Sverre Torp - Academia.edu (original) (raw)

Papers by Sverre Torp

Molecular and Clinical Oncology, Aug 22, 2023

In general, human meningiomas grow slowly and have a favourable prognosis; however, some are pron... more In general, human meningiomas grow slowly and have a favourable prognosis; however, some are prone to recur despite their benign histology. Therefore, knowledge of their tumour biology is essential to determine objective biomarkers that can identify cases with an increased risk for recurrence and to generate effective treatment options. Thus, studies on the epidermal growth factor receptor (EGFR) family, comprising ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4, are important. We have recently published papers on the expression of each of these receptor proteins in human meningiomas. The present study aimed to assess the clinicopathological significance of their concurrent expression. A total of 185 grade 1 and 2 meningiomas with robust clinical data underwent immunohistochemical analyses with antibodies against the aforementioned receptors. All meningiomas exhibited upregulation of these receptor proteins relative to normal meninges. In addition, the expression of phosphorylated/activated ErbB1/EGFR1 and phosphorylated/activated ErbB2/HER2 was significantly associated with histological malignancy grade and prognosis, respectively. The concurrent upregulation of ErbB receptors in human meningioma supports their fundamental role in the tumourigenesis of these tumours, and they could thus be exploited in diagnostics, prognosis, and ultimately, in targeted clinical interventions.

Journal of Leukocyte Biology, Mar 1, 2001

Human Toll-like receptor 2 (TLR2) is a receptor for a variety of microbial products and mediates ... more Human Toll-like receptor 2 (TLR2) is a receptor for a variety of microbial products and mediates activation signals in cells of the innate immune system. We have investigated expression and regulation of the TLR2 protein in human blood cells and tissues by using two anti-TLR2 mAbs. Only myelomonocytic cell lines expressed surface TLR2. In tonsils, lymph nodes, and appendices, activated B-cells in germinal centers expressed TLR2. In human blood, CD14 ؉ monocytes expressed the highest level of TLR2 followed by CD15 ؉ granulocytes, and CD19 ؉ B-cells, CD3 ؉ T-cells, and CD56 ؉ NK cells did not express TLR2. The level of TLR2 on monocytes was after 20 h up-regulated by LPS, GM-CSF, IL-1, and IL-10 and down-regulated by IL-4, IFN-␥, and TNF. On purified granulocytes, LPS, GM-CSF, and TNF down-regulated, and IL-10 modestly increased TLR2 expression after 2 h. These data suggest that TLR2 protein expression in innate immune cells is differentially regulated by inflammatory mediators.

Apmis, Jul 1, 1992

The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic cond... more The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic conditions for expression of epidermal growth factor receptor (EGFR) using an improved histochemical method, namely biotinylated epidermal growth factor. EGFR was found in all the examined meningiomas (12 benign and three anaplastic) and in neonatal rat meninges, whereas normal and injured adult human and rat meninges did not exhibit detectable EGFR. These observations indicate that EGFR is involved in the development of meningeal tissue. Further, EGFR is abnormally expressed in meningeal tumours, indicating a role of EGFR in the neoplastic process of these tumours. The regular expression of EGFR in human meningiomas suggests EGFR as a tumour marker for this tumour type.

Cell and Tissue Research, Mar 22, 2013

The regenerating islet-derived (REG) gene family encodes a group of proteins highly expressed in ... more The regenerating islet-derived (REG) gene family encodes a group of proteins highly expressed in several human pathologies, many of which are associated with epithelial inflammation. All human family members, namely REG1A, REG1B, REG3A and REG4, are closely related in genomic sequence and all are part of the c-type lectin superfamily. REGs are highly expressed during inflammatory bowel disease (IBD)-related colonic inflammation and the in vivo expression pattern of REG1A and REG4 has been localised by using immunohistochemistry. However, the function of the encoded proteins is largely unknown and the cellular localisation of REG expression during colonic inflammation has not been described. Therefore, we have used in situ hybridisation to demonstrate the cellular localisation of REG expression in healthy and diseased colonic mucosa. Samples drawn from an IBD cohort including both inflamed and un-inflamed colonic mucosa are described, as are samples from non-IBD inflammation and healthy controls. Immunohistochemistry against known cell-type markers on serial sections has localised the expression of REGs to metaplastic Paneth cells (REG1A, REG1B and REG3A) and enteroendocrine cells (REG4), with a marked expansion of expression during inflammation. The group of REGs can, based on gene expression patterns, be divided into at least two groups; REG1A, REG1B and REG3A with their expression focused in the crypt base spreading from Paneth cells and REG4 being more highly expressed towards the luminal face. This exploration of expression pattern forms provides the background for further exploration of REG function in the intestine.

International Congress Series, Feb 1, 2004

The treatment of malignant intracranial tumors varies internationally. In our institution, the tr... more The treatment of malignant intracranial tumors varies internationally. In our institution, the treatment has been based on surgery. Adjuvant therapy has been tailored to the needs of the patient. The objective of this retrospective study was to analyze the prognostic effect of surgery and adjuvant therapy. A total of of 186 patients, treated in a single institution over a period of 6.5 years, were included in the study; 172 were operated. Clinical information was obtained from the medical records. Survival analysis was performed using the Kaplan-Meier model. The most important factors related to survival were repeated resection, Karnofsky Performance Score (KPS), extent of resection and age. Patients with glioblastoma multiforme (GBM) showed a 10-month prolonged survival after repeated resection. Our results suggest that irradiation, in combination with chemotherapy, is the best strategy of adjuvant therapy for GBM and anaplastic astrocytoma. Tumours located centrally near the skull base resulted in a higher complication rate and a significantly reduced neurological outcome. Our results suggest that surgery should be performed, as radically as possible, and repeated resection should be considered if recurrency is confirmed.

Cancers, Mar 12, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Neuro-oncology, Nov 21, 2016

identifying patients with risk of recurrence compared with the traditional methods used in the cu... more identifying patients with risk of recurrence compared with the traditional methods used in the current clinical practice. MCM7 may thus improve diagnostics, prediction of prognosis and treatment decision making in patients sufering from meningiomas.

Case reports in neurological medicine, Jun 28, 2018

Parkinson's disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, g... more Parkinson's disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

Clinical Neuropathology, Mar 1, 2007

A133 eficiaries who had a diagnosis of hypertension and CKD, aged 67 and above and continuously e... more A133 eficiaries who had a diagnosis of hypertension and CKD, aged 67 and above and continuously enrolled in Medicare Part D from 2008 to 2013 are included. Baseline characteristics examined using a two year lookback period. Adherence to ACEIs, ARBs and other blood pressure/ lipid lowering agents was measured using proportion of days covered (PDC). Multivariate Cox regression models were used to assess the association between medication adherence and progression to end stage renal disease (ESRD) and death. Results: A total of 115,769 hypertensive patients with CKD were included. Approximately 2.5% of them developed ESRD and 57.5% of them died during 2008-2013. Adherence to ACEIs and ARBs was associated with a significant decreased hazard of developing ESRD (Hazard Ratio: 0.29 95%CI [0.25-0.33] p< 0.0001; 0.49 95% CI [0.42, 0.57] p< 0.0001, respectively) after adjusting for demographic and clinical confounders. Patients with increased use of ACEIs and ARBs had reduced risk of death (Hazard Ratio: 0.76 95%CI [0.74-0.78] p< 0.0001; 0.64 95% CI [0.62, 0.66] p< 0.0001, respectively). Increased adherence to diuretics and statins were associated with lower ESRD and mortality risk, while calcium channel blockers and beta blockers were associated with increased ESRD risk and lower mortality risk. ConClusions: Increased adherence to ACEIs and ARBs for elderly patients diagnosed with hypertensive CKD is associated with delay in CKD progression and lower mortality risk. These findings could have significant implications for hypertension management in this population.

Ultrasound in Medicine and Biology, May 1, 2023

Inflammatory Bowel Diseases, Apr 1, 2014

Background: Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory b... more Background: Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory bowel disease (IBD). Screening the poly(I:C) response in an intestinal epithelial cell line, we found complement factor B mRNA (CFB) potently upregulated and went on to further study local and systemic activation of CFB in ulcerative colitis (UC) and Crohn's disease (CD). Methods: In a transcriptome analysis of poly(I:C) stimulated HT-29 cells, we found CFB highly upregulated downstream of TLR3. We sought to confirm CFB upregulation in a microarray gene expression analysis on colonic biopsies from an IBD population (n=133). Immunohistochemical staining and in situ hybridization was done to identify cellular sources of complement factor B protein (fB) and CFB. Systemic complement activation was assessed in plasma (n=18) using neoepitope-based ELISA. Results: Complement factor B mRNA and protein were abundantly expressed in the colonic epithelial cell line, and synthesis enhanced by the poly(I:C) TLR3 ligand. In inflamed vs. normal colonic mucosa of ulcerative colitis (UC) and Crohn`s disease (CD) CFB mRNA was the most significantly overexpressed gene and the mRNA abundance ratio was among the 50 highest.. Epithelial cells were the dominating site of fB expression. Systemic complement activation was significantly higher in active than in non-active IBD. Conclusion: This study is the first to link TLR3 to activation of the alternative complement pathway, and complement factor B is potently upregulated locally in IBD in addition to having a possible central role in systemic complement activation. This suggests a prominent role for complement in IBD pathogenesis.

World Neurosurgery, Mar 1, 2017

Since the prognostic importance of radical resection was introduced in 1957, the neurosurgery pra... more Since the prognostic importance of radical resection was introduced in 1957, the neurosurgery practice has undergone several technologic advancements. The aim of this study was to evaluate whether the prognostic value of the extent of resection is still relevant in modern neurosurgical practice. Over a 10-year period, all patients with histologic-confirmed World Health Organization grade I meningiomas and who underwent meningioma surgery were retrospectively analyzed. Survival analyses were performed using Kaplan-Meier analysis and univariate and multivariate Cox proportional-hazards regression analyses. There were 113 patients included in this study. A better Simpson grade was associated with recurrence-free survival (RFS) 5, 10, and 15 years after surgery (P &amp;amp;lt; 0.001). Comparing Simpson grade I with Simpson grades III and IV, 13.1 and 36.6 times higher hazard ratios were revealed with respect to RFS, respectively. A 7.5 times higher hazard ratio was revealed when comparing Simpson grades II and IV. Additional survival analyses were performed within specific locations and groups with low and high mitotic indices, demonstrating that the extent of resection can add additional information about RFS. Simpson grade remains a highly significant predictor of RFS in meningioma-resected patients in modern neurosurgical practice. Extent of resection should therefore be emphasized when predicting prognosis and considering postoperative treatment and frequency of radiologic follow-up after surgery.

Acta neurochirurgica, Sep 5, 2008

Objective The purpose of the study was to compare the ability of navigated 3D ultrasound to disti... more Objective The purpose of the study was to compare the ability of navigated 3D ultrasound to distinguish tumour and normal brain tissue at the tumour border zone in subsequent phases of resection. Materials and methods Biopsies were sampled in the tumour border zone as seen in the US images before and during surgery. After resection, biopsies were sampled in the resection cavity wall. Histopathology was compared with the surgeon's image findings. Results Before resection, the tumour border was delineated by ultrasound with high specificity and sensitivity (both 95%). During resection, ultrasound had acceptable sensitivity (87%), but poor specificity (42%), due to biopsies falsely classified as tumour by the surgeon. After resection, sensitivity was poor (26%), due to tumour or infiltrated tissue in several biopsies deemed normal by ultrasound, but the specificity was acceptable (88%). Conclusions Our study shows that although glioblastomas are well delineated prior to resection, there seem to be overestimation of tumour tissue during resection. After resection tumour remnants and infiltrated brain tissue in the resection cavity wall may be undetected. We believe that the benefits of intraoperative ultrasound outweigh the shortcomings, but users of intraoperative ultrasound should keep the limitations shown in our study in mind.

Pathology Research and Practice, Oct 1, 2019

HER3 and HER4 are tyrosine kinase receptors of the ErbB family that have been detected in several... more HER3 and HER4 are tyrosine kinase receptors of the ErbB family that have been detected in several cancers but lack substantial investigation in human meningiomas. In this study, HER3 and-4 expression levels were evaluated as potential biomarkers by immunohistochemistry and explored for association to clinical features in a large series of human meningiomas. 186 primary intracranial meningiomas from adult patients were investigated with antibodies against HER3 and-4 intracellular domains. Tumors were scored with a staining index (SI) based on cytoplasmic/membranous staining intensity and on the percentage of positive cells. SIs were tested for associations with WHO malignancy grade, tumor subtype, localization, and prognosis. HER3 and HER4 were highly expressed in most tumors. Both cytoplasmic and membranous immunoreactivity occurred, and for HER4 nuclear immunoreactivity was observed as well. Non-neoplastic meningeal tissue was not immunoreactive. HER3 and-4 immunoreactivity was not associated with WHO malignancy grade, nor with recurrence or survival in adjusted analyses. Meningiomas of all grades were shown to widely express both HER3 and HER4 receptors. This feature may have diagnostic value since non-neoplastic meninges were not immunoreactive. There was no prognostic significance in adjusted survival analyses.

Pathology Research and Practice, Apr 1, 2017

Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks int... more Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase II␣ (TII␣) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs. astrocytomas, IDH1-mutated. Uni-/multivariable COX-regression analyses showed that greater expression of both survivin and TII␣ were associated with poorer survival when stratified for IDH1-mutation status and, additionally, achieved hazard rates surpassing clinically established prognostic factors such as age and WHO performance status. Ki67 achieved only statistical significance in univariable analyses, whereas mitoses did not reveal any relation to survival. IDH1-mutated astrocytomas had significantly better survival than astrocytomas, NOS. Among IDH1-mutated astrocytomas no significant difference in survival was shown between DA and AA. Our findings suggest a potential usefulness of proliferation markers in the prognostic setting of astrocytomas independent of IDH1-mutation status, and survivin and TII␣ are potential candidates in that regard.

Journal of clinical & experimental pathology, 2012

Glioblastoma is the most common primary brain tumour in humans. Diagnostic challenges can occur a... more Glioblastoma is the most common primary brain tumour in humans. Diagnostic challenges can occur as glioblastomas are highly heterogeneous tumours. The aim of this study was to investigate the frequencies and correlations between several histological features in primary glioblastomas and describe any link to tumour biology. Two hundred consecutively diagnosed adult patients with primary glioblastoma located supratentorally were included after revision according to the 2007 World Health Organization criteria. Several histological features were examined. All tumours contained necrosis and/or microvascular proliferation, with frequencies of 98.5% (197/200) and 84.5% (169/200) respectively. Most tumours had detectable mitoses (192/200, 96%), with a median value of 8.5 per 10 high power fields. Further, pseudopalisades (158/200, 79%), thromboses (157/200, 78.5%), atypical mitoses (119/200, 59.5%), and haemorrhages (106/200, 53%) were other common features. Among relevant correlations necroses were positively associated with pseudopalisades, thromboses, small cells and mitoses. In conclusion, glioblastomas present a variety of cell types and histological features, important to know and be aware of for the diagnostic pathologist. Interestingly, microvascular proliferation and necroses were frequently found in coexistence. Further, several of these features are closely linked to tumour biology, making histopathology fundamental for increased understanding of gliomagenesis.

Journal of Applied Physiology, May 1, 2010

Clinical Neuropathology, Nov 1, 2011

Introduction: Astroblastoma is a rare glial tumor of uncertain origin affecting mostly children, ... more Introduction: Astroblastoma is a rare glial tumor of uncertain origin affecting mostly children, adolescents and young adults. Given the rarity and the definitional problems concerning this tumor entity, the prognosis and appropriate treatment are at this point unclear. Case report: A 50-yearold Caucasian female presented with a seizure. Radiological findings showed a welldefined circumscribed tumor located in the right cerebral frontal lobe. The patient underwent primary surgery followed by postoperative radiotherapy. After 6 months the tumor recurred with multiple small lesions not available for surgery. Chemotherapy was administered with complete radiological response. Seven years after surgery and more than 6 years after completed chemotherapy the patient is free of disease. Histopathology revealed a gliomatous tumor with gemistocyte-like tumor cells arranged in palisades or strings and areas with perivascular pseudorosettes, consistent with astroblastoma. Immunophenotype and ultrastructural findings confirmed the diagnosis and verified the neuroepithelial origin. Conclusion: Astroblastomas are rare brain tumors and pose a challenge in the diagnostic and clinical approach. In general, they have an unpredictable course with a tendency of recurrence. This and other case reports support a survival benefit of chemotherapy, suggesting this as an important treatment option for these patients.

Pathology Research and Practice, 2002

Low-grade diffuse astrocytomas are generally slow-growing tumors; however, they may progress to a... more Low-grade diffuse astrocytomas are generally slow-growing tumors; however, they may progress to anaplastic astrocytomas or glioblastomas. As existing grading systems fail to distinguish these tumors, ongoing research strives to identify new prognostic markers. In this study, 22 adult patients with supratentorial diffuse astrocytomas, WHO grade II, were investigated to clarify whether proliferative activity, assessed by different Ki67 antibodies (MIB-1, NC-MM1, NC-Ki67p, rahKi67), expression of basic fibroblast growth factor (bFGF) or microvessel density have prognostic power. The Ki67 antibodies revealed low proliferation indices (PI); however, there was a wide spread of values, ranging from 0.1% to about 10%. In general, a positive correlation between the different Ki67 PIs was found. In 12 of 22 cases, bFGF immunoreactivity was recorded. Microvessel density was generally low. MIB-1 PI was the only prognostic factor of statistical significance. Ki67 PI, obtained by using the monoclonal antibody MIB-1, can thus serve as a prognostic factor capable of identifying subsets of low-grade diffuse astrocytomas with a potentially more aggressive clinical behavior.

Apmis, Jul 1, 1992

Biopsy specimens of human brain metastases were examined for amplification and expression of the ... more Biopsy specimens of human brain metastases were examined for amplification and expression of the proto‐oncogene c‐erbB1 (located on chromosome 7) encoding the epidermal growth factor receptor (EGFR). Moreover, the tumour DNA was also examined for amplification of other cancer‐related genes on this chromosome: the proto‐oncogene c‐met, the gene for platelet‐derived growth factor A‐chain, and the gene for plasminogen activator inhibitor type 1. All 18 brain metastases demonstrated positive binding of biotinylated EGF on cryosections. Three out of 18 metastases had amplification of the EGFR gene; the other chromosome‐7 genes tested were not amplified. Thus, an increased EGFR gene expression seems to be a general finding in a wide range of carcinomas metastatic to the brain, whereas we found only occasional selective EGFR gene amplifications in single cases.

Molecular and Clinical Oncology, Aug 22, 2023

In general, human meningiomas grow slowly and have a favourable prognosis; however, some are pron... more In general, human meningiomas grow slowly and have a favourable prognosis; however, some are prone to recur despite their benign histology. Therefore, knowledge of their tumour biology is essential to determine objective biomarkers that can identify cases with an increased risk for recurrence and to generate effective treatment options. Thus, studies on the epidermal growth factor receptor (EGFR) family, comprising ErbB1/EGFR, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4, are important. We have recently published papers on the expression of each of these receptor proteins in human meningiomas. The present study aimed to assess the clinicopathological significance of their concurrent expression. A total of 185 grade 1 and 2 meningiomas with robust clinical data underwent immunohistochemical analyses with antibodies against the aforementioned receptors. All meningiomas exhibited upregulation of these receptor proteins relative to normal meninges. In addition, the expression of phosphorylated/activated ErbB1/EGFR1 and phosphorylated/activated ErbB2/HER2 was significantly associated with histological malignancy grade and prognosis, respectively. The concurrent upregulation of ErbB receptors in human meningioma supports their fundamental role in the tumourigenesis of these tumours, and they could thus be exploited in diagnostics, prognosis, and ultimately, in targeted clinical interventions.

Journal of Leukocyte Biology, Mar 1, 2001

Human Toll-like receptor 2 (TLR2) is a receptor for a variety of microbial products and mediates ... more Human Toll-like receptor 2 (TLR2) is a receptor for a variety of microbial products and mediates activation signals in cells of the innate immune system. We have investigated expression and regulation of the TLR2 protein in human blood cells and tissues by using two anti-TLR2 mAbs. Only myelomonocytic cell lines expressed surface TLR2. In tonsils, lymph nodes, and appendices, activated B-cells in germinal centers expressed TLR2. In human blood, CD14 ؉ monocytes expressed the highest level of TLR2 followed by CD15 ؉ granulocytes, and CD19 ؉ B-cells, CD3 ؉ T-cells, and CD56 ؉ NK cells did not express TLR2. The level of TLR2 on monocytes was after 20 h up-regulated by LPS, GM-CSF, IL-1, and IL-10 and down-regulated by IL-4, IFN-␥, and TNF. On purified granulocytes, LPS, GM-CSF, and TNF down-regulated, and IL-10 modestly increased TLR2 expression after 2 h. These data suggest that TLR2 protein expression in innate immune cells is differentially regulated by inflammatory mediators.

Apmis, Jul 1, 1992

The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic cond... more The aim of this study was to examine meningeal tissue under normal, reactive, and neoplastic conditions for expression of epidermal growth factor receptor (EGFR) using an improved histochemical method, namely biotinylated epidermal growth factor. EGFR was found in all the examined meningiomas (12 benign and three anaplastic) and in neonatal rat meninges, whereas normal and injured adult human and rat meninges did not exhibit detectable EGFR. These observations indicate that EGFR is involved in the development of meningeal tissue. Further, EGFR is abnormally expressed in meningeal tumours, indicating a role of EGFR in the neoplastic process of these tumours. The regular expression of EGFR in human meningiomas suggests EGFR as a tumour marker for this tumour type.

Cell and Tissue Research, Mar 22, 2013

The regenerating islet-derived (REG) gene family encodes a group of proteins highly expressed in ... more The regenerating islet-derived (REG) gene family encodes a group of proteins highly expressed in several human pathologies, many of which are associated with epithelial inflammation. All human family members, namely REG1A, REG1B, REG3A and REG4, are closely related in genomic sequence and all are part of the c-type lectin superfamily. REGs are highly expressed during inflammatory bowel disease (IBD)-related colonic inflammation and the in vivo expression pattern of REG1A and REG4 has been localised by using immunohistochemistry. However, the function of the encoded proteins is largely unknown and the cellular localisation of REG expression during colonic inflammation has not been described. Therefore, we have used in situ hybridisation to demonstrate the cellular localisation of REG expression in healthy and diseased colonic mucosa. Samples drawn from an IBD cohort including both inflamed and un-inflamed colonic mucosa are described, as are samples from non-IBD inflammation and healthy controls. Immunohistochemistry against known cell-type markers on serial sections has localised the expression of REGs to metaplastic Paneth cells (REG1A, REG1B and REG3A) and enteroendocrine cells (REG4), with a marked expansion of expression during inflammation. The group of REGs can, based on gene expression patterns, be divided into at least two groups; REG1A, REG1B and REG3A with their expression focused in the crypt base spreading from Paneth cells and REG4 being more highly expressed towards the luminal face. This exploration of expression pattern forms provides the background for further exploration of REG function in the intestine.

International Congress Series, Feb 1, 2004

The treatment of malignant intracranial tumors varies internationally. In our institution, the tr... more The treatment of malignant intracranial tumors varies internationally. In our institution, the treatment has been based on surgery. Adjuvant therapy has been tailored to the needs of the patient. The objective of this retrospective study was to analyze the prognostic effect of surgery and adjuvant therapy. A total of of 186 patients, treated in a single institution over a period of 6.5 years, were included in the study; 172 were operated. Clinical information was obtained from the medical records. Survival analysis was performed using the Kaplan-Meier model. The most important factors related to survival were repeated resection, Karnofsky Performance Score (KPS), extent of resection and age. Patients with glioblastoma multiforme (GBM) showed a 10-month prolonged survival after repeated resection. Our results suggest that irradiation, in combination with chemotherapy, is the best strategy of adjuvant therapy for GBM and anaplastic astrocytoma. Tumours located centrally near the skull base resulted in a higher complication rate and a significantly reduced neurological outcome. Our results suggest that surgery should be performed, as radically as possible, and repeated resection should be considered if recurrency is confirmed.

Cancers, Mar 12, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Journal of Neuro-oncology, Nov 21, 2016

identifying patients with risk of recurrence compared with the traditional methods used in the cu... more identifying patients with risk of recurrence compared with the traditional methods used in the current clinical practice. MCM7 may thus improve diagnostics, prediction of prognosis and treatment decision making in patients sufering from meningiomas.

Case reports in neurological medicine, Jun 28, 2018

Parkinson's disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, g... more Parkinson's disease (PD) is a clinical diagnosis based on the presence of cardinal motor signs, good response to levodopa, and no other explanations of the syndrome. Earlier diagnostic criteria required autopsy for a definite diagnosis based on neuronal loss in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies and neurites. Here, we present a patient who developed parkinsonism around the age of 20, with an excellent response to levodopa who, at age 65, received bilateral STN deep brain stimulation (DBS). The patient died at age 79. The autopsy showed severe neuronal loss in the SN without any Lewy bodies in the brainstem or in the hemispheres. Genetic screening revealed a homozygous deletion of exon 3-4 in the Parkin gene. In this case report we discuss earlier described pathological findings in Parkin cases without Lewy body pathology, the current diagnostic criteria for PD, and their clinical relevance.

Clinical Neuropathology, Mar 1, 2007

A133 eficiaries who had a diagnosis of hypertension and CKD, aged 67 and above and continuously e... more A133 eficiaries who had a diagnosis of hypertension and CKD, aged 67 and above and continuously enrolled in Medicare Part D from 2008 to 2013 are included. Baseline characteristics examined using a two year lookback period. Adherence to ACEIs, ARBs and other blood pressure/ lipid lowering agents was measured using proportion of days covered (PDC). Multivariate Cox regression models were used to assess the association between medication adherence and progression to end stage renal disease (ESRD) and death. Results: A total of 115,769 hypertensive patients with CKD were included. Approximately 2.5% of them developed ESRD and 57.5% of them died during 2008-2013. Adherence to ACEIs and ARBs was associated with a significant decreased hazard of developing ESRD (Hazard Ratio: 0.29 95%CI [0.25-0.33] p< 0.0001; 0.49 95% CI [0.42, 0.57] p< 0.0001, respectively) after adjusting for demographic and clinical confounders. Patients with increased use of ACEIs and ARBs had reduced risk of death (Hazard Ratio: 0.76 95%CI [0.74-0.78] p< 0.0001; 0.64 95% CI [0.62, 0.66] p< 0.0001, respectively). Increased adherence to diuretics and statins were associated with lower ESRD and mortality risk, while calcium channel blockers and beta blockers were associated with increased ESRD risk and lower mortality risk. ConClusions: Increased adherence to ACEIs and ARBs for elderly patients diagnosed with hypertensive CKD is associated with delay in CKD progression and lower mortality risk. These findings could have significant implications for hypertension management in this population.

Ultrasound in Medicine and Biology, May 1, 2023

Inflammatory Bowel Diseases, Apr 1, 2014

Background: Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory b... more Background: Recent studies link Toll-like receptor 3 (TLR3) to the pathogenesis of inflammatory bowel disease (IBD). Screening the poly(I:C) response in an intestinal epithelial cell line, we found complement factor B mRNA (CFB) potently upregulated and went on to further study local and systemic activation of CFB in ulcerative colitis (UC) and Crohn's disease (CD). Methods: In a transcriptome analysis of poly(I:C) stimulated HT-29 cells, we found CFB highly upregulated downstream of TLR3. We sought to confirm CFB upregulation in a microarray gene expression analysis on colonic biopsies from an IBD population (n=133). Immunohistochemical staining and in situ hybridization was done to identify cellular sources of complement factor B protein (fB) and CFB. Systemic complement activation was assessed in plasma (n=18) using neoepitope-based ELISA. Results: Complement factor B mRNA and protein were abundantly expressed in the colonic epithelial cell line, and synthesis enhanced by the poly(I:C) TLR3 ligand. In inflamed vs. normal colonic mucosa of ulcerative colitis (UC) and Crohn`s disease (CD) CFB mRNA was the most significantly overexpressed gene and the mRNA abundance ratio was among the 50 highest.. Epithelial cells were the dominating site of fB expression. Systemic complement activation was significantly higher in active than in non-active IBD. Conclusion: This study is the first to link TLR3 to activation of the alternative complement pathway, and complement factor B is potently upregulated locally in IBD in addition to having a possible central role in systemic complement activation. This suggests a prominent role for complement in IBD pathogenesis.

World Neurosurgery, Mar 1, 2017

Since the prognostic importance of radical resection was introduced in 1957, the neurosurgery pra... more Since the prognostic importance of radical resection was introduced in 1957, the neurosurgery practice has undergone several technologic advancements. The aim of this study was to evaluate whether the prognostic value of the extent of resection is still relevant in modern neurosurgical practice. Over a 10-year period, all patients with histologic-confirmed World Health Organization grade I meningiomas and who underwent meningioma surgery were retrospectively analyzed. Survival analyses were performed using Kaplan-Meier analysis and univariate and multivariate Cox proportional-hazards regression analyses. There were 113 patients included in this study. A better Simpson grade was associated with recurrence-free survival (RFS) 5, 10, and 15 years after surgery (P &amp;amp;lt; 0.001). Comparing Simpson grade I with Simpson grades III and IV, 13.1 and 36.6 times higher hazard ratios were revealed with respect to RFS, respectively. A 7.5 times higher hazard ratio was revealed when comparing Simpson grades II and IV. Additional survival analyses were performed within specific locations and groups with low and high mitotic indices, demonstrating that the extent of resection can add additional information about RFS. Simpson grade remains a highly significant predictor of RFS in meningioma-resected patients in modern neurosurgical practice. Extent of resection should therefore be emphasized when predicting prognosis and considering postoperative treatment and frequency of radiologic follow-up after surgery.

Acta neurochirurgica, Sep 5, 2008

Objective The purpose of the study was to compare the ability of navigated 3D ultrasound to disti... more Objective The purpose of the study was to compare the ability of navigated 3D ultrasound to distinguish tumour and normal brain tissue at the tumour border zone in subsequent phases of resection. Materials and methods Biopsies were sampled in the tumour border zone as seen in the US images before and during surgery. After resection, biopsies were sampled in the resection cavity wall. Histopathology was compared with the surgeon's image findings. Results Before resection, the tumour border was delineated by ultrasound with high specificity and sensitivity (both 95%). During resection, ultrasound had acceptable sensitivity (87%), but poor specificity (42%), due to biopsies falsely classified as tumour by the surgeon. After resection, sensitivity was poor (26%), due to tumour or infiltrated tissue in several biopsies deemed normal by ultrasound, but the specificity was acceptable (88%). Conclusions Our study shows that although glioblastomas are well delineated prior to resection, there seem to be overestimation of tumour tissue during resection. After resection tumour remnants and infiltrated brain tissue in the resection cavity wall may be undetected. We believe that the benefits of intraoperative ultrasound outweigh the shortcomings, but users of intraoperative ultrasound should keep the limitations shown in our study in mind.

Pathology Research and Practice, Oct 1, 2019

HER3 and HER4 are tyrosine kinase receptors of the ErbB family that have been detected in several... more HER3 and HER4 are tyrosine kinase receptors of the ErbB family that have been detected in several cancers but lack substantial investigation in human meningiomas. In this study, HER3 and-4 expression levels were evaluated as potential biomarkers by immunohistochemistry and explored for association to clinical features in a large series of human meningiomas. 186 primary intracranial meningiomas from adult patients were investigated with antibodies against HER3 and-4 intracellular domains. Tumors were scored with a staining index (SI) based on cytoplasmic/membranous staining intensity and on the percentage of positive cells. SIs were tested for associations with WHO malignancy grade, tumor subtype, localization, and prognosis. HER3 and HER4 were highly expressed in most tumors. Both cytoplasmic and membranous immunoreactivity occurred, and for HER4 nuclear immunoreactivity was observed as well. Non-neoplastic meningeal tissue was not immunoreactive. HER3 and-4 immunoreactivity was not associated with WHO malignancy grade, nor with recurrence or survival in adjusted analyses. Meningiomas of all grades were shown to widely express both HER3 and HER4 receptors. This feature may have diagnostic value since non-neoplastic meninges were not immunoreactive. There was no prognostic significance in adjusted survival analyses.

Pathology Research and Practice, Apr 1, 2017

Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks int... more Distinguishing WHO grade II astrocytomas from grade III is a difficult task. This study looks into the potential prognostic use of mitotic activity and the proliferation markers Ki67/MiB-1 (Ki67), survivin and DNA topoisomerase II␣ (TII␣) in 59 WHO grade II diffuse astrocytomas (DA) and 33 WHO grade III anaplastic astrocytomas (AA), IDH1 R132H-mutated and not otherwise specified (NOS) by means of immunohistochemistry. All proliferation markers showed higher expression in AA compared with DA. Only Ki67 had significantly greater expression in astrocytomas, NOS vs. astrocytomas, IDH1-mutated. Uni-/multivariable COX-regression analyses showed that greater expression of both survivin and TII␣ were associated with poorer survival when stratified for IDH1-mutation status and, additionally, achieved hazard rates surpassing clinically established prognostic factors such as age and WHO performance status. Ki67 achieved only statistical significance in univariable analyses, whereas mitoses did not reveal any relation to survival. IDH1-mutated astrocytomas had significantly better survival than astrocytomas, NOS. Among IDH1-mutated astrocytomas no significant difference in survival was shown between DA and AA. Our findings suggest a potential usefulness of proliferation markers in the prognostic setting of astrocytomas independent of IDH1-mutation status, and survivin and TII␣ are potential candidates in that regard.

Journal of clinical & experimental pathology, 2012

Glioblastoma is the most common primary brain tumour in humans. Diagnostic challenges can occur a... more Glioblastoma is the most common primary brain tumour in humans. Diagnostic challenges can occur as glioblastomas are highly heterogeneous tumours. The aim of this study was to investigate the frequencies and correlations between several histological features in primary glioblastomas and describe any link to tumour biology. Two hundred consecutively diagnosed adult patients with primary glioblastoma located supratentorally were included after revision according to the 2007 World Health Organization criteria. Several histological features were examined. All tumours contained necrosis and/or microvascular proliferation, with frequencies of 98.5% (197/200) and 84.5% (169/200) respectively. Most tumours had detectable mitoses (192/200, 96%), with a median value of 8.5 per 10 high power fields. Further, pseudopalisades (158/200, 79%), thromboses (157/200, 78.5%), atypical mitoses (119/200, 59.5%), and haemorrhages (106/200, 53%) were other common features. Among relevant correlations necroses were positively associated with pseudopalisades, thromboses, small cells and mitoses. In conclusion, glioblastomas present a variety of cell types and histological features, important to know and be aware of for the diagnostic pathologist. Interestingly, microvascular proliferation and necroses were frequently found in coexistence. Further, several of these features are closely linked to tumour biology, making histopathology fundamental for increased understanding of gliomagenesis.

Journal of Applied Physiology, May 1, 2010

Clinical Neuropathology, Nov 1, 2011

Introduction: Astroblastoma is a rare glial tumor of uncertain origin affecting mostly children, ... more Introduction: Astroblastoma is a rare glial tumor of uncertain origin affecting mostly children, adolescents and young adults. Given the rarity and the definitional problems concerning this tumor entity, the prognosis and appropriate treatment are at this point unclear. Case report: A 50-yearold Caucasian female presented with a seizure. Radiological findings showed a welldefined circumscribed tumor located in the right cerebral frontal lobe. The patient underwent primary surgery followed by postoperative radiotherapy. After 6 months the tumor recurred with multiple small lesions not available for surgery. Chemotherapy was administered with complete radiological response. Seven years after surgery and more than 6 years after completed chemotherapy the patient is free of disease. Histopathology revealed a gliomatous tumor with gemistocyte-like tumor cells arranged in palisades or strings and areas with perivascular pseudorosettes, consistent with astroblastoma. Immunophenotype and ultrastructural findings confirmed the diagnosis and verified the neuroepithelial origin. Conclusion: Astroblastomas are rare brain tumors and pose a challenge in the diagnostic and clinical approach. In general, they have an unpredictable course with a tendency of recurrence. This and other case reports support a survival benefit of chemotherapy, suggesting this as an important treatment option for these patients.

Pathology Research and Practice, 2002

Low-grade diffuse astrocytomas are generally slow-growing tumors; however, they may progress to a... more Low-grade diffuse astrocytomas are generally slow-growing tumors; however, they may progress to anaplastic astrocytomas or glioblastomas. As existing grading systems fail to distinguish these tumors, ongoing research strives to identify new prognostic markers. In this study, 22 adult patients with supratentorial diffuse astrocytomas, WHO grade II, were investigated to clarify whether proliferative activity, assessed by different Ki67 antibodies (MIB-1, NC-MM1, NC-Ki67p, rahKi67), expression of basic fibroblast growth factor (bFGF) or microvessel density have prognostic power. The Ki67 antibodies revealed low proliferation indices (PI); however, there was a wide spread of values, ranging from 0.1% to about 10%. In general, a positive correlation between the different Ki67 PIs was found. In 12 of 22 cases, bFGF immunoreactivity was recorded. Microvessel density was generally low. MIB-1 PI was the only prognostic factor of statistical significance. Ki67 PI, obtained by using the monoclonal antibody MIB-1, can thus serve as a prognostic factor capable of identifying subsets of low-grade diffuse astrocytomas with a potentially more aggressive clinical behavior.

Apmis, Jul 1, 1992

Biopsy specimens of human brain metastases were examined for amplification and expression of the ... more Biopsy specimens of human brain metastases were examined for amplification and expression of the proto‐oncogene c‐erbB1 (located on chromosome 7) encoding the epidermal growth factor receptor (EGFR). Moreover, the tumour DNA was also examined for amplification of other cancer‐related genes on this chromosome: the proto‐oncogene c‐met, the gene for platelet‐derived growth factor A‐chain, and the gene for plasminogen activator inhibitor type 1. All 18 brain metastases demonstrated positive binding of biotinylated EGF on cryosections. Three out of 18 metastases had amplification of the EGFR gene; the other chromosome‐7 genes tested were not amplified. Thus, an increased EGFR gene expression seems to be a general finding in a wide range of carcinomas metastatic to the brain, whereas we found only occasional selective EGFR gene amplifications in single cases.