-mRNA was expressed in placental tissue, suggesting a potential for placental taurine synthesis. Our observations show that the placenta has the capacity to a bilateral taurine release, indicating a fundamental role of taurine in the human placental homeostasis beyond the supply to the fetus.
-
Holme, Ane Moe; Holm, Maia Blomhoff; Roland, Marie Cecilie; Horne, Hildegunn; Michelsen, Trond Melbye & Haugen, Guttorm
[Show all 7 contributors for this article]
(2017).
The 4-vessel sampling approach to integrative studies of human placental physiology in vivo.
Journal of Visualized Experiments.
2017(126).
doi:
10.3791/55847.
Full text in Research Archive
Show summary
The human placenta is highly inaccessible for research while still in utero. The current understanding of human placental physiology in vivo is therefore largely based on animal studies, despite the high diversity among species in placental anatomy, hemodynamics and duration of the pregnancy. The vast majority of human placenta studies are ex vivo perfusion studies or in vitro trophoblast studies. Although in vitro studies and animal models are essential, extrapolation of the results from such studies to the human placenta in vivo is uncertain. We aimed to study human placenta physiology in vivo at term, and present a detailed protocol of the method. Exploiting the intraabdominal access to the uterine vein just before the uterine incision during planned cesarean section, we collect blood samples from the incoming and outgoing vessels on the maternal and fetal sides of the placenta. When combining concentration measurements from blood samples with volume blood flow measurements, we are able to quantify placental and fetal uptake and release of any compound. Furthermore, placental tissue samples from the same mother-fetus pairs can provide measurements of transporter density and activity and other aspects of placental functions in vivo. Through this integrative use of the 4-vessel sampling method we are able to test some of the current concepts of placental nutrient transfer and metabolism in vivo, both in normal and pathological pregnancies. Furthermore, this method enables the identification of substances secreted by the placenta to the maternal circulation, which could be an important contribution to the search for biomarkers of placenta dysfunction.
-
Holm, Maia Blomhoff; Bastani, Nasser Ezzatkhah; Holme, Ane Moe; Zucknick, Manuela; Jansson, Thomas & Refsum, Helga
[Show all 10 contributors for this article]
(2017).
Uptake and release of amino acids in the fetal-placental unit in human pregnancies.
PLOS ONE.
12(10).
doi:
10.1371/journal.pone.0185760.
Full text in Research Archive
Show summary
Objectives: The current concepts of human fetal-placental amino acid exchange and metabolism are mainly based on animal-, in vitro- and ex vivo models. We aimed to determine and assess the paired relationships between concentrations and arteriovenous differences of 19 amino acids on the maternal and fetal sides of the human placenta in a large study sample. Methods: This cross-sectional in vivo study included 179 healthy women with uncomplicated term pregnancies. During planned cesarean section, we sampled blood from incoming and outgoing vessels on the maternal (radial artery and uterine vein) and fetal (umbilical vein and artery) sides of the placenta. Amino acid concentrations were measured by liquid chromatography—tandem mass spectrometry. We calculated paired arteriovenous differences and performed Wilcoxon signed-rank tests and Spearman’s correlations. Results: In the umbilical circulation, we observed a positive venoarterial difference (fetal uptake) for 14 amino acids and a negative venoarterial difference (fetal release) for glutamic acid (p<0.001). In the maternal circulation, we observed a positive arteriovenous difference (uteroplacental uptake) for leucine (p = 0.005), isoleucine (p = 0.01), glutamic acid (p<0.001) and arginine (p = 0.04) and a negative arteriovenous difference (uteroplacental release) for tyrosine (p = 0.002), glycine (p = 0.01) and glutamine (p = 0.02). The concentrations in the maternal artery and umbilical vein were correlated for all amino acids except tryptophan, but we observed no correlations between the uteroplacental uptake and the fetal uptake or the umbilical vein concentration. Two amino acids showed a correlation between the maternal artery concentration and the fetal uptake. Conclusions: Our human in vivo study expands the current insight into fetal-placental amino acid exchange, and discloses some differences from what has been previously described in animals. Our findings are consistent with the concept that the fetal supply of amino acids in the human is the result of a dynamic interplay between fetal and placental amino acid metabolism and interconversions.
View all works in NVA
Published
Nov. 18, 2024 3:38 PM
- Last modified
Nov. 18, 2024 3:38 PM
