Publications by authors named "Ben Davidson"

307 Publications

Update on Sentinel Lymph Node Biopsy in Surgical Staging of Endometrial Carcinoma.

J Clin Med 2021 Jul 13;10(14). Epub 2021 Jul 13.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316 Oslo, Norway.

Sentinel lymph node (SLN) biopsy has emerged as an alternative staging approach in women with assumed early-stage endometrial carcinoma. Through image-guided surgery and pathologic ultrastaging, the SLN approach is introducing "precision medicine" to the surgical management of gynecologic cancers, providing a comprehensive evaluation of high-yield lymph nodes. This approach improves the surgeons' ability to detect small-volume metastatic disease while reducing intraoperative and postoperative morbidity associated with lymphadenectomy. Although the majority of clinicians in Europe and the USA have recognized the value of SLN biopsy in endometrial carcinoma and introduced this as part of clinical practice, there is ongoing debate regarding its role in very low-risk patients as well as in patients at high risk of nodal metastasis. The significance of low-volume metastasis is not fully understood, and there is no consensus in regard to how the presence of isolated tumor cells should guide adjuvant therapy. Standardized protocols for histopathologic evaluation of SLNs are lacking. In this review article we aim to provide a framework for the introduction of SLN biopsy in endometrial cancer, give an updated overview of the existing literature, as well as discuss potential controversies and unanswered questions regarding this approach and future directions.
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http://dx.doi.org/10.3390/jcm10143094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306601PMC
July 2021

Anti-Angiogenic Treatment in Pseudomyxoma Peritonei-Still a Strong Preclinical Rationale.

Cancers (Basel) 2021 Jun 5;13(11). Epub 2021 Jun 5.

Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, P.O. Box 4953 Nydalen, 0424 Oslo, Norway.

Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options.
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http://dx.doi.org/10.3390/cancers13112819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201024PMC
June 2021

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Repurposing F-FMISO as a PET tracer for translational imaging of nitroreductase-based gene directed enzyme prodrug therapy.

Theranostics 2021 7;11(12):6044-6057. Epub 2021 Apr 7.

Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 65, N-5021, Bergen, Norway.

Nitroreductases (NTR) are a family of bacterial enzymes used in gene directed enzyme prodrug therapy (GDEPT) that selectively activate prodrugs containing aromatic nitro groups to exert cytotoxic effects following gene transduction in tumours. The clinical development of NTR-based GDEPT has, in part, been hampered by the lack of translational imaging modalities to assess gene transduction and drug cytotoxicity, non-invasively. This study presents translational preclinical PET imaging to validate and report NTR activity using the clinically approved radiotracer, F-FMISO, as substrate for the NTR enzyme. The efficacy with which F-FMISO could be used to report NfsB NTR activity was investigated using the MDA-MB-231 mammary carcinoma xenograft model. For validation, subcutaneous xenografts of cells constitutively expressing NTR were imaged using F-FMISO PET/CT and fluorescence imaging with CytoCy5S, a validated fluorescent NTR substrate. Further, examination of the non-invasive functionality of F-FMISO PET/CT in reporting NfsB NTR activity was assessed in metastatic orthotopic NfsB NTR expressing xenografts and metastasis confirmed by bioluminescence imaging. F-FMISO biodistribution was acquired by an automatic gamma counter measuring radiotracer retention to confirm results. To assess the functional imaging of NTR-based GDEPT with F-FMISO, PET/CT was performed to assess both gene transduction and cytotoxicity effects of prodrug therapy (CB1954) in subcutaneous models. F-FMISO retention was detected in NTR subcutaneous xenografts, displaying significantly higher PET contrast than NTR xenografts ( < 0.0001). Substantial F-FMISO retention was evident in metastases of orthotopic xenografts ( < 0.05). Accordingly, higher F-FMISO biodistribution was prevalent in NTR xenografts. F-FMISO NfsB NTR PET/CT imaging proved useful for monitoring NTR transduction and the cytotoxic effect of prodrug therapy. F-FMISO NfsB NTR PET/CT imaging offered significant contrast between NTR and NTR tumours and effective resolution of metastatic progression. Furthermore, F-FMISO NfsB NTR PET/CT imaging proved efficient in monitoring the two steps of GDEPT, NfsB NTR transduction and response to CB1954 prodrug therapy. These results support the repurposing of F-FMISO as a readily implementable PET imaging probe to be employed as companion diagnostic test for NTR-based GDEPT systems.
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http://dx.doi.org/10.7150/thno.55092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058731PMC
July 2021

Primary uterine ectomesenchymoma harboring a DICER1 mutation: case report with molecular analysis.

Virchows Arch 2021 Aug 17;479(2):419-424. Epub 2021 Feb 17.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Montebello, N-0310, Oslo, Norway.

Ectomesenchymoma is an exceedingly rare biphasic malignant tumor characterized by the presence of mesenchymal and neuroectodermal elements. The majority of patients are infants or children. We describe the first case of this entity diagnosed as a primary uterine tumor. A 72-year-old female presented with post-menopausal bleeding. Dilatation and curettage showed irregular mesenchymal proliferation of uncertain nature. In the hysterectomy specimen, a myxoid spindle cell tumor with areas of skeletal muscle and neural differentiation was found in the uterus, with direct invasion of the small intestine, and biphasic differentiation into rhabdomyosarcoma and ganglioneuroblastoma was unequivocally seen in a lymph node metastasis. The morphological findings were validated by immunohistochemistry. Massive parallel sequencing identified TP53, PTEN, and DICER1 mutations in the tumor. This report describes the presence of ectomesenchymoma in an unusual primary organ and in an uncharacteristic age and presents novel data regarding the genetic characteristics of this tumor.
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http://dx.doi.org/10.1007/s00428-021-03057-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364549PMC
August 2021

Spatial and temporal changes in follicle distribution in the human ovarian cortex.

Reprod Biomed Online 2021 Feb 25;42(2):375-383. Epub 2020 Oct 25.

Department of Reproductive Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.

Research Question: How does follicle distribution evolve in the human ovarian cortex between the ages of 20 and 35 years?

Design: Fragments of ovarian cortex from women undergoing unilateral oophorectomy for fertility preservation were obtained for quantitative histological assessment, including recording the two-dimensional coordinates of the follicles. Data were analysed using spatial statistical methods.

Results: A total of 53 ovarian cortex tissue samples, containing 1-803 follicles each, were obtained from 14 women aged 20-35 years. Primordial and transitory follicles lay in a clustered manner in the human ovarian cortex, with an average cluster radius of around 270 µm (95% confidence interval 154-377 µm; n = 49). Follicle density declined with age (P = 0.006, n = 13), and the distance from the nearest neighbouring follicle increased (P = 0.004, n = 13). Cluster radius decreased with age (P = 0.02, n = 13), but the degree of clustering tended to increase (P = 0.11, n = 13). In the majority of the samples, follicles at different stages lay in different clusters (P < 0.05, n = 13).

Conclusions: This study shows that primordial and transitory follicles lie in different clusters in the human ovarian cortex. Spatio-temporal computer simulation suggests that interfollicular signals may hinder follicle loss and may therefore drive clustered follicle distribution. In clinical practice, the woman's age should be taken into account when assessing follicle density, as follicle distribution is increasingly clustered with advancing age.
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http://dx.doi.org/10.1016/j.rbmo.2020.10.013DOI Listing
February 2021

The Biological Role of the Long Non-coding RNA in Ovarian Carcinoma.

Anticancer Res 2020 Dec;40(12):6677-6684

Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

Aim: To analyze the biological role of the long non-coding RNA LINK-A.

Materials And Methods: An 850-bp segment from the second exon of LINK-A was removed using the CRISPR/Cas9 system in OVCA433 ovarian serous carcinoma cells. Spheroid formation, migration, invasion, proliferation, matrix metalloproteinase (MMP) activity and expression of cell-signaling proteins were assessed in vitro.

Results: OVCA433 cells with LINK-A deletion were more invasive (p=0.0008) but had reduced migration and MMP9 secretion compared to controls (p=0.003 and p=0.005, respectively). LINK-A deletion did not affect proliferation but induced phosphorylation of extracellular signal-regulated kinase (10-fold; p=0.005). LINK-A knock out additionally reduced spheroid formation.

Conclusion: Added to our previous data from analysis of clinical specimens, LINK-A is likely to be a tumor suppressor.
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http://dx.doi.org/10.21873/anticanres.14691DOI Listing
December 2020

The phosphatase PTPN1/PTP1B is a candidate marker of better chemotherapy response in metastatic high-grade serous carcinoma.

Cytopathology 2021 Mar 20;32(2):161-168. Epub 2020 Nov 20.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.

Objective: To analyse the expression and clinical role of the phosphatase PTPN1 (PTP1B) in serous effusions.

Methods: PTPN1 mRNA expression by quantitative RT-PCR was analysed in 83 high-grade serous carcinoma (HGSC) and 15 malignant mesothelioma (MM) effusions. PTP1B and phospho-PTP1B (pPTP1B) protein expression by immunohistochemistry was analysed in 62 HGSC and 44 MM effusions.

Results: PTPN1 mRNA (P = .048), PTP1B protein (P = .047) and pPTP1B protein (P < .001) were overexpressed in HGSC compared to MM effusions. PTPN1 mRNA was additionally overexpressed in post-chemotherapy HGSC effusions compared to chemo-naïve effusions (P = .005). However, pPTP1B protein expression was higher in effusions from patients with FIGO stage III compared to stage IV (P = .006), and higher expressions of both PTPN1 mRNA (P = .041) and PTP1B protein (P = .035) in HGSC effusions were associated with better (complete) chemotherapy response at diagnosis. PTPN1 RNA and protein expression was unrelated to survival in HGSC, whereas a trend for shorter overall survival (P = .06) was found for MM patients whose tumours expressed pPTP1B protein.

Conclusion: PTPN1 is overexpressed in HGSC compared to MM effusions, and may be a marker of better chemotherapy response in the former. Whether PTPN1 activation is informative of adverse outcome in MM merits further investigation.
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http://dx.doi.org/10.1111/cyt.12921DOI Listing
March 2021

Inhibition of the MYC-Regulated Glutaminase Metabolic Axis Is an Effective Synthetic Lethal Approach for Treating Chemoresistant Ovarian Cancers.

Cancer Res 2020 10 28;80(20):4514-4526. Epub 2020 Aug 28.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Amplification and overexpression of the oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a target of MYC and a key enzyme in glutaminolysis, are intrinsically resistant to platinum-based chemotherapy and are enriched with intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not in low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLS cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, and prolonged survival in tumor-bearing mice. These findings suggest consideration of applying a combined therapy of GLS inhibitor and PARP inhibitor to treat chemoresistant ovarian cancers, especially those with high GLS expression. SIGNIFICANCE: Targeting glutaminase disturbs redox homeostasis and nucleotide synthesis and causes replication stress in cancer cells, representing an exploitable vulnerability for the development of effective therapeutics. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4514/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572606PMC
October 2020

Mutation analysis and genomic imbalances of cells found in effusion fluids from patients with ovarian cancer.

Oncol Lett 2020 Sep 26;20(3):2273-2279. Epub 2020 Jun 26.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, 0424 Oslo, Norway.

Ovarian carcinomas and carcinosarcomas often cause malignant effusions, an accumulation within serous cavities of fluid containing cancer cells. Few studies have focused on the molecular alterations and genetic mechanisms behind effusion formation. The present study investigated the mutation status of and in effusion fluids from 103 patients with ovarian cancer. In addition, array Comparative Genomic Hybridization (aCGH) analysis was performed on 20 effusions from patients with high-grade serous carcinoma (10 cases positive for mutation and 10 with wild-type). mutations, two of which were novel: c.826_830delCCTGT and c.475_476GC>TT, were identified in 44% of the cases. Mutations in , and were identified in two, two and four cases, respectively. None of the effusions analysed showed or mutations. The aCGH analysis revealed highly imbalanced genomes similar to those described in primary ovarian carcinomas. No specific profile was indicated to distinguish tumors with mutations from those without. The molecular profiling of cells found in effusion fluids from patients with ovarian cancer thus showed considerable molecular heterogeneity. seems to be the most frequently mutated gene in these cells and may serve a leading role in the metastatic process.
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http://dx.doi.org/10.3892/ol.2020.11782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400987PMC
September 2020

Expression of palladin is associated with disease progression in metastatic high-grade serous carcinoma.

Cytopathology 2020 11 4;31(6):572-578. Epub 2020 Sep 4.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.

Objective: To analyse the expression and clinical role of the actin-associated molecule palladin in serous effusions.

Methods: PALLD mRNA expression was analysed by quantitative reverse transcription polymerase chain reaction in 83 high-grade serous carcinoma (HGSC) effusions. Fifteen malignant mesothelioma (MM) effusions and 18 surgical HGSC specimens from the ovary were studied for comparative purposes. Palladin protein expression by immunohistochemistry was analysed in another series consisting of 261 HGSC effusions.

Results: PALLD mRNA was significantly overexpressed in HGSC compared to MM effusions (P < .001). Palladin expression by immunohistochemistry was found in HGSC cells in 106/261 (41%) effusions, most commonly focally (<5% of cells). PALLD expression was additionally higher in ovarian HGSC specimens compared to HGSC effusions (P < .001). However, immunohistochemistry showed only stromal expression of this protein in surgical specimens. PALLD mRNA expression in HGSC effusions was unrelated to clinicopathological parameters, chemotherapy response or survival. Palladin protein expression was higher in post-chemotherapy, mainly disease recurrence, specimens compared to chemo-naïve effusions tapped at diagnosis (P = .018), although it was unrelated to other clinicopathological parameters or survival.

Conclusion: PALLD mRNA is overexpressed in HGSC compared to MM effusions, and its protein product is overexpressed in post-chemotherapy compared to pre-chemotherapy HGSC effusions, suggesting upregulation along tumour progression. The presence of this molecule in HGSC effusions, at the mRNA or the protein level, is unrelated to disease outcome.
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http://dx.doi.org/10.1111/cyt.12895DOI Listing
November 2020

The Biological and Clinical Role of the Long Non-Coding RNA LOC642852 in Ovarian Carcinoma.

Int J Mol Sci 2020 Jul 23;21(15). Epub 2020 Jul 23.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316 Oslo, Norway.

The objective of the present study was to analyze the biological and clinical role of the long non-coding RNA LOC642852 in ovarian carcinoma (OC). LOC642852 expression was analyzed in seven OC cell lines (OVCAR-3, OVCAR-8, OVCA 433, OVCA 429, OC 238, DOV13, ES-2) and 139 high-grade serous carcinoma (HGSC) specimens (85 effusions, 54 surgical specimens). Following LOC642852 knockout (KO) using the CRISPR/Cas9 system, OVCAR-8 HGSC cells were analyzed for spheroid formation, migration, invasion, proliferation, matrix metalloproteinase (MMP) activity, and expression of cell signaling proteins. OVCAR-8 cells with LOC642852 KO were significantly less motile and less invasive compared to controls, with no differences in spheroid formation, proliferation, or matrix metalloproteinase (MMP) activity. Total Akt and Erk levels were comparable in controls and KO cells, but their phosphorylation was significantly increased in the latter. In clinical specimens, LOC642852 was overexpressed in ovarian tumors and omental/peritoneal metastases compared to effusion specimens ( = 0.013). A non-significant trend for shorter overall ( = 0.109) and progression-free ( = 0.056) survival was observed in patients with HGSC effusions with high LOC642852 levels. Bioinformatics analysis showed potential roles for LOC642852 as part of the TLE3/miR-221-3p ceRNA network and in relation to the FGFR3 protein. In conclusion, LOC642852 inactivation via CRISPR/Cas9 affects cell signaling, motility, and invasion in HGSC cells. LOC642852 is differentially expressed in HGSC cells at different anatomical sites. Its potential role in regulating the TLE3/miR-221-3p ceRNA network and FGFR3 merits further research.
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http://dx.doi.org/10.3390/ijms21155237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432776PMC
July 2020

Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma.

Virchows Arch 2020 Dec 12;477(6):857-864. Epub 2020 Jun 12.

Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Montebello, N-0310, Oslo, Norway.

The objective of this study was to analyze the expression and clinical role of mitosis regulators α-thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX) in metastatic high-grade serous carcinoma (HGSC). ATRX and DAXX protein expression by immunohistochemistry was analyzed in 400 HGSC effusions. DAXX expression was additionally studied in 15 cancer cell lines, including 4 ovarian carcinoma lines, and in 81 of the 400 HGSC effusions using Western blotting. ATRX and DAXX were expressed in HGSC cells in 386/400 (96%) and 348/400 (87%) effusions, respectively. Western blotting showed DAXX expression in all 15 cell lines and in 70/81 (86%) HGSC effusions. DAXX expression by immunohistochemistry was higher in pleural compared to peritoneal effusions (p = 0.006) and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.004), and its expression was significantly associated with poor overall survival in univariate of the entire cohort (p = 0.014), as well as analysis limited to chemo-naïve effusions tapped at diagnosis (p = 0.038). The former association retained its prognostic role in Cox multivariate survival analysis (p = 0.011). ATRX expression was unrelated to clinicopathologic parameters or survival. In conclusion, DAXX is associated with disease progression and could be a prognostic marker in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.
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http://dx.doi.org/10.1007/s00428-020-02842-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683463PMC
December 2020

Expression of the cancer stem cell marker SSEA1 is associated with poor survival in metastatic high-grade serous carcinoma.

Virchows Arch 2020 Nov 29;477(5):677-685. Epub 2020 May 29.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310, Oslo, Norway.

The objective of the present study was to perform a quantitative analysis of cancer stem cell (CSC) marker expression in ovarian carcinoma effusions. The clinical role of SSEA1 in metastatic high-grade serous carcinoma (HGSC) was additionally analyzed. CD133, Nanog, SOX2, Oct3/4, SSEA1, and SSEA4 protein expressions were quantitatively analyzed using flow cytometry (FCM) in 24 effusions. SSEA1 expression by immunohistochemistry was analyzed in 384 HGSC effusions. Highly variable expression of CSC markers by FCM was observed, ranging from 0 to 78% of Ber-EP4-positive cells in the case of CD133, with the largest number of negative specimens seen for SSEA4. SSEA1 expression by immunohistochemistry was found in HGSC cells in 336/384 (89%) effusions, most commonly focally (< 5% of cells). SSEA1 was overexpressed in post-chemotherapy disease recurrence specimens compared with chemo-naïve HGSC effusions tapped at diagnosis (p = 0.029). In univariate survival analysis, higher SSEA1 expression was significantly associated with poor overall survival (p = 0.047) and progression-free survival (p = 0.018), though it failed to retain its prognostic role in Cox multivariate survival analysis in which it was analyzed with clinical parameters (p = 0.059 and p = 0.111 for overall and progression-free survival, respectively). In conclusion, CSC markers are variably expressed in ovarian carcinoma effusions. SSEA1 expression is associated with disease progression and poor survival in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.
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http://dx.doi.org/10.1007/s00428-020-02850-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581515PMC
November 2020

CD24-targeted intraoperative fluorescence image-guided surgery leads to improved cytoreduction of ovarian cancer in a preclinical orthotopic surgical model.

EBioMedicine 2020 Jun 23;56:102783. Epub 2020 May 23.

Center for Cancer Biomarkers, CCBIO, Department of Clinical Science, University of Bergen, Jonas Lies vei 91B, 5021 Bergen, Norway. Electronic address:

Background: The completeness of resection is a key prognostic indicator in patients with ovarian cancer, and the application of tumour-targeted fluorescence image-guided surgery (FIGS) has led to improved detection of peritoneal metastases during cytoreductive surgery. CD24 is highly expressed in ovarian cancer and has been shown to be a suitable biomarker for tumour-targeted imaging.

Methods: CD24 expression was investigated in cell lines and heterogenous patient-derived xenograft (PDX) tumour samples of high-grade serous ovarian carcinoma (HGSOC). After conjugation of the monoclonal antibody CD24 to the NIR dye Alexa Fluor 750 and the evaluation of the optimal pharmacological parameters (OV-90, n = 21), orthotopic HGSOC metastatic xenografts (OV-90, n = 16) underwent cytoreductive surgery with real-time feedback. The impact of intraoperative CD24-targeted fluorescence guidance was compared to white light and palpation alone, and the recurrence of disease was monitored post-operatively (OV-90, n = 12). CD24-AF750 was further evaluated in four clinically annotated orthotopic PDX models of metastatic HGSOC, to validate the translational potential for intraoperative guidance.

Findings: CD24-targeted intraoperative NIR FIGS significantly (47•3%) improved tumour detection and resection, and reduced the post-operative tumour burden compared to standard white-light surgery in orthotopic HGSOC xenografts. CD24-AF750 allowed identification of minuscule tumour lesions which were undetectable with the naked eye in four HGSOC PDX.

Interpretation: CD24-targeted FIGS has translational potential as an aid to improve debulking surgery of ovarian cancer.

Funding: This study was supported by the H2020 program MSCA-ITN [675743], Helse Vest RHF, and Helse Bergen HF [911809, 911852, 912171, 240222, 911974, HV1269], as well as by The Norwegian Cancer Society [182735], and The Research Council of Norway through its Centres of excellence funding scheme [223250, 262652].
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http://dx.doi.org/10.1016/j.ebiom.2020.102783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248677PMC
June 2020

Molecular testing on serous effusions.

Authors:
Ben Davidson

Diagn Cytopathol 2021 May 5;49(5):640-646. Epub 2020 Feb 5.

Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Serous effusions constitute a significant part of the material processed and diagnosed by cytopathology laboratories. Effusions may occur in a variety of clinical settings and the differential diagnosis between these conditions often requires ancillary tests. Immunohistochemistry is still the most frequently used method in this context. However, a wide array of other methods measuring the expression of DNA, mRNA, noncoding RNA, proteins, and other compounds may be applied to the diagnosis of serous effusions, particularly in the setting of cancer, as well as to studies focusing on tumor biology and understanding of tumor progression. In addition, as serous effusions provide ideal material for molecular testing, they have in recent years assumed central role as specimens informative of prediction in the context of targeted therapy, as well as prognostication. This review discusses recent studies in this field.
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http://dx.doi.org/10.1002/dc.24392DOI Listing
May 2021

The clinical, morphological, and genetic heterogeneity of endometrial stromal sarcoma.

Virchows Arch 2020 04 28;476(4):489-490. Epub 2020 Jan 28.

Department of Pathology, Hospital Graz II, Graz, Austria.

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http://dx.doi.org/10.1007/s00428-020-02762-3DOI Listing
April 2020

Expression of Wnt pathway molecules is associated with disease outcome in metastatic high-grade serous carcinoma.

Virchows Arch 2020 Aug 3;477(2):249-258. Epub 2020 Jan 3.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310, Oslo, Norway.

The objective of this study was to analyze the expression and clinical role of Wnt pathway molecules in metastatic high-grade serous carcinoma (HGSC). mRNA expression by qPCR of 20 molecules related to Wnt signaling (WNT1, WNT2, WNT3, WNT4, WNT5A, WNT6, WNT7, WNT11, FZD1, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, LRP5, LRP6, DKK, CCND, RUNX2) was analyzed in 87 HGSC effusions. Thirty-nine surgical specimens (19 ovarian, 20 from other intra-abdominal sites) were analyzed for comparative purposes. Protein expression of YAP and LRP and their phosphorylated forms by western blotting were analyzed in 52 tumors. Significant differences in mRNA expression as a function of the anatomic site were observed for WNT3 (p = 0.005), WNT5A (p = 0.008), WNT7 (p < 0.001), FRZ5 (p = 0.04), and FRZ6 (p < 0.001). YAP and LRP and their phosphorylated forms were detected in HGSC specimens. FZD10 was overexpressed in effusions from patients who had complete response to chemotherapy compared with those with less favorable response (p = 0.037). WNT4 (p = 0.005), WNT7 (p = 0.047), RUNX2 (p = 0.038), LRP5 (p = 0.022), LRP6 (p = 0.011), FZD6 (p = 0.036), FZD7 (p = 0.004), and FZD10 (p = 0.015) levels were inversely related to primary chemoresistance. High FZD5 levels in pre-chemotherapy effusions tapped at diagnosis and high WNT2 levels in post-chemotherapy disease recurrence effusions were related to shorter overall survival (p = 0.018 and p = 0.011, respectively), whereas high RUNX2 (p = 0.031) and FZD1 (p = 0.029) in post-chemotherapy effusions were associated with longer overall survival. In multivariate analysis of post-chemotherapy cases, WNT2 (p = 0.002), RUNX2 (p = 0.017), FZD1 (p = 0.036), and FZD4 (p = 0.013) were independent prognosticators. In conclusion, expression of Wnt pathway molecules is anatomic site dependent. In HGSC effusions, it is informative of chemoresponse and survival.
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http://dx.doi.org/10.1007/s00428-019-02737-zDOI Listing
August 2020

Efficacy and Animal Welfare Impacts of Novel Capture Methods for Two Species of Invasive Wild Mammals in New Zealand.

Animals (Basel) 2019 Dec 24;10(1). Epub 2019 Dec 24.

School of Veterinary and Life Sciences, Murdoch University, 90 South Street, Murdoch, WA 6150, Australia.

All capture methods impose animal welfare impacts, but these impacts are rarely quantified or reported. We present data from two wildlife capture studies that trialled new methods for capturing Bennett's wallabies () and red deer () in New Zealand. We used helicopter net-gunning for both species, and compared this method with ground-based netting for wallabies and helicopter darting for red deer, using, for the first time in New Zealand, the fast-acting opioid thiafentanil. Efficacy and animal welfare parameters quantified were duration of handling and recovery, and frequency of adverse events, including escape, injury, and mortality. Cost-effectiveness was quantified for each method. Capture mortalities occurred for all methods for both species. For red deer, chemical immobilisation led to fewer traumatic injuries and fewer mortalities, while for wallabies, net-gunning led to fewer mortalities. Net-gunning was an efficient capture method for deer in open habitat, but led to the escape of 54% of wallabies and one wallaby mortality (4%). Ground-based netting resulted in the mortality of 17% of wallabies at the time of capture, and the capture of non-target species. The cost per captured wallaby was 40% more expensive for net-gunning (NZ$1045) than for ground-based netting (NZ$745), but, once corrected for mortalities at the time of capture and suitability of individuals for GPS-collar deployment, this was reduced to 29% and 12% more expensive, respectively. Net-gunning for red deer resulted in the escape of 13% of animals and mortality of 10% of animals at the time of capture. Helicopter-based darting for red deer using thiafentanil (c. 0.03-0.06 mg/kg) had high capture efficacy (zero escapes), rapid induction times (mean of 3 min), and a low mortality rate at 14 days post-capture (3%), but it was more expensive per deer captured and collared than aerial netting (NZ$2677 and NZ$2234, respectively). We recommend reporting of adverse event data for all wildlife capture techniques to permit continual refinement of field methods.
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http://dx.doi.org/10.3390/ani10010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022690PMC
December 2019

Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing.

Sci Rep 2019 12 6;9(1):18555. Epub 2019 Dec 6.

Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

We have surveyed 191 prospectively sampled familial cancer patients with no previously detected pathogenic variant in the BRCA1/2, PTEN, TP53 or DNA mismatch repair genes. In all, 138 breast cancer (BC) cases, 34 colorectal cancer (CRC) and 19 multiple early-onset cancers were included. A panel of 44 cancer-predisposing genes identified 5% (9/191) pathogenic or likely pathogenic variants and 87 variants of uncertain significance (VUS). Pathogenic or likely pathogenic variants were identified mostly in familial BC individuals (7/9) and were located in 5 genes: ATM (3), BRCA2 (1), CHEK2 (1), MSH6 (1) and MUTYH (1), followed by multiple early-onset (2/9) individuals, affecting the CHEK2 and ATM genes. Eleven of the 87 VUS were tested, and 4/11 were found to have an impact on splicing by using a minigene splicing assay. We here report for the first time the splicing anomalies using this assay for the variants ATM c.3806A > G and BUB1 c.677C > T, whereas CHEK1 c.61G > A did not result in any detectable splicing anomaly. Our study confirms the presence of pathogenic or likely pathogenic variants in genes that are not routinely tested in the context of the above-mentioned clinical phenotypes. Interestingly, more than half of the pathogenic germline variants were found in the moderately penetrant ATM and CHEK2 genes, where only truncating variants from these genes are recommended to be reported in clinical genetic testing practice.
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http://dx.doi.org/10.1038/s41598-019-54517-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898579PMC
December 2019

MGMT promoter methylation is a rare epigenetic change in malignant effusions.

Cytopathology 2020 01 5;31(1):12-15. Epub 2019 Dec 5.

Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Objective: The aim of this study was to analyse the promoter methylation status of the gene O6-methylguanine-DNA methyltransferase (MGMT) in malignant effusions, with focus on serous carcinoma.

Methods: Fresh-frozen cell pellets from 81 effusions (42 peritoneal, 38 pleural, one pericardial), consisting of 71 carcinomas of different origin (33 ovarian, 23 breast, six lung, five uterine corpus and four cervical carcinomas) and 10 malignant mesotheliomas, were analysed for MGMT methylation using pyrosequencing analysis.

Results: MGMT methylation at all four cytosine-guanine dinucleotide sites examined was detected in only 2/81 (2%) specimens, consisting of a high-grade serous carcinoma with high frequency of methylation, and a breast carcinoma with low methylation frequency.

Conclusion: The findings in the present study suggest that MGMT methylation is a rare epigenetic change in malignant effusions of different origin.
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http://dx.doi.org/10.1111/cyt.12782DOI Listing
January 2020

Diverse Effects of Lysophosphatidic Acid Receptors on Ovarian Cancer Signaling Pathways.

J Oncol 2019 17;2019:7547469. Epub 2019 Sep 17.

Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.

Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression, and resistance. It is produced mainly by autotaxin and acts on six G-protein-coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. However, mitogenic pathways stimulated by LPA via its receptors may involve any novel, thus far uncharacterized, signaling pathway(s). Here we show that three LPA receptors are involved in tumor progression by activation of both the AKT and ERK signaling pathways. CRISPR-edited LPAR2 and LPAR3 knockouts have opposing effects on ERK activation, whereas LPAR6 is involved in the activation of AKT, affecting cell migration and invasion. Our study identifies specific molecular machinery triggered by LPA and its receptors that modulates tumor cells and can serve as therapeutic target in this malignancy.
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http://dx.doi.org/10.1155/2019/7547469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766155PMC
September 2019

Spleen tyrosine kinase activity regulates epidermal growth factor receptor signaling pathway in ovarian cancer.

EBioMedicine 2019 Sep 3;47:184-194. Epub 2019 Sep 3.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States of America. Electronic address:

Background: Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation.

Methods: We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates.

Findings: Induced expression of constitutively active SYK reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFR, but not SYK non-phosphorylatable EGFR mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYK cells, SYK cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients.

Interpretation: These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. FUND: Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796592PMC
September 2019

Molecular characterization of carcinosarcomas arising in the uterus and ovaries.

Oncotarget 2019 Jun 4;10(38):3614-3624. Epub 2019 Jun 4.

Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Gynaecological carcinosarcomas are rare biphasic tumours which are highly aggressive. We performed molecular investigations on a series of such tumours arising in the uterus ( = 16) and ovaries ( = 10) to gain more information on their mutational landscapes and the expression status of the genes , , , and , the pseudogenes and , and the miRNAs known to influence expression of the above-mentioned genes. In uterine carcinosarcomas (UCS), we identified mutations in , , and with a frequency of 6%, 31%, and 75%, respectively, whereas in ovarian carcinosarcomas (OCS), was the only mutated gene found (30%). An inverse correlation was observed between overexpression of , , and and downregulation of miRNAs such as let-7a, let-7d, miR26a, miR16, miR214, and miR30c in both UCS and OCS. was expressed in its full length in 14 UCS and 9 OCS; in the remaining tumours, it was expressed in its truncated form. Because was normally expressed while miR30c was downregulated, not both downregulated as is the case in several other carcinomas, alterations of the epithelial-mesenchymal transition through an as yet unknown mechanism seems to be a feature of carcinosarcomas.
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http://dx.doi.org/10.18632/oncotarget.26942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557202PMC
June 2019

Biomarkers of drug resistance in ovarian cancer - an update.

Authors:
Ben Davidson

Expert Rev Mol Diagn 2019 06 16;19(6):469-476. Epub 2019 May 16.

a Department of Pathology , Oslo University Hospital, Norwegian Radium Hospital , Oslo , Norway.

: Ovarian cancer, consisting predominantly of ovarian carcinoma, is the most lethal gynecologic malignancy. Diagnosis at the advanced stage, particularly in high-grade serous carcinoma which is the most common and clinically aggressive histotype, is a major factor negatively affecting survival, while tumor heterogeneity and chemoresistance often preclude complete elimination of tumor cells even following radical surgery and combination chemotherapy. Recently, inhibition of angiogenesis and inhibition of poly (ADP-ribose) polymerase (PARP) have shown benefit in the treatment of this cancer. : Extensive research has identified molecules associated with resistance to chemotherapy and implicated several biomarkers affecting response to antiangiogenic therapy and PARP inhibition. This review discusses recent data in this field. The presented data, gathered in a PubMed search focusing on the years 2016-2018, focus on regulators of the cell cycle and mitosis, cancer stem cell-related molecules, the immune response, receptor tyrosine kinases and related signaling pathways, BRCA and other DNA repair molecules, microRNAs, and other cancer-associated molecules. : Future research is likely to focus on histotype-specific analyses of clinical specimens and patient-generated cultures applying cutting-edge molecular technology, in the aim of identifying major regulators of chemotherapy response.
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http://dx.doi.org/10.1080/14737159.2019.1618187DOI Listing
June 2019

ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis.

Eur J Surg Oncol 2021 01 22;47(1):134-138. Epub 2019 Apr 22.

Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address:

Background: The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial.

Methods: This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with mitomycin C. Overall survival (OS) and disease-free survival (DFS) were secondary endpoints. Twenty-one patients received the study drug at four dose levels on the first postoperative day, including six patients constituting an expansion cohort.

Results: With a 34-month follow-up, the median OS was not reached and the estimated 3-year OS was 78%. Median DFS for all patients was 21 months and the 3-year DFS was 33%, with a median follow-up of 31 months. When excluding patients with potential favorable characteristics from the analysis (n = 4), the median DFS was 13 months and the 3-year OS 72%.

Conclusions: The promising long-term outcome combined with low systemic absorbance, high drug concentration and cytotoxic activity in peritoneal fluid support further investigations of clinical efficacy.
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http://dx.doi.org/10.1016/j.ejso.2019.04.014DOI Listing
January 2021

SOX2 and SOX9 are markers of clinically aggressive disease in metastatic high-grade serous carcinoma.

Gynecol Oncol 2019 06 21;153(3):651-660. Epub 2019 Mar 21.

Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, N-0310 Oslo, Norway; University of Oslo, Faculty of Medicine, Institute of Clinical Medicine, N-0316 Oslo, Norway. Electronic address:

Objective: The aim of this study was to analyze the expression, biological role and clinical relevance of cancer stem cell markers in high-grade serous carcinoma (HGSC).

Methods: mRNA expression by qRT-PCR of NANOG, OCT4, SOX2, SOX4, SOX9, LIN28A and LIN28B was analyzed in 134 HGSC specimens (84 effusions, 50 surgical specimens). Nanog, OCT3/4, SOX2 and SOX9 protein expression by immunohistochemistry was analyzed in 52 HGSC effusions. Nanog protein expression in exosomes from 80 HGSC effusions was studied by Western Blotting. OVCAR3 cells underwent CRISPR/Cas9 Nanog knockout (KO), and the effect of Nanog KO on migration, invasion, proliferation and proteolytic activity was analyzed in OVCAR3 and OVCAR8 cells.

Results: OCT4 mRNA was overexpressed in effusions compared to solid specimens (p = 0.046), whereas SOX9 was overexpressed in the ovarian tumors compared to effusions and solid metastases (p = 0.003). Higher SOX2 and SOX9 expression was associated with primary (intrinsic) chemoresistance (p = 0.009 and p = 0.02, respectively). Higher SOX9 levels were associated with shorter overall survival in univariate (p = 0.04) and multivariate (p = 0.049) analysis. OCT3/4, SOX2 and SOX9 proteins were found in HGSC cells, whereas Nanog was detected only in exosomes. Higher SOX2 protein expression was associated with shorter overall survival in univariate analysis (p = 0.049). OVCAR cells exposed to OVCAR3 NANOG KO exosomes had reduced migration, invasion and MMP9 activity.

Conclusions: SOX2 and SOX9 mRNA levels in HGSC effusions may be markers of clinically aggressive disease. Nanog is secreted in HGSC exosomes in effusions and modulates tumor-promoting cellular processes in vitro.
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http://dx.doi.org/10.1016/j.ygyno.2019.03.099DOI Listing
June 2019

Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response.

Cold Spring Harb Mol Case Stud 2019 04 1;5(2). Epub 2019 Apr 1.

Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, 0310 Oslo, Norway.

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. were identified as the main mutational drivers together with homozygous loss of and , which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.
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http://dx.doi.org/10.1101/mcs.a003566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549577PMC
April 2019

Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.

Clin Cancer Res 2019 04 7;25(7):2155-2165. Epub 2019 Jan 7.

Department of Oncology-Pathology, Karolinska Institutet, and Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.

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 with full clinicopathologic annotation were analyzed for gene expression ( = 50), copy-number variation (CNV, = 40), cell morphometry ( = 39), and protein expression ( = 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.

Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup.

Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2792DOI Listing
April 2019

High-grade Endometrial Carcinomas: Morphologic and Immunohistochemical Features, Diagnostic Challenges and Recommendations.

Int J Gynecol Pathol 2019 Jan;38 Suppl 1:S40-S63

Department of Pathology, Memorial Sloan Kettering Cancer Center (R.M., R.A.S.) New York University Medical Center and School of Medicine, Tisch Hospital (K.M.), New York Department of Pathology, University Hospital, Stony Brook School of Medicine, Stony Brook (C.T.), New York Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital; Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (B.D.) Department of Pathology, University of California San Diego, San Diego (O.F.) Department of Pathology, Cedars-Sinai Medical Center, Los Angeles (J.K.L.R.), California Department of Pathology, Karolinska Institutet, Stockholm, Sweden (J.A.C.) Department of Pathology, Brigham and Women's Hospital, Harvard Medical School (C.P.C.) Department of Pathology, Massachussetts General Hospital, Harvard Medical School (E.O.), Boston, Massachussetts Department of Pathology, University of British Columbia, Vancouver (C.B.G., J.A.I.) Department of Laboratory Medicine, Pathology and Medical Genetics, Royal Jubilee Hospital, Victoria (J.A.I.), BC, Canada Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas (A.M.) Department of Pathology, Hospital University Arnau de Vilanova; and Department of Pathology, Hospital University de Bellvitge, IRBLLEIDA, IDIBELL, University of Lleida, CIBERONC, Barcelona, Spain (X.M.-G.) Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK (W.G.M.) Department of Pathology and Obstetrics and Gynecology, Yale School of Medicine and Yale School of Publich Health, New Haven, Connecticut (V.P.) Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland (P.N.S.) Department of Pathology, KEMH and School for Women's and Infants' Health, University of Western Australia, Perth, WA, Australia (C.J.R.S.).

This review of challenging diagnostic issues concerning high-grade endometrial carcinomas is derived from the authors' review of the literature followed by discussions at the Endometrial Cancer Workshop sponsored by the International Society of Gynecological Pathologists in 2016. Recommendations presented are evidence-based, insofar as this is possible, given that the levels of evidence are weak or moderate due to small sample sizes and nonuniform diagnostic criteria used in many studies. High-grade endometrioid carcinomas include FIGO grade 3 endometrioid carcinomas, serous carcinomas, clear cell carcinomas, undifferentiated carcinomas, and carcinosarcomas. FIGO grade 3 endometrioid carcinoma is diagnosed when an endometrioid carcinoma exhibits >50% solid architecture (excluding squamous areas), or when an architecturally FIGO grade 2 endometrioid carcinoma exhibits marked cytologic atypia, provided that a glandular variant of serous carcinoma has been excluded. The most useful immunohistochemical studies to make the distinction between these 2 histotypes are p53, p16, DNA mismatch repair proteins, PTEN, and ARID1A. Endometrial clear cell carcinomas must display prototypical architectural and cytologic features for diagnosis. Immunohistochemical stains, including, Napsin A and p504s can be used as ancillary diagnostic tools; p53 expression is aberrant in a minority of clear cell carcinomas. Of note, clear cells are found in all types of high-grade endometrial carcinomas, leading to a tendency to overdiagnose clear cell carcinoma. Undifferentiated carcinoma (which when associated with a component of low-grade endometrioid carcinoma is termed "dedifferentiated carcinoma") is composed of sheets of monotonous, typically dyscohesive cells, which can have a rhabdoid appearance; they often exhibit limited expression of cytokeratins and epithelial membrane antigen, are usually negative for PAX8 and hormone receptors, lack membranous e-cadherin and commonly demonstrate loss of expression of DNA mismatch repair proteins and SWI-SNF chromatin remodeling proteins. Carcinosarcomas must show unequivocal morphologic evidence of malignant epithelial and mesenchymal differentiation.
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http://dx.doi.org/10.1097/PGP.0000000000000491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296248PMC
January 2019
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