Joseph W Carlson

Karolinska Institutet | KI · Department of Oncology-Pathology

Objectives p53abn endometrial cancer (EC) is associated with a high risk of recurrence. Molecular classification of EC cohorts has shown that ~5% of low-grade endometrioid EC (EEC) are p53abn. There is debate whether these are misclassified glandular variants of serous EC, and whether the risk of recurrence justifies adjuvant therapy. Here, we aim...

Fibrillar collagens promote cell proliferation, migration, and survival in various epithelial cancers and are generally associated with tumor aggressiveness. However, the impact of fibrillar collagens on soft tissue sarcoma behavior remains poorly understood. Unexpectedly, this study finds that fibrillar collagen‐related gene expression is associat...

Fibrillar collagen deposition, stiffness, and downstream signalling support the development of leiomyomas (LM), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared to epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uter...

Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the cells of the myometrium. Diagnosis is based on histopathological features. Developing effective therapies against uLMS is a challenge due its resistance to conventional radiation and chemotherapy. In vivo and in vitro models for uLMS are urgently needed and it has been pr...

The expression, abundance, and microarchitecture of fibrillar collagens are associated with tumor development and aggressiveness in various carcinomas. However, the impact of fibrillar collagens on mesenchymal tumors is less understood. While uterine leiomyomas, also known as fibroids, are characterized by high fibrillar collagen deposition and dep...

Fibrillar collagens promote cell proliferation, migration, and survival in various epithelial cancers and are generally associated with tumour aggressiveness. However, the impact of fibrillar collagens on soft tissue sarcoma behaviour remains poorly understood. Unexpectedly, we find here that fibrillar collagen-related gene expression is associated...

Uterine sarcomas are rare but deadly malignancies without effective treatment. Immunotherapy is a promising new approach to treat these tumors but has shown heterogeneous effects in sarcoma patients. With the goal of identifying key factors for improved patient treatment, we characterized the tumor immune landscape in 58 uterine sarcoma cases with...

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation seque...

Due to its dynamic nature, the evolution of cancer cell-extracellular matrix (ECM) crosstalk, critically affecting metastasis and treatment resistance, remains elusive. Our results show that platinum-chemotherapy itself enhances resistance by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding ECM. Examining ova...

Introduction In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system. Materials and methods W...

New therapeutic options for patients with ovarian cancer are urgently needed. Therefore, we evaluated the efficacy of two second-generation mesothelin (MSLN)-directed CAR T cells in orthotopic mouse models of ovarian cancer. Treatment with CAR T cells expressing an MSLN CAR construct including the CD28 domain (M28z) significantly prolonged survival...

Aims HER2 amplification in endometrial cancer (EC) is almost completely confined to the p53‐abnormal (p53abn) molecular subtype and independent of histologic subtype. HER2 testing should therefore be molecular subtype‐directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC‐sp...

Purpose Uterine sarcomas are rare but deadly malignancies without effective treatment. The goal of this study was to characterize and identify potential mechanisms underlying observed variations in the immune microenvironment of different sarcoma subtypes, using integrated clinicopathological and molecular methods. Experimental design Fifty-eight...

Introduction In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system. Materials and methods We...

Objective: Pre-clinical studies have identified marker- and tumor compartment-defined functionally distinct macrophage subsets. Our study analyzes marker-defined macrophage subsets in different tumor compartments of high-grade serous ovarian cancer (HGSC). Methods: A discovery cohort (N = 113) was subjected to immunohistochemistry (IHC) analyses...

Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according t...

Identification of the molecular mechanism of action (MoA) of bioactive compounds is a crucial step for drug development but remains a challenging task despite recent advances in technology. In this study, we applied multidimensional proteomics, sensitivity correlation analysis, and transcriptomics to identify a common MoA for the anticancer compoun...

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single‐classifier (POLE exonuclease domain mutati...

Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (“POLE‐ultramutated”) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity...

Sarcomas are deadly malignant tumors of mesenchymal origin occurring at all ages. The expression and function of the membrane-type matrix metalloproteinase MMP14 is closely related to the mesenchymal cell phenotype, and it is highly expressed in most sarcomas. MMP14 regulates the activity of multiple extracellular and plasma membrane proteins, infl...

Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort. Experimental design: Fifty cases of UUS...

Purpose: Gene signatures and Ki67 stratify the same breast tumour into opposing good/poor prognosis groups in approximately 20% of patients. Given this discrepancy, we hypothesized that the combination of a clinically relevant signature and immunohistochemical (IHC) markers may provide more prognostic information than either classifier alone. Exp...

Undifferentiated uterine sarcomas (UUS) are a heterogenous group of high-grade mesenchymal tumors. Although these tumors are highly aggressive, a subset of patients may experience long-term survival. These tumors have previously been divided morphologically into uniform and pleomorphic types. A previous study demonstrated that a mitotic index cutof...

PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytom...

There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers...

In our previous studies we have shown that patients with serous ovarian carcinoma in advanced surgical stage disease have a particularly poor prognosis if they carry the HLA-A*02 genotype. This represent a stronger prognostic factor than loss or down regulation of the MHC-class I heavy chain (HC) on tumour cells. In this study, we investigated the...

Epithelial ovarian carcinoma (EOC), the major cause of gynaecological cancer death, is a heterogeneous disease classified into five subtypes. Each subtype has distinct clinical characteristics and is associated with different genetic risk factors and molecular events, but all are treated with surgery and platinum/taxane regimes. Tumour progression...

Proliferation-related gene signatures have been proposed to aid breast cancer management by providing reproducible prognostic and predictive information on a patient-by-patient basis. It is unclear however, whether a less demanding assessment of cell division rate (as determined in clinical setting by expression of Ki67) can function in place of ge...

Undifferentiated uterine sarcomas (UUS) are rare tumors with a heterologous biology and a poor prognosis. The goal of this study was to examine clinicopathology, biomarkers and YWHAE-FAM22 translocation status, in the prognosis of these tumors. Twenty-six cases of UUS were included. All original slides were re-reviewed and age at diagnosis, tumor s...

The origin of pelvic serous carcinoma continues to be controversial. Recent studies of patients undergoing primary surgery for ovarian, primary peritoneal, and uterine serous carcinomas have indicated the value of complete fimbrial sampling for detecting occult serous tubal intraepithelial carcinoma (STIC). Evidence suggests that a significant prop...

Our understanding of the biology and clinical behavior of serous neoplasms of the ovary has changed enormously over the past decade. It is now clear that although all serous tumors share a cell type reflecting tubal epithelium in various levels of differentiation, they appear to have different origins and distinct behaviors. Benign and borderline s...

Background: Epithelial ovarian carcinoma (EOC) is the 5th leading cause of total cancer death in women. Despite initial responsiveness to treatment, >75% of patients relapse into metastatic and essentially incurable chemoresistant disease. In carcinomas, metastasis is associated with the dedifferentiation process termed epithelial-to-mesenchymal tr...

Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in bre...

Objectives: To assess the difficulties associated with diagnosing endometrial stromal tumors (ESTs) on endometrial biopsy. Methods: We examined 25 endometrial biopsy specimens from 19 consecutive women diagnosed with either endometrial stromal nodule (n = 3) or endometrial stromal sarcoma (n = 16). Results: Rereview of the biopsy specimens rev...

To assess the variation in ovarian carcinoma type diagnosis among gynaecological pathologists from Nordic countries, and whether a rationally designed panel of immunohistochemical markers could improve diagnostic reproducibility. Eight pathologists from four countries (Sweden, Denmark, Norway and Finland) received an educational lecture on diagnosi...

A deregulated energy metabolism is a hallmark of malignant disease that offers possible future targets for treatment. We investigated the prognostic value of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and pyruvate kinase type M2 (PKM2), mitochondrial beta-F1-ATPase (ATP5B) and the bioenergetic cellular (BEC) index in ad...

In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF)-activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts a...

Heat shock protein 60 (HSP60) plays an essential role in malignant cell survival. We evaluated the prognostic and treatment predictive value of HSP60 in advanced ovarian cancer. Fresh tumor samples were prospectively collected from 123 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 57 fulfilled the eligibility...

In recent years, evidence is accumulating that cancer cells develop strategies to escape immune recognition. HLA class I HC down-regulation is one of the most investigated. In addition, different HLA haplotypes are known to correlate to both risk of acquiring diseases and also prognosis in survival of disease or cancer. We have previously shown tha...

Human papillomavirus (HPV) infection is the major cause of cervical cancer, but the prevalence of different HPV types varies depending on geographical location and may change dramatically after introduction of HPV vaccination. Here, we aimed to gain some information regarding the recent prevalence of different HPV types, in cancer of the uterine ce...

Serous tubal intraepithelial carcinoma (STIC) is detected in between 5% and 7% of women undergoing risk-reduction salpingooophorectomy for mutations in the BRCA1 or 2 genes (BRCA+), and seems to play a role in the pathogenesis of many ovarian and "primary peritoneal" serous carcinomas. The recognition of STIC is germane to the management of BRCA+ w...

Pathology provides a critical bridge between the patients, their physicians and the therapeutic and surgical interventions that can be provided to them. Clinicians caring for patients in resource poor settings may provide basic healthcare, which does not include access to pathologic services; however, the value of pathology in alleviating health di...

Most serous adenocarcinomas involving both the endometrium and ovary are presumed to arise in the endometrium. Recently, serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. This study explored the potential relationship between STIC and uterine serous carcinoma. Twenty-two consecutive ca...

A diagnosis of primary peritoneal serous carcinoma (PPSC) requires exclusion of a source in other reproductive organs. Serous tubal intraepithelial carcinoma (STIC; stage 0) has been described in asymptomatic women with BRCA mutations and linked to a serous cancer precursor in the fimbria. This study examined the frequency of STIC in PPSC and its c...

Endometrial intraepithelial neoplasia (EIN) is a monoclonal precursor to endometrioid endometrial adenocarcinoma characterized by a geographic cluster of crowded glands with epithelial cytology altered relative to the background. It may demonstrate epithelial metaplastic changes, or arise within polyps, but the frequencies of these features as enco...

In the past 50 years, the concept of serous ovarian cancer has been progressively refined, with the distinction of the borderline serous tumour, identification of a smaller subset of well-differentiated serous malignancies and, recently, closer attention to the pathogenesis of high-grade serous malignancies. High-grade serous carcinoma, traditional...

Magnetic resonance imaging (MRI) has an evolving role in the evaluation of breast lesions and is currently being used for the screening of high-risk patients (eg, women with a personal or family history of breast cancer), for the evaluation of extent of disease in patients with a current diagnosis of cancer, and for patients with suspicious, but in...

Breast magnetic resonance imaging (MRI) has been implemented as a screening tool for early detection and as a diagnostic test in the management of breast cancer. Lesions identified by MRI but not amenable to conventional biopsy techniques require MRI wire-guided excisional biopsy (MRIbx). We hypothesized that more tissue would be resected with MRIb...

Nuclear staining for beta-catenin by immunohistochemistry is being used increasingly to diagnose desmoid tumours (deep fibromatoses), especially where the differential diagnosis includes other abdominal spindle cell neoplasms. This study aimed to define the prevalence of beta-catenin positivity in desmoid tumours and other morphologically similar s...

Small cell carcinoma of the ovary, hypercalcaemic-type (SCCOH) is morphologically similar to small cell carcinomas from other sites. The aims of this study were to (i) determine if a biomarker panel would distinguish small cell carcinomas of the ovary, cervix (SCCCx) and lung (SCCLu) and (ii) potentially determine the histogenesis of SCCOH. Nine ov...

This chapter focuses on three different aspects of biologically derived nanostructured materials. One of the aspects—use of scanning probe microscopy (SPM) in studying biological assemblies that specifically support biological membranes, nucleic acids, and nucleoprotein complexes. Second, the use of more general protein phospholipid assemblies as n...

Atomic force microscopy can be used to determine the vertical dimension of biological molecules under native conditions with high resolution. Deformation of soft proteins by the scanning force, however, introduces error in the magnitude of the measurement. In this work, the force-dependent height of NADPH-cytochrome P450 reductase, an integral memb...

A nanolithography method for altering the composition of supported phospholipid bilayers has been developed. Although a number of lithography procedures for various chemical systems currently exist, these methods typically rely on covalent bonding to stabilize the resulting structure. The method described here is suitable for an entirely noncovalen...

One of the primary difficulties of imaging under aqueous solution with the scanning force microscope (SFM) is a lack of reliable tip characterization. The requirements of imaging under solution greatly limit the utility of available standards. We report the synthesis of metal binding colloidal gold (MBG) which allows direct deconvolution of tip sha...

A phospholipid bilayer of nanometer dimension has been used as a support for the study of reconstituted functional single-membrane proteins. This nanobilayer consists of an approximately 10-nm-diameter circular phospholipid domain stabilized by apolipoprotein A1. As a demonstration of this methodology, we formed the nanobilayers in the presence of...

The atomic force microscope (AFM) has been used to image a variety of biological systems, but has rarely been applied to soluble protein-lipid complexes. One of the primary physiological protein-lipid complexes is the high-density lipoproteins (HDL), responsible for the transport of cholesterol from the peripheral tissues and other lipoproteins to...

Continuous oscillation on the (2)P(3/2) ? (4)I(11/2) transition of Nd(3+) in a f luorozirconate glass (ZBLAN) fiber at room temperature has been observed. When pumped at ~590 nm, a Nd:ZBLAN f iber 39 cm in length lases in the violet at 412 nm and produces ~0.5 mW of power for 320 mW of pump power and a cavity output coupling of 0.4%. The breadth of...

Lasing at 381 nm (4D3/2 - 4I9/2) and at 412 nm (2P3/2 - 4I9/2) has been observed in a Nd3+- doped ZBLAN fiber at room temperature with a single pump laser operating in the 580 to 600 nm wavelength region. The output power, excitation spectrum, line width, and temporal behavior of the laser are discussed.

Lasing in the ultraviolet has been observed in neodymium-doped fluorozirconate glass (ZBLAN) fibres at room temperature. For a cavity output coupling of <0.1%, 74 μW of power was obtained at 381 nm ( ⁴D_γ2→⁴I_11/2 transition of Nd³⁺) when a 45 cm long fibre was pumped with 275 mW at a wavelength...

Because of the inherent heterogeneity of proteins and the existence of many intermediate states, the conformational changes involved in a particular reaction are obscured when measuring an ensemble of molecules. Single molecule spectroscopy allows one to investigate the degree of heterogeneity in proteins as well as the variety of reaction pathways...

Molecular complexes play a number of key roles in medicine and biology. Understanding how these complexes behave at interfaces, as well as controlling their structure, is of fundamental interest to science and technology. Lipoproteins, a complex of protein and lipid, serve as the primary transporter of cholesterol and other lipids throughout the bo...