G K Jacobsen

Rigshospitalet, København, Capital Region, Denmark

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Publications (103)451.48 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Testicular spermatocytic seminoma (SS) is a rare tumor type predominantly found in elderly men. It is thought to originate from spermatogonia and shows cytological and genetic heterogeneity. In this study, we performed for the first time a comprehensive analysis of epigenetic modifications in a series of 36 SS samples. We assessed by immunohistochemistry tumor DNA methylation levels, the expression of methyltransferases DNMT3A, DNMT3B and DNMT3L as well as levels of histone modifications H3K9me2, H3K27me3, H3K4me1, H3K4me2/3, H3K9ac, and H2A.Z. We did not identify any epigenetic marks that matched the pattern of the supposed cell-of-origin, the spermatogonia, and found no correlation between specific marks and the size of the SS cells. The emerging epigenetic picture of SS is a heterogeneous "salt-and-pepper"-like pattern, with neighboring cells displaying very variable levels of epigenetic marks. We conclude that SS cells display apparent epigenetic heterogeneity and instability, with loss of the organized manner typical for normal germ cell maturation in the adult testis, likely due to the lack of regulatory signals from the absent somatic cell niche.
    Cancer Genetics 07/2012; 205(9):425-31. · 1.92 Impact Factor
  • Histopathology 11/2011; 59(5):1010-1. · 2.86 Impact Factor
  • Histopathology 11/2011; 59(5):1014. · 2.86 Impact Factor
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    Histopathology 11/2011; 59(5):1012-3. · 2.86 Impact Factor
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    ABSTRACT: Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from A(dark) spermatogonia.
    The Journal of Pathology 04/2011; 224(4):473-83. · 7.59 Impact Factor
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    ABSTRACT: Prompted by the recently reported expression of POU5F1 (OCT3/4) in epididymis, a panel of markers for carcinoma in situ (CIS) testis and testicular germ cell tumours (TGCT), including AP-2γ(TFAP2C), NANOG, OCT3/4, KIT, placental-like alkaline phosphatase (PLAP), M2A/PDPN and MAGE-A4 were examined by immunohistochemistry or in situ hybridisation in urogenital epithelia, which may interfere with detection of CIS cells in semen. In addition to OCT3/4, the expression of AP-2γ and NANOG or their variants was detected in urogenital epithelia, while other CIS markers, including PLAP/alkaline phosphatase were absent. A combination of immunocytological staining for AP-2γ or OCT3/4 and rapid cytochemical alkaline phosphatase reaction was subsequently developed. This approach was tested in 22 patients with TGCT. In 14 patients (63.6%), double stained cells were found and thus the method was proven suitable for the detection of CIS cells in semen. In conclusion, transcription factors related to pluripotency and undifferentiated state of cells, which most likely have several variants or modifications, are unexpectedly detected using currently available antibodies in urogenital epithelial cells which may be shed into semen. Combining the immunohistochemical nuclear markers with a rapid cytochemical alkaline phosphatase reaction for detection of CIS cells in ejaculates may provide a more reliable diagnostic method.
    Andrologia 02/2011; 44(2):78-85. · 1.55 Impact Factor
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    ABSTRACT: Dysregulated angiogenesis is a hallmark of chronic inflammatory diseases, including psoriasis, a common skin disorder that affects approximately 2% of the population. Studying both human psoriasis in 2 complementary xenotransplantation models and psoriasis-like skin lesions in transgenic mice with epidermal expression of human TGF-β1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue. High-resolution ultrasound revealed reduced cutaneous blood flow in vivo after electroporation with RDD but not with control plasmids. In addition, angiogenesis- and inflammation-related molecular markers, keratinocyte proliferation, epidermal thickness, and clinical disease scores were downregulated in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.
    The Journal of clinical investigation 01/2011; 121(1):410-21. · 15.39 Impact Factor
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    ABSTRACT: Proper examination and accurate reporting of radical prostatectomy specimens (RPS) is essential in determining post-surgical treatment and predicting patient outcome. Surveys have demonstrated the absence of consensus on handling of RPS. The aim of this study was to determine whether significant information is lost when only half the horizontal tissue sections are examined. During a 1-year period, 238 RPS were sectioned into horizontal slices. Apex and basis was cut sagittally, and remaining slices were embedded in quadrants. Glass slides from every second horizontal slice were withheld. The remaining slides were evaluated microscopically, and essential pathological parameters were recorded. Subsequently, a full report was compiled, including the withheld slides. A median of 12 slides (30%) were withheld during initial assessment. In eight RPS (3.2%) the pTNM stage had to be changed; in six cases (2.6%) from pT2b to pT2c and in two cases (0.8%) from pT2c to pT3a. In one RPS (0.4%) the surgical margin status was changed. Only little information is lost with systematic partial embedding, overlooking features significant for the postoperative treatment in only 1.2%. Partial embedding as suggested, decreasing the laboratory workload by 30%, is concluded to be acceptable for valid histopathological assessment.
    Histopathology 01/2011; 58(2):211-6. · 2.86 Impact Factor
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    ABSTRACT: The transcription factor OCT4 plays a crucial role in the earliest differentiation of the mammalian embryo and in self-renewal of embryonic stem cells. However, it remains controversial whether this gene is also expressed in somatic tissues. Here, we use a combination of RT-PCR on whole and microdissected tissues, in situ hybridization, immunohistochemistry and western blotting to show that OCT4 and SOX2 together with downstream targets, UTF1 and REX1/ZFP42, are expressed in the human male urogenital tract. We further support these results by the analysis of DNA methylation of a region in the OCT4 promoter. In culture, human primary epididymal cells formed spheres that continued to express the investigated genes for at least 20 days. Transcriptomic analysis of cultured cells showed up-regulation of CD29, CD44 and CD133 that are normally associated with sphere-forming cancer stem cells. Furthermore, stimulation with retinoic acid resulted in down-regulation of OCT4 expression, however, without multilineage differentiation. Our results show that OCT4 and associated genes are expressed in somatic epithelial cells from the urogenital tract and that these cells can form spheres, a general marker of stem cell behaviour.
    Molecular Human Reproduction 11/2010; 16(11):835-45. · 4.54 Impact Factor
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    ABSTRACT: Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.
    Nature Genetics 11/2009; 41(11):1247-52. · 35.21 Impact Factor
  • LISE GRUPE LARSEN, GRETE KRAG JACOBSEN
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    ABSTRACT: A carcinoid tumor of the larynx is reported. The tumor was initially interpreted as a poorly differentiated squamous carcinoma and treated with irradiation. One year later a laryngectomy was performed and a carcinoid tumor was found in the resection specimen. The patient died after 2 years with disseminated disease. Carcinoid tumors in the larynx are rare. In the literature 45 cases of laryngeal carcinoid tumors have been reported. The diagnosis of this laryngeal tumor is difficult but important because irradiation is ineffective. Surgical treatment should be performed.
    Apmis 08/2009; 97(7‐12):748 - 753. · 2.07 Impact Factor
  • Karsten Nielsen, Grete Krag Jacobsen
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    ABSTRACT: The fifteenth case of malignant Sertoli cell tumour is reported and the literature is reviewed. The reported case was unilateral with lung metastases. Immunohistochemical examination showed positive staining reaction within the tumour cells for vimentin and cytokeratin, while AFP, HCG, PLAP, EMA and CEA were not found, which is in accordance with the staining pattern found in normal Sertoli cells.
    Apmis 08/2009; 96(7‐12):755 - 760. · 2.07 Impact Factor
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    ABSTRACT: A case of melanotic neuroectodermal tumour (MNT), or so-called retinal anlage tumour, as a predominant component of an immature testicular teratoma is presented. The patient was a 17-year-old man who furthermore had a mature mediastinal teratoma. The MNT was composed mainly of two cell types: small immature neuroblast-like cells and large columnar or cuboidal epithelial-like cells with or without melanin granules. The tumour cells were arranged in solid formations, nests, cords, alveolar and pseudoglandular structures with cleft-like or glomeruloid-like spaces. Myogenic differentiation was found in minor foci. Immunohistochemistry showed both neuroepithelial and mesenchymal features with positive staining reaction for neuron-specific enolase (NSE), S-100 protein (S-100), melanoma antigen (HMB45), cytokeratin and vimentin. Vimentin, desmin and actin were present in the myoid cells. To the best of our knowledge this is the first reported case of MNT originating in the testis. As this tumour component occurred in an immature teratoma, neuroectodermal differentiation of germ cell origin is considered most likely.
    Apmis 08/2009; 100(7‐12):809 - 816. · 2.07 Impact Factor
  • N. MILMAN, N. GRAUDAL, G. K. JACOBSEN
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    ABSTRACT: During a 7-year period bronchoalveolar lavage (BAL) was performed as a routine diagnostic procedure at fiberoptic bronchoscopy in 172 consecutive patients with diffuse pulmonary lesions. In 42 patients, BAL was technically insufficient or data were incomplete. These patients were excluded. The remaining 130 patients consisted of 78 men and 52 women with a median age of 43 years (range 19–79); 59 were smokers. They were divided into 6 groups: I. sarcoidosis (n=77); II. cryptogenic fibrosing alveolitis (n=16); III. secondary fibrosing alveolitis (n=7); IV. malignancy (n=7); V. allergic alveolitis (n=6); VI. miscellaneous (n=17). Group VI was not included in the statistical evaluation, which involved only the 113 patients in groups I-V. BAL was performed in a segment of the right middle lobe with 150–200 ml isotonic saline. The return fluid (BALF) was filtered through two layers of cotton gauze, and total and differential cell counts were assessed. Median BALF return volume was 67% (range 35–90). Eighty percent of the procedures were performed by the same operator. Total cell count displayed no significant difference amongst the five diagnostic groups (p=0.06). Differential cell count displayed differences amongst the groups respecting macrophages (p=0.002), lymphocytes (p=0.0004), neutrophils (p=0.0001) and eosinophils (p=0.04). Patients with sarcoidosis had a higher percentage of lymphocytes, patients with secondary fibrosis a higher percentage of neutrophils, and patients with cryptogenic fibrosis a higher percentage of eosinophils than the other groups. Malignant cells were observed in BALF in 14.3% of patients with malignant lesions. Among the patients with sarcoidosis, 75% had a lymphocyte-dominated BALF (>10%) compared with 31% of the patients with cryptogenic fibrosis, 14% of the patients with secondary fibrosis, and 43% of the patients with malignancy. Dominance of neutrophils (>10%) and/or eosinophils (>5%) in BALF was observed in cryptogenic and secondary fibrosis. In most patients, BAL cannot provide a definite diagnosis, but may support the clinical suspicion of a specific diagnosis. In clinical practice, BAL seems to be of limited value in the diagnostic evaluation of radiologically detected diffuse, non-infectious pulmonary lesions.
    Apmis 08/2009; 103(7‐8):764 - 768. · 2.07 Impact Factor
  • GRETE KRAG Jacobsen
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    ABSTRACT: Thirty-five testicular germ cell tumours comprising 16 yolk sac tumours, 15 embryonal carcinomas and 13 seminomas were examined for the presence and distribution of laminin using an indirect immunoperoxi-dase technique. In addition, nine normal yolk sacs and 23 carcinomas of the lung were studied. All the yolk sac tumours were positively stained for laminin. Both extra- and intracellular staining were found. Hyaline, eosinophilic material present within the tumours was positively stained, although with varying intensity. In 12 out of 15 embryonal carcinomas, laminin was found as a membrane staining but cytoplasmic staining also occurred. In 10 out of 13 classical seminomas, a membrane staining of many tumour cells was found, while cytoplasmic staining occurred in only a few seminomas. In all but one of the yolk sacs, laminin was present in the membrane beneath both the mesoblastic outer cell layer and the visceral endoderm. Intracellular staining was seen in some of the cells in both cell layers. In nine out of 23 carcinomas of the lung, laminin occurred extra- as well as intracellularly. Thus, this study showed that in normal yolk sacs the presence of laminin was not found to be particularly associated with any of the cell layers. Likewise, demonstration of laminin within yolk sac tumours did not define different patterns or subtypes of the yolk sac tumour. In addition, demonstration of laminin was not found to be useful in differentiating either between yolk sac tumours and embryonal carcinomas or between seminomas and non-seminomatous germ cell tumours. The findings add, however, interesting knowledge to histogenesis and embryogenesis.
    Apmis 08/2009; 98(7‐12):875 - 880. · 2.07 Impact Factor
  • Grete Krag Jacobsen, Marianne Jacobsen
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    ABSTRACT: 189 orchidectomy specimens with germ cell tumours were studied for the presence of ferritin (FER) using the indirect immunoperoxidase technique. FER was demonstrated in 93% of seminomas and 90% of non-seminomas. Various epithelial cell types in embryonal carcinoma (EC), yolk sac tumours (YST) and teratoma (T) were FER positive. Carcinoma-in-situ (CIS) which was present in the seminiferous tubules adjacent to the tumours was positively stained for FER in 94% of the specimens whether the tumour was a seminoma or a non-seminoma indicating a functional relationship of CIS to seminomatous as well as to non-seminomatous germ cell tumours.
    Apmis 08/2009; 91A(1‐6):177 - 181. · 2.07 Impact Factor
  • TORBEN HÆRSLEV, GRETE KRAG JACOBSEN, NINA HORN, ELSE DAMSGAARD
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    ABSTRACT: Menkes' disease is a recessive X-linked disturbance of copper metabolism, resulting in accumulation of copper in several extra-hepatic tissues including the placenta. Metallothionein (MT) is a low-molecular weight protein with a high affinity for group II metal ions, such as copper. Its synthesis is induced by the presence of the ions. The aim of this study was to investigate the pattern of the MT immunoreactivity in placental tissue obtained from women at-risk of Menkes' disease in order to examine whether the MT occurrence and distribution may reflect the copper content. Placental tissue from six women with a family history of Menkes' disease, from 4 women without a family history, and from 2 hydatiform moles was studied. Positive MT immunostaining was found to be independent of the length of fixation, whether the tissue samples were fixed in 4% buffered formaldehyde or Bouin's fixative. The avidin-biotin-complex (ABC)-technique was used. The copper content was measured by neutron activation analysis (NAA). In all placental tissue sections positive MT immunostaining appeared only in the trophoblast and only in proliferating cells. In placental tissue sections obtained from foetuses and children affected by Menkes' disease an additional MT immunostaining appeared in the Hofbauer cells of the chorionic villi. This staining was associated with an increased content of copper as measured by NAA. We conclude that the immunohistochemical demonstration of MT reflects the copper content and may be useful in pre- and postnatal diagnosis of Menkes' disease.
    Apmis 08/2009; 103(7‐8):568 - 573. · 2.07 Impact Factor
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    ABSTRACT: The S100A4 protein is reported as a pivotal player in the tumor microenvironment with a metastasis-promoting function. Moreover, the upregulation of S100A4 is found in other non-malignant human disorders as cardiac and pulmonary systems and rheumatoid arthritis. In this study, we investigated the expression and significance of S100A4 in psoriasis. We found significant upregulation of S100A4 in the dermis of psoriatic skin compared with normal skin. This pattern of S100A4 expression differs considerably from that of other S100 proteins, S100A7 and S100A8/9, with predominant expression in the epidermis of psoriasis. Furthermore, we revealed a massive release of the biologically active forms of S100A4 from psoriatic skin. Interestingly, we found stabilization (increase) of p53 in the basal layer of epidermis in close proximity to cells expressing S100A4. To examine the possible implication of S100A4 in the pathogenesis of psoriasis, we analyzed the effect of S100A4 blocking antibodies in a human psoriasis xenograft SCID mouse model and observed a significant reduction of the epidermal thickness and impairment in cell proliferation and dermal vascularization. In conclusion, we showed strong upregulation and release of S100A4 in the upper dermis of psoriatic skin and found evidence indicating that S100A4 might actively contribute to the pathogenesis of psoriasis.
    Journal of Investigative Dermatology 08/2009; 130(1):150-60. · 6.19 Impact Factor
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    ABSTRACT: Fast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC. We randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization. From January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups. The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)
    New England Journal of Medicine 08/2009; 361(1):32-9. · 54.42 Impact Factor
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    ABSTRACT: Exact staging of patients with non-small-cell lung cancer (NSCLC) is important to improve selection of resectable and curable patients for surgery. Positron emission tomography with integrated computed tomography (PET/CT) and endoscopic ultrasound guided fine needle aspiration biopsy (EUS-FNA) are new and promising methods, but indications in lung cancer staging are controversial. Only few studies have compared the 2 methods. The aim of this study was to assess and compare the diagnostic values of PET/CT and EUS-FNA for diagnosing advanced lung cancer in patients, who had both procedures performed. 27 patients considered to be potential candidates for resection of NSCLC underwent PET/CT and EUS-FNA. Diagnoses were confirmed either by open thoracotomy, mediastinoscopy or clinical follow-up. Advanced lung cancer was defined as tumour-stage ≥ IIIA(N2), corresponding to T4- and/or N2-N3- and/or M1 disease. Diagnostic values of PET/CT and EUS-FNA, with regard to the diagnosis of advanced lung cancer, were assessed and compared. The sensitivity of PET/CT and EUS-FNA were respectively 60% and 60% for T4 disease, 56% versus 100% for N2-N3 disease (p=0.12) and 100% versus 33% for M1 disease (p=0.50). For diagnosing advanced lung cancer PET/CT had a sensitivity of 79%, specificity of 61%, positive predictive value (PPV) of 69%, negative predictive value (NPV) of 73%, and an accuracy of 70%. EUS-FNA had a sensitivity of 79%, specificity of 100%, PPV of 100%, NPV of 81%, and an accuracy of 89% for advanced lung cancer. PET/CT and EUS-FNA had a comparable sensitivity and NPV for diagnosing advanced lung cancer, but EUS-FNA had superior specificity and PPV. The two methods seem to complement each other.
    Current health sciences journal. 01/2009; 35(1):5-12.

Publication Stats

2k Citations
451.48 Total Impact Points

Institutions

  • 1991–2012
    • Rigshospitalet
      • • Department of Pathology
      • • Department of Oncology
      København, Capital Region, Denmark
  • 2011
    • Odense University Hospital
      Odense, South Denmark, Denmark
  • 1993–2009
    • Copenhagen University Hospital Gentofte
      Hellebæk, Capital Region, Denmark
    • Aarhus University Hospital
      • Department of Oncology
      Århus, Central Jutland, Denmark
  • 1979–2009
    • Herlev Hospital
      • Department of Pathology
      Herlev, Capital Region, Denmark
  • 2006
    • Copenhagen University Hospital
      København, Capital Region, Denmark
    • Universitatea de Medicina si Farmacie Craiova
      • Center for Research in Gastroenterology and Hepatology
      Croiova, Dolj, Romania
  • 1993–1997
    • University of Copenhagen
      København, Capital Region, Denmark
  • 1984–1986
    • Copenhagen University Hospital Hvidovre
      • Department of Pathology
      Hvidovre, Capital Region, Denmark
  • 1983
    • University of Copenhagen Herlev Hospital
      Herlev, Capital Region, Denmark