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  • 1. Alfstad, K Å
    et al.
    Lossius, M I
    Røste, G K
    Mowinckel, P
    Scheie, D
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Dept. of Laboratory medicine/Pathology, Umeå University, Umeå Sweden.
    Larsson, P G
    Nakken, K O
    Acute postoperative seizures after epilepsy surgery: a long-term outcome predictor?2011In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, no 1, p. 48-53Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The prognostic value of acute postoperative seizures (APS) after epilepsy surgery is much debated. This study evaluated APS, defined as seizures in the first week post-surgery, as a predictor of long-term seizure outcome, and investigated the utility of other potential outcome predictors.

    MATERIALS AND METHODS: Medical records of 48 patients with temporal and extra-temporal epilepsy surgery were studied. Forty patients had lesional surgery. All had at least 2 year postoperative follow-up.

    RESULTS: At 2 year follow-up, 25 patients (53%) were seizure free. Univariate analysis showed that APS (P = 0.048), using ≥ six AEDs prior to surgery (P = 0.03), pathological postoperative EEG (P = 0.043) and female gender (P = 0.012) were associated with seizure recurrence.

    CONCLUSIONS: Univariate analysis indicate that APS, a high number of AEDs used prior to surgery, and pathological postoperative EEG are possible predictors of seizure recurrence after epilepsy surgery. Only gender retained significance in the multivariate analysis.

  • 2. Asa, S L
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Chanson, P
    Delgrange, E
    Earls, P
    Ezzat, S
    Grossman, A
    Ikeda, H
    Inoshita, N
    Karavitaki, N
    Korbonits, M
    Laws, E R
    Lopes, M B
    Maartens, N
    McCutcheon, I E
    Mete, O
    Nishioka, H
    Raverot, G
    Roncaroli, F
    Saeger, W
    Syro, L V
    Vasiljevic, A
    Villa, C
    Wierinckx, A
    Trouillas, J
    From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 4, p. C5-C8Article in journal (Refereed)
    Abstract [en]

    The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

  • 3. Borota, OC
    The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response.2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197Article in journal (Refereed)
  • 4.
    Casar Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Stigare, Jerker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Boldt, Henning Bünsow
    Kristensen, Bjarne Winther
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Trouillas, Jacqueline
    Serotonin, ATRX, and DAXX Expression in Pituitary Adenomas: Markers in the Differential Diagnosis of Neuroendocrine Tumors of the Sellar Region.2017In: American Journal of Surgical Pathology, ISSN 0147-5185, E-ISSN 1532-0979, Vol. 41, no 9, p. 1238-1246Article in journal (Refereed)
    Abstract [en]

    Differential diagnosis based on morphology and immunohistochemistry between a clinically nonfunctioning pituitary neuroendocrine tumor (NET)/pituitary adenoma and a primary or secondary NET of nonpituitary origin in the sellar region may be difficult. Serotonin, a frequently expressed marker in the NETs, has not been systematically evaluated in pituitary NETs. Although mutations in ATRX or DAXX have been reported in a significant proportion of pancreatic NETs, the mutational status of ATRX and DAXX and their possible pathogenetic role in pituitary NETs are unknown. Facing a difficult diagnostic case of an invasive serotonin and adrenocorticotroph hormone immunoreactive NET in the sellar region, we explored the immunohistochemical expression of serotonin, ATRX, and DAXX in a large series of pituitary endocrine tumors of different types from 246 patients and in 2 corticotroph carcinomas. None of the pituitary tumors expressed serotonin, suggesting that serotonin immunoreactive sellar tumors represent primary or secondary NETs of nonpituitary origin. Normal expression of ATRX and DAXX in pituitary tumors suggests that ATRX and DAXX do not play a role in the pathogenesis of pituitary endocrine tumors that remain localized to the sellar and perisellar region. A lack of ATRX or DAXX in a sellar NET suggests a nonpituitary NET, probably of pancreatic origin. One of the 2 examined corticotroph carcinomas, however, demonstrated negative ATRX immunolabeling due to an ATRX gene mutation. Further studies on a larger cohort of pituitary carcinomas are needed to clarify whether ATRX mutations may contribute to the metastatic potential in a subset of pituitary NETs.

  • 5.
    Casar Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fougner, Stine Lyngvi
    Bollerslev, Jens
    Nesland, Jahn Marthin
    KIT protein expression and mutational status of KIT gene in pituitary adenomas2012In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 460, no 2, p. 171-181Article in journal (Refereed)
    Abstract [en]

    KIT protein expression and mutational status of KIT gene in different types of tumours have been intensively studied since Imatinib Mesylate, KIT/PDGFRA tyrosine kinase inhibitor became available. However, only one immunohistochemical study on KIT expression in pituitary adenomas has been published. There are currently no reports on mutational status of KIT gene in pituitary adenomas. We have immunohistochemically investigated KIT expression in 252 pituitary adenomas and found cytoplasmic reactivity in 52.4% and membranous reactivity in 8.3% of all adenomas. There was statistically significant difference in KIT expression between clinically non-functioning, growth hormone- and adrenocorticotroph hormone-producing adenomas. The group with membranous expression was dominated by somatotropinomas and clinically non-functioning adenomas. KIT expression in a subset of adenomas was also confirmed by western blot analysis of 48 adenomas. Immunohistochemical KIT expression was correlated with basic clinical data and in a cohort of acromegalic patients with additional data (somatostatin receptor type 2A expression, response to somatostatin analogue treatment and mutational status of gsp oncogene). Exons 9, 11, 13 and 17 of KIT gene were searched for mutations in the tumours with membranous KIT expression and in a minority of tumours with cytoplasmic KIT expression using denaturing high-performance liquid chromatography and in suspected cases sequencing of one or more exons. No mutations in the examined exons were found. Our results may suggest a role of KIT in the pathogenesis of a subset of pituitary adenomas and point out the need for further research to find out if KIT-reactive adenomas could be sensitive to Imatinib Mesylate.

  • 6.
    Casar Borota, Olivera
    et al.
    Tromsö University.
    Kloster, Roar
    Lindal, Sigurd
    Carcinoid tumour metastatic to the orbit with infiltration to the extraocular orbital muscle.2005In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 113, no 2, p. 135-9Article in journal (Refereed)
    Abstract [en]

    Ninety-three percent of symptomatic patients with small intestinal carcinoid tumours have metastases. The most common sites of metastases are lymph nodes and liver. Orbital metastases have rarely been described and the majority of them involve the choroid rather than extraocular orbital structures. We report a patient who developed proptosis, impairment of vision and reduced ocular motility on the left side, eighteen months after operation for primary intestinal carcinoid tumour with hepatic metastases. CT and MR studies revealed the tumour mass infiltrating the inferior rectus muscle. Biopsy examined by imprint and frozen section showed tumour consistent with metastatic carcinoid. The tumour was removed. HE and staining for cytokeratin, chromogranin, NSE, serotonin, somatostatin and gastrin showed that the tumour tissue corresponded to that of the primary intestinal carcinoid tumour. Intramuscular orbital metastasis from a carcinoid tumour is a rare occurrence. Diagnosis may be difficult, especially where no evidence of primary carcinoid tumour is present. Metastatic orbital carcinoid should be suspected in patients with a clinical history of carcinoid tumour and who develop ocular complaints and mass lesion in the orbit. Complete surgical removal of the tumour is important for optimal restitution of vision and eye movements.

  • 7.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Heck, A.
    Schulz, S.
    Nesland, J. M.
    Bollerslev, J.
    Expression of SSTR2a, but not of SSTRs 1, 3 or 5 in somatotroph adenomas assessed by monoclonal antibodies was reduced by octreotide and correlated with the acute and long-term effects of octreotide2014In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, no S1, p. 90-90Article in journal (Other academic)
  • 8.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Heck, Ansgar
    Schulz, Stefan
    Nesland, Jahn Marthin
    Ramm-Pettersen, Jon
    Lekva, Tove
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bollerslev, Jens
    Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 11, p. E1730-E1739Article in journal (Refereed)
    Abstract [en]

    Context: Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. Objective: We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. Design, Setting, Patients: The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. Intervention: Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). Main Outcome Measure: SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. Results: The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2 a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. Conclusion: Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.

  • 9.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jacobsen, Eva Astrid
    Scheie, David
    Bilateral atypical choroid plexus papillomas in cerebellopontine angles mimicking neurofibromatosis 2.2006In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 111, no 5, p. 500-2Article in journal (Refereed)
  • 10.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jacobsson, J.
    Libelius, R.
    Moslemi, A. R.
    Hedberg, C.
    Oldfors, A.
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with unusual clinical presentation and necklace fibres2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 843-843Article in journal (Other academic)
    Abstract [en]

    Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy are morphologic features of centronuclear myopathy (CNM) related to dynamin-2 (DNM2) gene defects, whereas necklace fibres characterise late-onset myopathy associated with myotubularin-1 (MTM1) gene defects. We report a 40-year-old woman with 1-year history of pain and paresthesia in the left shoulder and arm that was clinically interpreted as brachial plexus neuritis. Electromyography revealed both myopathic and neuropathic abnormalities, and because of the myopathic changes a muscle biopsy was performed. The typical morphologic features of dynamin-2 CNM with additional numerous necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a not previously described heterozygous missense mutation in exon 18 of DNM2 leading to replacement of highly conserved Proline in position 647 by Arginine. The muscle symptoms have not progressed during the two-year follow-up, but the patient has developed bilateral subtle lens opacities. Necklace fibres were originally described as fibres that had usually a small diameter and internalized nuclei aligned in a basophilic ring at a few micrometers beneath the sarcolemma. They were described in association with myopathies caused by MTM1 mutations, and similar but not identical fibres have also been reported in a case of DNM2 associated CNM. Our findings support the concept that necklace fibres are not specific but indicate common pathogenic mechanisms in DNM2 and MTM1 associated CNM. This case report expands the clinical, morphological and molecular genetic variability of DNM2 associated CNM.

  • 11.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Jacobsson, Johan
    Libelius, Rolf
    Oldfors, Carola Hedberg
    Malfatti, Edoardo
    Romero, Norma Beatriz
    Oldfors, Anders
    A novel dynamin-2 gene mutation associated with a late-onset centronuclear myopathy with necklace fibres2015In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 25, no 4, p. 345-348Article in journal (Refereed)
    Abstract [en]

    Nuclear centralisation and internalisation, sarcoplasmic radiating strands and type 1 muscle fibre predominance and hypotrophy characterise dynamin-2 (DNM2) associated centronuclear myopathy, whereas necklace fibres are typically seen in late onset myotubularin-1 (MTM1)-related myopathy.

    We report a woman with unilateral symptoms probably related to brachial plexus neuritis. Electromyography revealed localised neuropathic and generalised myopathic abnormalities. The typical features of DNM2 centronuclear myopathy with additional necklace fibres were found in the muscle biopsy. Sequencing of the DNM2 and MTM1 genes revealed a novel heterozygous missense mutation in exon 18 of the DNM2, leading to replacement of highly conserved proline at position 647 by arginine. The muscle symptoms have not progressed during the 3-year follow-up. However, the patient has developed bilateral subtle lens opacities.

    Our findings support the concept that necklace fibres may occasionally be found in DNM2-related myopathy, possibly indicating a common pathogenic mechanism in DNM2 and MTM1 associated centronuclear myopathy.

  • 12.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Oslo Univ Hosp, Dept Pathol, Sognsvannsveien 20, N-0372 Oslo, Norway..
    Oystese, Kristin Astrid Berland
    Oslo Univ Hosp, Dept Specialised Endocrinol, Sognsvannsveien 20, N-0372 Oslo, Norway.;Univ Oslo, Fac Med, Klaus Torgardsvei 3, N-0372 Oslo, Norway..
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Melchior, Linea
    Copenhagen Univ Hosp, Rigshosp, Dept Pathol, Frederik Vs Vei 11, DK-2100 Copenhagen, Denmark..
    Popovic, Vera
    Univ Belgrade, Fac Med, Dr Subotica 8, Belgrade 11000, Serbia..
    A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas2016In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 19, no 4, p. 407-414Article in journal (Refereed)
    Abstract [en]

    Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas. We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses. In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses. IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.

  • 13.
    Casar-Borota, Olivera
    et al.
    Oslo University.
    Scheie, D
    Bjerkhagen, B
    Jacobsen, E A
    Skullerud, K
    Gliosarcoma with liposarcomatous component, bone infiltration and extracranial growth.2006In: Clinical Neuropathology, ISSN 0722-5091, Vol. 25, no 4, p. 200-3Article in journal (Refereed)
    Abstract [en]

    Gliosarcoma is a highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. The latter typically resembles fibrosarcoma, but differentiation patterns resembling osteosarcoma, chondrosarcoma, angiosarcoma and rhabdomyosarcoma have also been described. Molecular-genetic studies have shown that both glioblastoma and the mesenchymal component share identical cytogenetic abnormalities or mutations, suggesting a monoclonal origin from glial cells. We report an unusual case of gliosarcoma that presented as a large intracerebral tumor with infiltration of the temporal bone and the soft tissues in the infratemporal fossa. Microscopically, the tumor consisted of alternating areas of glioblastoma and fibrosarcoma. Focally, areas ofosteosarcomatous and liposarcomatous differentiation were found. Although gliosarcoma with transcranial penetration is very rare, it should be suspected in case of intracranial tumor with glioblastoma-imaging features, infiltration of bone and extracranial growth. Our case of liposarcomatous differentiation in gliosarcoma--together with another very recently reported similar case--expands the morphologic heterogeneity of this peculiar brain tumor.

  • 14.
    Casar-Borota, Olivera
    et al.
    Olivera Casar-Borotas publikationer.
    Scheithauer, B W
    Fougner, S Lyngvi
    Hald, J K
    Ramm-Pettersen, J
    Bollerslev, J
    Spindle cell oncocytoma of the adenohypophysis: report of a case with marked cellular atypia and recurrence despite adjuvant treatment.2009In: Clinical Neuropathology, ISSN 0722-5091, Vol. 28, no 2, p. 91-95Article in journal (Refereed)
    Abstract [en]

    Spindle cell oncocytoma (SCO) of the adenohypophysis is a recently defined pituitary tumor mimicking a non-functioning macroadenoma and composed of mitochondrion rich tumor cells, positive for S-100, vimentin, epithelial membrane antigen and galectin-3 but lacking cytokeratins, pituitary hormones, and neuroendocrine markers. Derivation from pituitary folliculostellate cells (FSCs) has been suggested based upon immunohistochemical and ultrastructural characteristics shared by SCO and FSCs. 10 cases of SCO have been reported to date; of these, 8 underwent a benign clinical course and 2 recurred. We report a case of SCO with typical histologic and immunohistochemical features in addition to marked cellular pleomorphism and nuclear atypia. It showed slow regrowth over a 30-month period of follow-up despite combined surgical and radiotherapy. Despite the benign course of most reported cases, additional experience with longer follow-up are needed to assess clinical, histopathologic, and proliferative indices and their relevance to optimal therapy for this rare pituitary tumor.

  • 15.
    Ehrstedt, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Canto Moreira, Nuno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Ahlsten, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Glioneuronal tumors in childhood - Before and after surgery. A long-term follow-up study2017In: Epilepsy & Behavior, ISSN 1525-5050, E-ISSN 1525-5069, Vol. 72, p. 82-88Article in journal (Refereed)
    Abstract [en]

    Aim: To give a detailed description of the long-term outcome of a cohort of children with glioneuronal tumors regarding pre-and postsurgical factors, including "dual" and "double" pathology, seizure freedom, and psychosocial outcome.

    Methods: During a fifteen-year period (1995-2009), all patients (age 0-17.99 years) with a glioneuronal brain tumor diagnosed and treated at Uppsala University Children's Hospital were identified from the National Brain Tumor Registry and the National Epilepsy Surgery Registry. Hospital medical records were reviewed and neuroradiological and neuropathological findings were re-evaluated. A cross-sectional long-term follow-up prospective evaluation, including an interview, neurologic examination, and electroencephalogram, was accomplished in patients accepting participants in the study.

    Results: A total of 25 out of 28 (89%) eligible patientswere included. The M: F ratiowas 1.5: 1. Mean follow-up time after surgery was 12.1 years (range 5.0-19.3). Twenty patients were adults (N18 years) at follow-up. Seizure freedomwas achieved in 64%. Gross total resection (GTR) was the only preoperative factor significantly correlating to seizure freedom (p= 0.027). Thirty-eight percent were at some time postoperatively admitted for a psychiatric evaluation. There was a trend towards both higher educational level and employment status in adults who became seizure free.

    Conclusion: Long-termoutcome is good regarding seizure freedom if GTR can be achieved, but late seizure recurrence can occur. "Dual" and "double" pathology is uncommon and does not influence seizure outcome. Obtaining seizure freedomseems to be important for psychosocial outcome, but there is a risk for psychiatric comorbidities and long-term follow-up by a multi-professional team is advisable.

  • 16.
    Ehrstedt, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kristiansen, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Ahlsten, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dahl, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours2016In: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 20, no 4, p. 580-587Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate clinical characteristics and late effects of CNS tumours in childhood with a special focus on low-grade tumours, especially low-grade astrocytoma and glib neuronal tumours. Methods: A retrospective population based study was performed at Uppsala University Children's Hospital, a tertiary referral centre for children with CNS tumours. Patients were identified from the National Brain Tumour Registry and the National Epilepsy Surgery Registry. Hospital medical records were analysed for patients with a follow up of >= 5 years after diagnosis. A re-evaluation of the neuro-pathological diagnosis was performed. Results: A total of 193 patients (age 0-17.99 years) during a twelve-year period (1995-2006) were included; 149 survived >= 5 years. Three larger subgroups could be identified: astrocytic, embryonal and glioneuronal tumours. A supratentorial location was found in 52%. Medical late effects were mainly neurological and endocrinological, affecting 81% and 26% of surviving patients. Cognitive late effects were a frequent finding in the whole group but also in low-grade astrocytoma and glioneuronal tumours (53% and 67%). Thirty per cent had some kind of pedagogic support in school. Conclusion: Late effects are common in long-term survivors of CNS tumours in childhood. Low-grade astrocytoma and glioneuronal tumours are no exception, and the findings support the need for long-term follow up.

  • 17. Emblem, Kyrre E
    et al.
    Nedregaard, Baard
    Nome, Terje
    Due-Tonnessen, Paulina
    Hald, John K
    Scheie, David
    Casar-Borota, Olivera
    Olivera Casar-Borotas publikationer.
    Cvancarova, Milada
    Bjornerud, Atle
    Glioma grading by using histogram analysis of blood volume heterogeneity from MR-derived cerebral blood volume maps.2008In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 247, no 3, p. 808-17Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To retrospectively compare the diagnostic accuracy of an alternative method used to grade gliomas that is based on histogram analysis of normalized cerebral blood volume (CBV) values from the entire tumor volume (obtained with the histogram method) with that of the hot-spot method, with histologic analysis as the reference standard.

    MATERIALS AND METHODS: The medical ethics committee approved this study, and all patients provided informed consent. Fifty-three patients (24 female, 29 male; mean age, 48 years; age range, 14-76 years) with histologically confirmed gliomas were examined with dynamic contrast material-enhanced 1.5-T magnetic resonance (MR) imaging. CBV maps were created and normalized to unaffected white matter (normalized CBV maps). Four neuroradiologists independently measured the distribution of whole-tumor normalized CBVs and analyzed this distribution by classifying the values into area-normalized bins. Glioma grading was performed by assessing the normalized peak height of the histogram distributions. Logistic regression analysis and interobserver agreement were used to compare the proposed method with a hot-spot method in which only the maximum normalized CBV was used.

    RESULTS: For the histogram method, diagnostic accuracy was independent of the observer. Interobserver agreement was almost perfect for the histogram method (kappa = 0.923) and moderate for the hot-spot method (kappa = 0.559). For all observers, sensitivity was higher with the histogram method (90%) than with the hot-spot method (55%-76%).

    CONCLUSION: Glioma grading based on histogram analysis of normalized CBV heterogeneity is an alternative to the established hot-spot method, as it offers increased diagnostic accuracy and interobserver agreement.

  • 18. Evang, J Arild
    et al.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Dept. of laboratory medicine/pathology Umeå university hospital.
    Melum, Espen
    Holm, Ruth
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Berg, Jens P
    HDAC2 expression and variable number of repeats in exon 1 of the HDAC2 gene in corticotroph adenomas2010In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, no 2, p. 229-235Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Alterations in protein expression of histone deacetylase 2 (HDAC2) have been demonstrated in various neoplasms, and lack of nuclear expression of HDAC2 has previously been shown in some human and canine corticotroph adenomas. This study aimed to examine HDAC2 expression in a Norwegian cohort of corticotroph adenomas, screen for exonic HDAC2 gene variants in the adenomas and correlate the results with clinical data.

    PATIENTS AND DESIGN: Forty-four patients with verified Cushing's disease or Nelson's syndrome, positive ACTH staining and tissue available for immunohistochemistry and/or DNA sequencing were included. Ninety-four controls were chosen from the Norwegian Bone Marrow Registry.

    RESULTS: Histone deacetylase 2 expression examined by immunohistochemistry was strongly reduced in 3/30 adenomas. There were no association between HDAC2 expression and clinical variables. A previously unidentified insertion of three bases in a region coding for a polyserine cluster in exon 1 of the HDAC2 gene was identified in 6/32 adenomas. No other mutations in HDAC2 exons were found. Examination of DNA extracted from peripheral blood confirmed germ-line origin of the exon 1 insertion. The same insertion was also found in 28/94 of the controls (i.e., not significantly different from the patients).

    CONCLUSIONS: Strongly reduced HDAC2 protein expression was confirmed in a small portion of corticotroph tumours. Mutations in HDAC2 exons are unlikely to play an important role in the development of corticotroph adenomas.

  • 19. Evang, Johan Arild
    et al.
    Berg, Jens Petter
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lekva, Tove
    Kringen, Marianne Kristiansen
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours2011In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 75, no 6, p. 811-818Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Loss of E-cadherin is an important marker of epithelial tumour progression. The aims of this study were to explore whether E-cadherin expression and localization correlate to corticotroph tumour progression, relate the expression of the E-cadherin gene (CDH1) to immunohistochemical E-cadherin staining pattern, and study whether the E-cadherin levels were correlated to methylation status of the CDH1 promoter region.

    DESIGN:

    Immunohistochemical analyses of E-cadherin protein were performed, as was RT-qPCR of the CDH1 and the POMC genes. Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA.

    PATIENTS:

    Forty-five patients operated at a tertiary referral centre in Oslo, Norway. Adenoma tissue sections and RNA samples from patients with verified Cushing's disease or Nelson's syndrome were collected.

    MEASUREMENTS:

    Expression of E-cadherin mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter.

    RESULTS:

    Correlations were observed between tumour progression and both nuclear expression of E-cadherin and reduced CDH1 mRNA. The E-cadherin expression was not determined by the methylation pattern of the CDH1 promoter.

    CONCLUSIONS:

    Corticotroph tumour progression was associated with reduced expression of the epithelial marker E-cadherin.

  • 20. Evang, Johan Arild
    et al.
    Bollerslev, Jens
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lekva, Tove
    Ramm-Pettersen, Jon
    Berg, Jens Petter
    Different levels of various glucocorticoid-regulated genes in corticotroph adenomas2013In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 44, no 1, p. 220-227Article in journal (Refereed)
    Abstract [en]

    Recently, correlations between corticotroph tumor dedifferentiation and both E-cadherin immunostaining and reduced mRNA expression of the E-cadherin gene (CDH1) have been demonstrated. The purpose of this study was to explore whether tumor dedifferentiation correlated with glucocorticoid resistance and whether the resistance was associated with both positively and negatively regulated genes. Tumor material from 20 patients with verified Cushing's disease or Nelson's syndrome operated on at Rikshospitalet, Oslo. Reverse transcription polymerase chain reaction analysis of genes such as E-cadherin (CDH1), proopiomelanocortin (POMC), glucocorticoid-induced leucine zipper (GILZ), and thioredoxin-interacting protein (TXNIP) was performed. The correlations between the expression of the GILZ, TXNIP, and POMC genes in different stages of corticotroph adenomas, the E-cadherin mRNA expression and staining pattern, and the preoperative 24-h cortisol excretion were examined. The GILZ and TXNIP expression levels were positively correlated to the CDH1 expression and were highest in microadenomas and in tumors with a high membranous E-cadherin reactivity. In contrast, the POMC expression was not significantly different between the groups. This divergence between the genes that were positively and negatively regulated by glucocorticoids could not be supported by other gene expression analyses. No correlations to urinary cortisol were found. The expression of the glucocorticoid-responsive genes POMC, GILZ, and TXNIP in corticotroph adenomas showed a remarkable variation. The pattern and variability of glucocorticoid resistance in corticotroph adenomas seem to correlate with a loss of the epithelial phenotype associated with corticotroph tumor dedifferentiation.

  • 21.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Oldfors, Carola Hedberg
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Oldfors, Anders
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Tubular aggregates in congenital myasthenic syndrome2018In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, no 2, p. 174-175Article in journal (Other academic)
  • 22. Fougner, Stine L
    et al.
    Casar Borota, Olivera
    Oslo University.
    Berg, Jens Petter
    Hald, John K
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma.2008In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, no 3, p. 458-65Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G-protein alpha subunit (Gsalpha) mutation (gsp oncogene)-positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide.

    PATIENTS: Seventy-one patients were included. All underwent transsphenoidal surgery, 23 patients after preoperative octreotide treatment.

    MEASUREMENTS: The adenoma SSTR2a expression was examined by immunohistochemistry and Western blot analysis, and gsp status determined. An acute octreotide test was performed, and the change in IGF-1 level after 6 months preoperative octreotide treatment was recorded.

    RESULTS: The acute octreotide response in non-pretreated patients and the preoperative long-term octreotide response were significantly better in patients with adenomas containing a large proportion of cells that stained positively for SSTR2a by immunohistochemistry. However, the SSTR2a protein level assessed by Western blot did not correlate with the octreotide response. The preoperatively treated group had lower SSTR2a protein levels and fewer adenomas with a large percentage of positively stained cells. The gsp oncogene was detected in 43% of the adenomas but did not correlate to the octreotide response.

    CONCLUSION: The clinical effect of octreotide correlates with the proportion of cells positive for SSTR2a in immunohistochemical staining, rather than the adenoma SSTR2a protein level. There may be a down-regulation of SSTR2a during octreotide treatment.

  • 23. Fougner, Stine Lyngvi
    et al.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Heck, Ansgar
    Berg, Jens Petter
    Bollerslev, Jens
    Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 76, no 1, p. 96-102Article in journal (Refereed)
    Abstract [en]

    CONTEXT:

    Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas.

    OBJECTIVES:

    To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment.

    DESIGN/SETTINGS/PATIENTS:

    Seventy-eight patients with active acromegaly were included. Long-term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E-cadherin and SSTR2a. Protein levels of E-cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas.

    RESULTS:

    DG adenomas and the transitional group had higher serum levels of IGF-1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long-term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E-cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG.

    CONCLUSIONS:

    Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

  • 24. Heck, Ansgar
    et al.
    Emblem, Kyrre E
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bollerslev, Jens
    Ringstad, Geir
    Quantitative analyses of T2-weighted MRI as a potential marker for response to somatostatin analogs in newly diagnosed acromegaly2016In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 52, no 2, p. 333-343Article in journal (Refereed)
    Abstract [en]

    In growth hormone (GH)-producing adenomas, T2-weighted MRI signal intensity is a marker for granulation pattern and response to somatostatin analogs (SSA). Prediction of treatment response is necessary for individualized treatment, and T2 intensity assessment might improve preoperative classification of somatotropinomas. The objectives of this study are (I) to explore the feasibility of quantitative T2-weighted MRI histogram analyses in newly diagnosed somatotroph adenomas and their relation to clinical and histological parameters and (II) to compare the quantitative method to conventional, visual assessment of T2 intensity. The study was a retrospective cohort study of 58 newly diagnosed patients. In 34 of these, response to primary SSA treatment after median 6 months was evaluated. Parameters from the T2 histogram analyses (T2 intensity ratio and T2 homogeneity ratio) were correlated to visually assessed T2 intensity (hypo-, iso-, hyperintense), baseline characteristics, response to SSA treatment, and histological granulation pattern (anti-Cam5.2). T2 intensity ratio was lowest in the hypointense tumors and highest in the hyperintense tumors (0.66 ± 0.10 vs. 1.07 ± 0.11; p < 0.001). T2 intensity at baseline correlated with reduction in GH (r = -0.67; p < 0.001) and IGF-1 (r = -0.36; p = 0.037) after primary SSA treatment (n = 34). The T2 homogeneity ratio correlated with adenoma size reduction (r = -0.45; p = 0.008). Sparsely granulated adenomas had a higher T2 intensity than densely or intermediately granulated adenomas. T2 histogram analyses are an applicable tool to assess T2 intensity in somatotroph adenomas. Quantitatively assessed T2 intensity ratio in GH-producing adenomas correlates with conventional assessment of T2 intensity, baseline characteristics, response to SSA treatment, and histological granulation pattern.

  • 25. Heck, Ansgar
    et al.
    Emblem, Kyrre E
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ringstad, Geir
    Bollerslev, Jens
    MRI T2 characteristics in somatotroph adenomas following somatostatin analog treatment in acromegaly2016In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 53, no 1, p. 327-330Article in journal (Refereed)
  • 26. Heck, Ansgar
    et al.
    Ringstad, Geir
    Fougner, Stine L.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nome, Terje
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly2012In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 1, p. 72-78Article in journal (Refereed)
    Abstract [en]

    Background Primary, preoperative medical treatment is an option in selected patients with acromegaly, but a subset of patients respond poorly. Valid prediction of response to somatostatin analogues (SA) might thus alter treatment stratification. The aims of this study were to assess whether T2 signal intensity could determine long-term response to first-line SA treatment and to assess clinical and biochemical baseline characteristics, as well as histological subtype in relation to the magnetic resonance imaging (MRI) appearances. Methods In 45 newly diagnosed patients, T2-weighted signal intensity of the tumour was classified into hypo-, iso- or hyperintense. Biochemical and clinical baseline variables for the three groups were compared. In 25 patients primarily treated with long-acting SA for a median of 6 months [interquartile range (IQR):155180 days], GH and IGF-1 reduction was assessed, and in 34 cases, immunohistochemical granulation pattern was evaluated. Results The results showed that 12 (27%) adenomas were hypointense, 15 (33%) isointense and 18 (40%) hyperintense. Median IGF-1 [ratio IGF-1/ULN; (upper limit of normal)] was 3.5 (2.34.9), 2.9 (2.63.8) and 1.9 (1.32.6), respectively (P = 0.006 for difference between groups). Median GH values (mu g/l) of a 3- to 5-point profile were 17.5 (6.135), 9.3 (6.032.5) and 4.1 (1.58.3), (P = 0.025). Median IGF-1 reduction (% of baseline) after first-line SA treatment was 51 (4970), 36 (1974) and 13 (542) (P = 0.03); median reduction in GH (% of baseline) was 86 (7294), 78 (6285) and 46 (170) (P = 0.02). T2 hyperintensity was associated with sparse granulation pattern on immunohistochemistry. Conclusion In patients with acromegaly, T2 signal intensity at diagnosis correlates with histological features and predicts biochemical outcome of first-line SA treatment.

  • 27.
    Klar, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mäbert, Katrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Johansson, Anna C V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Entesarian, Miriam
    Örlén, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 4, p. 572-577Article in journal (Refereed)
    Abstract [en]

    Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM associated haplotype followed by whole exome sequencing. Within the conserved haplotype we identified a single heterozygous mutation c.1150G>A (p.E384K) in TIA1 in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7 and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared to controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1050 years, which coincides with the epoch of early seafaring across the Baltic Sea.

  • 28. Lekva, Tove
    et al.
    Berg, Jens Petter
    Lyle, Robert
    Heck, Ansgar
    Ringstad, Geir
    Olstad, Ole Kristoffer
    Michelsen, Annika Elisabet
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bollerslev, Jens
    Ueland, Thor
    Epithelial Splicing Regulator Protein 1 and Alternative Splicing in Somatotroph Adenomas2013In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 154, no 9, p. 3331-3343Article in journal (Refereed)
    Abstract [en]

    Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.

  • 29.
    Manojlovic-Gacic, Emilija
    et al.
    Univ Belgrade, Inst Pathol, Sch Med, Belgrade, Serbia.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Histopathological classification of non-functioning pituitary neuroendocrine tumors2018In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 21, no 2, p. 119-129Article, review/survey (Refereed)
    Abstract [en]

    Non-functioning pituitary neuroendocrine tumors do not cause endocrine symptoms related to hypersecretion of adenohypophyseal hormones and are clinically characterized by symptoms due to growing sellar tumor mass. Histopathological classification of this tumor group has always been challenging due to their heterogeneity, limited knowledge on their biology, and diverse methodological problems. We have searched PubMed database for data related to the histopathological classification of non-functioning pituitary tumors and methods for its application. Principles of the classification and grading presented in the recently released 4th edition of the World Health Organization classification of endocrine tumors have been summarized. Based on the expression of anterior pituitary hormones and pituitary specific transcription factors, gonadotroph tumors dominate within the group of clinically non-functioning tumors, followed by corticotroph type; however, other less common types of the non-functioning tumors can be identified. Assessment of tumor cell proliferation is important to identify "high-risk adenomas." A few subtypes of non-functioning tumors belong to the category of potentially aggressive tumors, independent of the cell proliferation rate. Here, we present up to date criteria for the classification of clinically non-functioning pituitary tumors, offer a diagnostic approach for the routine clinical use, and emphasize a need for inclusion of prognostic and predictive markers in the classification.

  • 30. Manojlovic-Gacic, Emilija
    et al.
    Skender-Gazibara, Milica
    Popovic, Vera
    Soldatovic, Ivan
    Boricic, Novica
    Raicevic, Savo
    Pekic, Sandra
    Doknic, Mirjana
    Miljic, Dragana
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Oncogene-Induced Senescence in Pituitary Adenomas-an Immunohistochemical Study.2016In: Endocrine pathology, ISSN 1046-3976, E-ISSN 1559-0097, Vol. 27, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal β-galactosidase (SA-β-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-β-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-β-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-β-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

  • 31.
    Marina, Djordje
    et al.
    Copenhagen Univ Hosp, Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark..
    Burman, Pia
    Skanes Univ Hosp, Dept Endocrinol, Malmo, Sweden..
    Klose, Marianne
    Copenhagen Univ Hosp, Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark..
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Luque, Raul M.
    Univ Cordoba, Hosp Univ Reina Sofia, Inst Maimonides Invest Biomed Cordoba IMIBIC, Dept Cell Biol Physiol & Immunol, Cordoba 14014, Spain.;CIBER Fisiopatol Obesidad & Nutr CIBERobn, Cordoba 14014, Spain..
    Castano, Justo P.
    Univ Cordoba, Hosp Univ Reina Sofia, Inst Maimonides Invest Biomed Cordoba IMIBIC, Dept Cell Biol Physiol & Immunol, Cordoba 14014, Spain.;CIBER Fisiopatol Obesidad & Nutr CIBERobn, Cordoba 14014, Spain..
    Feldt-Rasmussen, Ulla
    Copenhagen Univ Hosp, Rigshosp, Dept Med Endocrinol, Copenhagen, Denmark..
    Truncated somatostatin receptor 5 may modulate therapy response to somatostatin analogues - Observations in two patients with acromegaly and severe headache2015In: Growth Hormone & IGF Research, ISSN 1096-6374, E-ISSN 1532-2238, Vol. 25, no 5, p. 262-267Article in journal (Refereed)
    Abstract [en]

    Background: Somatotropinomas have unique "fingerprints" of somatostatin receptor (sst) expression, which are targets in treatment of acromegaly with somatostatin analogues (SSAs). However, a significant expression of sst is not always related to the biochemical response to SSAs. Headache is a common complaint in acromegaly and considered a clinical marker of disease activity. SSAs are reported to have an own analgesic effect, but the sst involved are unknown. Patients and methods: We investigated sst expression in two acromegalic patients with severe headache and no biochemical effects of octreotide, but a good response to pasireotide. We searched the literature for determinants of biochemical and analgesic effects of SSAs in somatotropinomas. Results: Case 1 had no biochemical or analgesic effects of octreotide, a semi-selective SSA, but a rapid and significant effect of pasireotide, a pan-SSA Case 2 demonstrated discordance between analgesic and biochemical effects of octreotide, in that headache disappeared, but without biochemical improvement. In contrast, pasireotide normalized insulin-like growth factor 1. Both adenomas were sparsely granulated and had strong membranous expressions of sst2a in 50-75% and sst5 in 75-100% of tumor cells. The truncated sst5 variant TMD4 (sst5TMD4) showed expression in 20-57% of tumor cells. Conclusions: A poor biochemical response to octreotide may be associated with tumor expression of a truncated sst5 variant, despite abundant sst2a expression, suggesting an influence from variant sst5 on common sst signaling pathways. Furthermore, unrelated analgesic and biochemical effects of SSAs supported a complex pathogenesis of acromegaly-associated headache. Finally, assessment of truncated sst5 in addition to full length sst could be important for a choice of postoperative SSA treatment in somatotropinomas.

  • 32.
    Oystese, Kristin Astrid
    et al.
    Oslo Univ Hosp, Sect Specialized Endocrinol, Dept Endocrinol, Rikshosp, Pb 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Fac Med, N-0316 Oslo, Norway.;OUS Rikshosp, Res Inst Internal Med, N-0424 Oslo, Norway..
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Oslo Univ Hosp, Dept Pathol, N-0372 Oslo, Norway..
    Normann, Kjersti Ringvoll
    Univ Oslo, Inst Clin Med, Fac Med, N-0316 Oslo, Norway.;OUS Rikshosp, Res Inst Internal Med, N-0424 Oslo, Norway..
    Zucknick, Manuela
    Univ Oslo, Dept Biostat, Oslo Ctr Biostat & Epidemiol, Inst Basic Med Sci, N-0317 Oslo, Norway..
    Berg, Jens Petter
    Univ Oslo, Inst Clin Med, Fac Med, N-0316 Oslo, Norway.;Oslo Univ Hosp, Dept Med Biochem, N-0424 Oslo, Norway..
    Bollerslev, Jens
    Oslo Univ Hosp, Sect Specialized Endocrinol, Dept Endocrinol, Rikshosp, Pb 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Inst Clin Med, Fac Med, N-0316 Oslo, Norway..
    Estrogen Receptor alpha, a Sex-Dependent Predictor of Aggressiveness in Nonfunctioning Pituitary Adenomas: SSTR and Sex Hormone Receptor Distribution in NFPA2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 9, p. 3581-3590Article in journal (Refereed)
    Abstract [en]

    Context: Nonfunctioning pituitary adenomas (NFPAs) are fairly common and require a multidisciplinary approach. Reliable markers of a clinically aggressive course are lacking. Medical treatment is not available, and transsphenoidal surgery is the preferred primary treatment. Objective: We aimed to characterize the somatostatin, estrogen, and progesterone receptor distribution for NFPAs and compare it with factors of tumor aggressiveness. Design: Tumor samples for immunohistochemistry (n = 145) and quantitative reverse transcription polymerase chain reaction (n = 106) analyses of somatostatin receptor (SSTR) 1, SSTR2, SSTR3, SSTR5, estrogen receptor alpha (ER alpha), and progesterone receptor (PR) were measured by immunoreactive score (IRS) andmessenger RNA relative quantity and retrospectively compared with variables of aggressiveness. Setting: All patients were operated at the same tertiary referral center. Participants: A total of 164 patients with NFPA and tumor tissue from the primary operation were included. Results: SSTR3 was expressed abundantly by immunohistochemistry in all NFPAs. The IRS of ER alpha correlated with that of SSTR2 in male patients only (males, P<0.001; females, P = 0.8). Low ER alpha level was linked to a higher reintervention rate (P = 0.001) and earlier reintervention (P = 0.004) in male patients only (females, P = 0.95 and P = 0.65, respectively). Absence of ER alpha together with age provided a good prediction model for reintervention in male patients with gonadotroph adenomas. Conclusions: SSTR3 is expressed abundantly in NFPAs and is therefore a possible target for medical treatment. Absence of ER alpha together with young age may predict tumor recurrence in groups of NFPAs. Further validation in systematic prospective studies is needed.

  • 33.
    Oystese, Kristin Astrid
    et al.
    Natl Hosp Norway, Sect Specialized Endocrinol, Dept Endocrinol, Oslo Univ Hosp, Pb 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Zucknick, Manuela
    Univ Oslo, Inst Basic Med Sci, Dept Biostat, Oslo Ctr Biostat & Epidemiol, Oslo, Norway..
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Oslo Univ Hosp, Dept Pathol, Sognsvannsveien 20, N-0372 Oslo, Norway..
    Ringstad, Geir
    Univ Oslo, Fac Med, Oslo, Norway.;Natl Hosp Norway, Dept Radiol & Nucl Med, Oslo Univ Hosp, Oslo, Norway..
    Bollerslev, Jens
    Natl Hosp Norway, Sect Specialized Endocrinol, Dept Endocrinol, Oslo Univ Hosp, Pb 4950 Nydalen, N-0424 Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Early postoperative growth in non-functioning pituitary adenomas: A tool to tailor safe follow-up2017In: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 57, no 1, p. 35-45Article in journal (Refereed)
    Abstract [en]

    Non-functioning pituitary adenomas are common, and the treatment and follow-up of these patients represent a multidisciplinary challenge. First line treatment is transphenoidal surgery, with debulking or total removal of tumour. A substantial portion of the tumours relapse after surgery, and there is no consensus of how to follow these patients postoperatively. Our aim was to characterize the postoperative growth of non-functioning pituitary adenomas and correlate it to clinical and paraclinical data.

    We retrospectively registered 52 patients operated for non-functioning pituitary adenomas, with four or more consecutive MR-investigations not interrupted by secondary treatment. Adenoma volumes were estimated by the Cavalieri principle with summation of manually drawn areas multiplied by slice interval. Growth curves were modelled and tumour volume doubling time was calculated for 39 tumours with regrowth after surgery.

    A total of 13 tumours showed exponential growth, 10 linear growth and 16 logistic growth after surgery. The remaining 13 did not show regrowth of tumour. Seven of the exponential growing tumours underwent secondary surgery, compared to one and two of linear and logistic growing tumours (p = 0.03), respectively. Initial tumour volume doubling time was significantly lower in logistic growing tumours than in exponential growing tumours (p < 0.01). Men had tumours with lower tumour volume doubling time than women (p = 0.03). None of the tumours demonstrated signs of accelerated growth.

    Residual tumours following surgery frequently grow. The logistic growing tumours had the fastest initial growth in our cohort. We found no indication of accelerated growth, whereby the tumour volume doubling time might be used to predict a "worst-case" scenario when planning follow-up of these patients.

  • 34.
    Rostami, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nyström, Petra Witt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Skandionkliniken, Uppsala, Sweden.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Gudjonsson, Olafur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.2017In: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, no 11, p. 2217-2221Article in journal (Refereed)
    Abstract [en]

    Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

  • 35.
    Sjöstedt, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Bollerslev, Jens
    Oslo Univ Hosp, Rikshosp, Dept Specialized Endocrinol, Oslo, Norway.; Univ Oslo, Fac Med, Oslo, Norway.
    Mulder, Jan
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 4, p. 675-677Article in journal (Other academic)
  • 36.
    Wilbe, Maria
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eurenius, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ericson, Katharina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Casar-Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Annerén, Göran
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    MuSK: a new target for lethal fetal akinesia deformation sequence (FADS).2015In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 52, no 3, p. 195-202Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fetal akinesia deformation sequence syndrome (FADS, OMIM 208150) is characterised by decreased fetal movement (fetal akinesia) as well as intrauterine growth restriction, arthrogryposis, and developmental anomalies (eg, cystic hygroma, pulmonary hypoplasia, cleft palate, and cryptorchidism). Mutations in components of the acetylcholine receptor (AChR) pathway have previously been associated with FADS.

    METHODS AND RESULTS: We report on a family with recurrent fetal loss, where the parents had five affected fetuses/children with FADS and one healthy child. The fetuses displayed no fetal movements from the gestational age of 17 weeks, extended knee joints, flexed hips and elbows, and clenched hands. Whole exome sequencing of one affected fetus and the parents was performed. A novel homozygous frameshift mutation was identified in muscle, skeletal receptor tyrosine kinase (MuSK), c.40dupA, which segregated with FADS in the family. Haplotype analysis revealed a conserved haplotype block suggesting a founder mutation. MuSK (muscle-specific tyrosine kinase receptor), a component of the AChR pathway, is a main regulator of neuromuscular junction formation and maintenance. Missense mutations in MuSK have previously been reported to cause congenital myasthenic syndrome (CMS) associated with AChR deficiency.

    CONCLUSIONS: To our knowledge, this is the first report showing that a mutation in MuSK is associated with FADS. The results support previous findings that CMS and/or FADS are caused by complete or severe functional disruption of components located in the AChR pathway. We propose that whereas milder mutations of MuSK will cause a CMS phenotype, a complete loss is lethal and will cause FADS.

1 - 36 of 36
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