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  • 1.
    Backman, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Cupisti, Kenko
    Marien Hosp, Dept Surg, Euskirchen, Germany..
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 44943Article in journal (Refereed)
    Abstract [en]

    Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.

  • 2.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Delgado Verdugo, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours2014In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 13, no 1, p. 121-125Article in journal (Refereed)
    Abstract [en]

    Pheochromocytoma (PCC) and Paraganglioma are rare tumours originating from neuroendocrine cells. Up to 60 % of cases have either germline or somatic mutation in one of eleven described susceptibility loci, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127 and MYC associated factor-X (MAX). Recently, germline mutations in MAX were found to confer susceptibility to PCC and paraganglioma (PGL). A subsequent multicentre study found about 1 % of PCCs and PGLs to have germline or somatic mutations in MAX. However, there has been no study investigating the frequency of MAX mutations in a Scandinavian cohort. We analysed tumour specimens from 63 patients with PCC and PGL treated at Uppsala University hospital, Sweden, for re-sequencing of MAX using automated Sanger sequencing. Our results show that 0 % (0/63) of tumours had mutations in MAX. Allele frequencies of known single nucleotide polymorphisms rs4902359, rs45440292, rs1957948 and rs1957949 corresponded to those available in the Single Nucleotide Polymorphism Database. We conclude that MAX mutations remain unusual events and targeted genetic screening should be considered after more common genetic events have been excluded.

  • 3.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Verdugo, Alberto Delgado
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma2013In: Endocrine connections, ISSN 2049-3614, Vol. 2, no 2, p. 104-111Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Recent findings have shown that up to 60% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are caused by germline or somatic mutations in one of the 11 hitherto known susceptibility genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A (EPAS1), RET, NF1, TMEM127 and MAX. This list of genes is constantly growing and the 11 genes together consist of 144 exons. A genetic screening test is extensively time consuming and expensive. Hence, we introduce next-generation sequencing (NGS) as a time-efficient and cost-effective alternative.

    METHODS:

    Tumour lesions from three patients with apparently sporadic PCC were subjected to whole exome sequencing utilizing Agilent Sureselect target enrichment system and Illumina Hi seq platform. Bioinformatics analysis was performed in-house using commercially available software. Variants in PCC and PGL susceptibility genes were identified.

    RESULTS:

    We have identified 16 unique genetic variants in PCC susceptibility loci in three different PCC, spending less than a 30-min hands-on, in-house time. Two patients had one unique variant each that was classified as probably and possibly pathogenic: NF1 Arg304Ter and RET Tyr791Phe. The RET variant was verified by Sanger sequencing.

    CONCLUSIONS:

    NGS can serve as a fast and cost-effective method in the clinical genetic screening of PCC. The bioinformatics analysis may be performed without expert skills. We identified process optimization, characterization of unknown variants and determination of additive effects of multiple variants as key issues to be addressed by future studies.

  • 4.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Verdugo, Alberto Delgado
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Stalberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Somatic Mutations in H-RAS in Sporadic Pheochromocytoma and Paraganglioma Identified by Exome Sequencing2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 7, p. E1266-E1271Article in journal (Refereed)
    Abstract [en]

    Context: Up to 60% of pheochromocytoma (PCC) and paraganglioma (PGL) are associated with either somatic or germline mutations in established PCC and PGL susceptibility loci. Most unexplained cases are characterized by an increased activity of the RAS/RAF/ERK signaling pathway. Mutations in RAS subtypes H, K, and N are common in human cancers; however, previous studies have been inconsistent regarding the mutational status of RAS in PCC and PGL. Objectives: The aim of this study was to identify novel disease causing genes in PCC and PGL tumors. Design, setting, and participants: Four benign and sporadic PCC and PGL tumors were subjected to whole exome sequencing using the Illumina HiSeq Platform. Sequences were processed by CLC genomics 4.9 bioinformatics software and the acquired list of genetic variants was filtered against the Catalogue of Somatic Mutations in Cancer database. Findings were validated in an additional 78 PCC and PGL tumor lesions. Results: Exome sequencing identified 2 cases with somatic mutations in the H-RAS. In total, 6.9% (n = 4/58) of tumors negative for mutations in major PCC and PGL loci had mutations in H-RAS: G13R, Q61K, and Q61R. There were 3 PCC and 1 PGL; all had sporadic presentation with benign tumor characteristics and substantial increases in norepinephrine and/or epinephrine. H-RAS tumors were exclusively found in male patients (P = .007). Conclusions: We identified recurrent somatic H-RAS mutations in pheochromocytoma and paraganglioma. Tumors with H-RAS mutations had activation of the RAS/RAF/ERK signaling pathway and were associated with male PCC patients having benign and sporadic disease characteristics. H-RAS could serve as a prognostic and predictive marker as well as a novel therapeutic target.

  • 5.
    Delgado, A. F.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden;Uppsala Univ, Dept Surg Sci, Uppsala, Sweden.
    De Luca, F.
    Univ G DAnnunzio, Sch Med & Hlth Sci, Fac Med & Surg, Chieti, Italy.
    Hanagandi, P.
    Karolinska Inst, Dept Neuroradiol, Stockholm, Sweden.
    van Westen, D.
    Lund Univ, Fac Med, Clin Sci, Lund, Sweden.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Arterial Spin-Labeling in Children with Brain Tumor: A Meta-Analysis2018In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 39, no 8, p. 1536-1542Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:The value of arterial spin-labeling in a pediatric population has not been assessed in a meta-analysis. PURPOSE:Our aim was to assess the diagnostic accuracy of arterial spin-labeling-derived cerebral blood flow to discriminate low- and high-grade tumors. DATA SOURCES:MEDLINE, EMBASE, the Web of Science Core Collection, and the Cochrane Library were used. STUDY SELECTION:Pediatric patients with arterial spin-labeling MR imaging with verified neuropathologic diagnoses were included. DATA ANALYSIS:Relative CBF and absolute CBF and tumor grade were extracted, including sequence-specific information. Mean differences in CBF between low- and high-grade tumors were calculated. Study quality was assessed. DATA SYNTHESIS:Data were aggregated using the bivariate summary receiver operating characteristic curve model. Heterogeneity was explored with meta-regression and subgroup analyses. The study protocol was published at PROSPERO (CRD42017075055). Eight studies encompassing 286 pediatric patients were included. The mean differences in absolute CBF were 29.62 mL/min/100 g (95% CI, 10.43-48.82 mL/min/100 g), I-2 = 74, P = .002, and 1.34 mL/min/100 g (95% CI, 0.95-1.74 mL/min/100 g), P < .001, I-2 = 38 for relative CBF. Pooled sensitivity for relative CBF ranged from 0.75 to 0.90, and specificity, from 0.77 to 0.92 with an area under curve = 0.92. Meta-regression showed no moderating effect of sequence parameters TE, TR, acquisition time, or ROI method. LIMITATIONS:Included tumor types, analysis method, and original data varied among included studies. CONCLUSIONS:Arterial spin-labeling-derived CBF measures showed high diagnostic accuracy for discriminating low- and high-grade tumors in pediatric patients with brain tumors. The relative CBF showed less variation among studies than the absolute CBF.

  • 6.
    Delgado, Alberto Verdugo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Exome Sequencing and CNV Analysis on Chromosome 18 in Small Intestinal Neuroendocrine Tumors: Ruling Out a Suspect?2015In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 47, no 6, p. 452-455Article in journal (Refereed)
    Abstract [en]

    The genetic background in small intestinal neuroendocrine tumors is poorly understood, but several studies have revealed numerical imbalances. Loss of one copy of chromosome 18 is the most frequent genetic aberration in this tumor type, which indirectly suggests that a driver mutation may be present in the remaining allele. The aim of this study was to evaluate the mutation status on chromosome 18 in small intestinal neuroendocrine tumors. DNAs from 7 small intestinal neuroendocrine tumors were subjected to whole exome capture, followed by next generation sequencing and high resolution SNP array followed by copy number variation analysis. Exome capture sequencing generated an average coverage of 50.6-138.2. Only 19 genes were covered less than 8X. No tumor-specific somatic mutation was identified. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 small intestinal neuroendocrine tumors and a number of other aberrancies. Loss of chromosome 18 is the most frequent genetic aberration in small intestinal neuroendocrine tumors, but no evidence for eventual mutations in the remaining allele. This suggests involvement of other mechanisms than point mutations in small intestinal neuroendocrine tumors tumorigenesis.

  • 7.
    Delgado, Anna F.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Tomtebodavagen 18A,Plan 5, S-17177 Stockholm, Sweden..
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Discrimination between Glioma Grades II and III Using Dynamic Susceptibility Perfusion MRI: A Meta-Analysis2017In: American Journal of Neuroradiology, ISSN 0195-6108, E-ISSN 1936-959X, Vol. 38, no 7, p. 1348-1355Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: DSC perfusion has been evaluated in the discrimination between low-grade and high-grade glioma but the diagnostic potential to discriminate beween glioma grades II and III remains unclear.

    PURPOSE: Our aim was to evaluate the diagnostic accuracy of relative maximal CBV from DSC perfusion MR imaging to discriminate glioma grades II and III.

    DATA SOURCES: A systematic literature search was performed in PubMed/MEDLINE, Embase, Web of Science, and ClinicalTrials.gov.

    STUDY SELECTION: Eligible studies reported on patients evaluated with relative maximal CBV derived from DSC with a confirmed neuropathologic diagnosis of glioma World Health Organization grades II and III. Studies reporting on mean or individual patient data were considered for inclusion.

    DATA ANALYSIS: Data were analyzed by using inverse variance with the random-effects model and receiver operating characteristic curves describing optimal cutoffs and areas under the curve. Bivariate diagnostic random-effects meta-analysis was used to calculate diagnostic accuracy.

    DATA SYNTHESIS: Twenty-eight studies evaluating 727 individuals were included in the meta-analysis. Individual data were available from 10 studies comprising 190 individuals. The mean difference of relative maximal CBV between glioma grades II and III (n = 727) was 1.76 (95% CI, 1.27-2.24; P < .001). Individual patient data (n = 190) had an area under the curve of 0.77 for discriminating glioma grades II and III at an optimal cutoff of 2.02. When we analyzed astrocytomas separately, the area under the curve increased to 0.86 but decreased to 0.61 when we analyzed oligodendrogliomas.

    LIMITATIONS: A substantial heterogeneity was found among included studies.

    CONCLUSIONS: Glioma grade III had higher relative maximal CBV compared with glioma grade II. A high diagnostic accuracy was found for all patients and astrocytomas; however, the diagnostic accuracy was substantially reduced when discriminating oligodendroglioma grades II and III.

  • 8.
    Delgado, Anna Falk
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden; Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Discrimination between primary low-grade and high-grade glioma with 11C-methionine PET: a bivariate diagnostic test accuracy meta-analysis2018In: British Journal of Radiology, ISSN 0007-1285, E-ISSN 1748-880X, Vol. 91, no 1082, article id 20170426Article, review/survey (Refereed)
    Abstract [en]

    Objective: To perform a meta-analysis evaluating the diagnostic accuracy of 11C-methionine (MET) positron emission tomography (PET) to discriminate between primary low-grade glioma (LGG) and high-grade glioma (HGG).

    Methods: A systematic database search was performed by a librarian in relevant databases with the latest search on 07 November 2016. Hits were assessed for inclusion independently by two authors. Individual patient data on relative MET uptake was extracted on patients examined pre-operatively with MET PET and subsequent neuropathological diagnosis of astrocytoma or oligodendroglioma. Individual patient data were analysed for diagnostic accuracy using a bivariate diagnostic random-effects meta-analysis model with restricted maximum likelihood estimation method. Bivariate meta-regression and subgroup analyses assessed study heterogeneity and validity. This study is registered with PROSPERO, number CRD42016050747.

    Results: Out of 1828 hits, 13 studies comprising of 241 individuals were included in the quantitative and qualitative analysis. MET PET had an area under the bivariate summary receiver operating characteristics curve of 0.78 to discriminate between LGG and HGG and a summary sensitivity of 0.80 with 95% confidence interval (CI) (0.66–0.88) and a summary false positive rate of 0.28, 95% CI (0.19–0.38). Heterogeneity was described by; bias in patient inclusion, study quality, and ratio method. Optimal cutoff for relative MET uptake was 2.21.

    Conclusion: MET PET had a moderately high diagnostic accuracy for the discrimination between primary LGG and HGG.

    Advances in knowledge: MET PET can be used as a clinical tool for the non-invasive discrimination between LGG and HGG with a moderately high accuracy at cut-off 2.21.

  • 9.
    Delgado, Anna Falk
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Neuroctr R1, S-17176 Stockholm, Sweden..
    Nilsson, Markus
    Lund Univ, Dept Diagnost Radiol, Fac Med, Lund, Sweden..
    van Westen, Danielle
    Lund Univ, Dept Clin Sci, Fac Med, Lund, Sweden..
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Glioma Grade Discrimination with MR Diffusion Kurtosis Imaging: A Meta-Analysis of Diagnostic Accuracy2018In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 287, no 1, p. 119-127Article in journal (Refereed)
    Abstract [en]

    Purpose: To assess the diagnostic test accuracy and sources of heterogeneity for the discriminative potential of diffusion kurtosis imaging (DKI) to differentiate low-grade glioma (LGG) (World Health Organization [WHO] grade II) from high-grade glioma (HGG) (WHO grade III or IV).

    Materials and Methods: The Cochrane Library, Embase, Medline, and the Web of Science Core Collection were systematically searched by two librarians. Retrieved hits were screened for inclusion and were evaluated with the revised tool for quality assessment for diagnostic accuracy studies (commonly known as QUADAS-2) by two researchers. Statistical analysis comprised a random-effects model with associated heterogeneity analysis for mean differences in mean kurtosis (MK) in patients with LGG or HGG. A bivariate restricted maximum likelihood estimation method was used to describe the summary receiver operating characteristics curve and bivariate meta-regression.

    Results: Ten studies involving 430 patients were included. The mean difference in MK between LGG and HGG was 0.17 (95% confidence interval [CI]: 0.11, 0.22) with a z score equal to 5.86 (P<.001). The statistical heterogeneity was explained by glioma subtype, echo time, and the proportion of recurrent glioma versus primary glioma. The pooled area under the curve was 0.94 for discrimination of HGG from LGG, with 0.85 (95% CI: 0.74, 0.92) sensitivity and 0.92 (95% CI: 0.81, 0.96) specificity. Heterogeneity was driven by neuropathologic subtype and DKI technique.

    Conclusion: MK shows high diagnostic accuracy in the discrimination of LGG from HGG.

  • 10.
    Delgado Verdugo, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Genetic Aspects of Endocrine Tumorigenesis: A Hunt for the Endocrine Neoplasia Gene2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Endocrine tumors arise from endocrine glands. Most endocrine tumors are benign but malignant variants exist. Several endocrine neoplasms display loss of parts of chromosome 11 or 18, produce hormones and responds poorly to conventional chemotherapeutics. The multiple endocrine neoplasia syndromes are mainly confined to endocrine tumors. This opens the question if there exists a single or several endocrine tumor genes.

    The aim of the study was to describe genetic derangements in endocrine tumors.

    Paper I: Investigation of mutational status of SDHAF2 in parathyroid tumors. SDHAF2 is located in the proximity of 11q13, a region that frequently displays loss in parathyroid tumors. We established that mutations in SDHAF2 are infrequent in parathyroid tumors.

    Paper II: Study of SDHAF2 gene expression in a cohort of benign pheochromocytomas (PCC) (n=40) and malignant PCC (n=10). We discovered a subset of  benign PCC (28/40) and all malignant PCC (10/10) with significantly lower SDHAF2 expression. Benign PCC with low SDHAF2 expression and malignant tumors consistently expressing low levels of SDHAF2 were methylated in the promoter region. SDHAF2 expression was restored in vitro after treatment with 5- aza-2-deoxycytidine.

    Paper III: HumanMethylation27 array (Illumina) covering 27578 CpG sites spanning over 14495 genes were analyzed in a discovery cohort of 10 primary small neuroendocrine tumors (SI-NETs) with matched metastases. 2697 genes showed different methylation pattern between the primary tumor and its metastasis. We identified several hypermethylated genes in key regions. Unsupervised clustering of the tumors identified three distinct clusters, one with a highly malignant behavior.

    Paper IV: Loss of chromosome 18 is the most frequent genetic aberration in SI-NETs. DNA from SI-NETs were subjected to whole exome capture sequencing and high resolution SNP array. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 SI-NETs. No tumor-specific somatic mutation on chromosome 18 was identified which suggests involvement of other mechanisms than point mutations in SI-NET tumorigenesis.

    Paper V: The cost for diagnostic genetic screening of common susceptibility genes in PCC is expensive and labor intensive. Three PCC from three patients with no known family history were chosen for exome capture sequencing. We identified three variants in known candidate genes. We suggest that exome-capture sequencing is a quick and cost-effective tool.

    List of papers
    1. Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism
    Open this publication in new window or tab >>Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism
    Show others...
    2010 (English)In: Endocrine, ISSN 0969-711X, Vol. 38, no 3, p. 397-401Article in journal (Refereed) Published
    Abstract [en]

    To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors occurring in about 40% of sporadic tumors. Only 15-19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in parathyroid tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 parathyroid tumors but no tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in parathyroid tissue. However, somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic pHPT.

    Keywords
    Hyperparathyroidism, Parathyroid, Paraganglioma, Succinate dehydrogenase, SDHAF2
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-139273 (URN)10.1007/s12020-010-9399-0 (DOI)000284116000010 ()
    Available from: 2010-12-22 Created: 2010-12-22 Last updated: 2016-12-20Bibliographically approved
    2. Epigenetic inactivation of SDHAF2 is a frequent event in benign and malignant pheochromocytomas.
    Open this publication in new window or tab >>Epigenetic inactivation of SDHAF2 is a frequent event in benign and malignant pheochromocytomas.
    (English)Manuscript (preprint) (Other academic)
    National Category
    Clinical Medicine Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-224109 (URN)
    Available from: 2014-05-04 Created: 2014-05-04 Last updated: 2018-01-11
    3. Global DNA methylation patterns in small intestinal neuroendocrine tumors (SI-NETs)
    Open this publication in new window or tab >>Global DNA methylation patterns in small intestinal neuroendocrine tumors (SI-NETs)
    Show others...
    2014 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 1, p. L5-L7Article in journal (Refereed) Published
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are rare hormone producing tumors and are often diagnosed at advanced stage. The genetic and epigenetic background of SI-NETs are poorly understood, but several reports have indicated chromosomal losses at 18.21-qter and 11q22-q23. The aim of this study was to characterize CpG DNA methylation status of primary SI-NETs and the corresponding lymph node metastases. We used the commercially available HumanMethylation27 Beadchip array (Illumina), which covers 27578 CpG sites spanning over 14495 genes, and analyzed a discovery cohort of 10 primary SI-NETs with matched metastases. Messenger- mRNA, were determined for selected genes in a 47 tumors. In comparison to the primary tumors, the metastases showed 2697 statistically significant differentially genes. Metastases were generally less methylated than primary tumors. The relative mRNA expression level of the differentially methylated genes AXL, CRMP1, FGF5, and APOBEC3C largely reflected the methylation status. MAPK4, RUNX3, TP73, CCND1, CHFR, AHRR, and Rb1 known to be hypermethylated in other cancer types, displayed overall high methylation level (β-value ≥ 0.9). Methylation (β -value >0,7) at 18q21-qter and 11q22-q23 were detected in genes SETBP1, ELAC1, MBD1, MAPK4, TCEB3C and ARVC1, MMP8, BTG4, APOA1, FAM89B, HSPB1, respectively. Furthermore unsupervised clustering of the tumors identified three distinct clusters, one with a highly malignant behavior. Our data supports involvement of CpG DNA methylation in metastatic progression of SI-NETs and this could present a possibility to identify more aggressive tumors based on DNA methylation.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-212142 (URN)10.1530/ERC-13-0481 (DOI)000334279600002 ()24192231 (PubMedID)
    Available from: 2013-12-06 Created: 2013-12-06 Last updated: 2017-12-06
    4. Exome Sequencing reveal no recurrent mutations on chromosome 18 in small intestinal neuroendocrine tumors; Ruling out a suspect?
    Open this publication in new window or tab >>Exome Sequencing reveal no recurrent mutations on chromosome 18 in small intestinal neuroendocrine tumors; Ruling out a suspect?
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-224110 (URN)
    Available from: 2014-05-04 Created: 2014-05-04 Last updated: 2018-01-11
    5. Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma
    Open this publication in new window or tab >>Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma
    Show others...
    2013 (English)In: Endocrine connections, ISSN 2049-3614, Vol. 2, no 2, p. 104-111Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Recent findings have shown that up to 60% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are caused by germline or somatic mutations in one of the 11 hitherto known susceptibility genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A (EPAS1), RET, NF1, TMEM127 and MAX. This list of genes is constantly growing and the 11 genes together consist of 144 exons. A genetic screening test is extensively time consuming and expensive. Hence, we introduce next-generation sequencing (NGS) as a time-efficient and cost-effective alternative.

    METHODS:

    Tumour lesions from three patients with apparently sporadic PCC were subjected to whole exome sequencing utilizing Agilent Sureselect target enrichment system and Illumina Hi seq platform. Bioinformatics analysis was performed in-house using commercially available software. Variants in PCC and PGL susceptibility genes were identified.

    RESULTS:

    We have identified 16 unique genetic variants in PCC susceptibility loci in three different PCC, spending less than a 30-min hands-on, in-house time. Two patients had one unique variant each that was classified as probably and possibly pathogenic: NF1 Arg304Ter and RET Tyr791Phe. The RET variant was verified by Sanger sequencing.

    CONCLUSIONS:

    NGS can serve as a fast and cost-effective method in the clinical genetic screening of PCC. The bioinformatics analysis may be performed without expert skills. We identified process optimization, characterization of unknown variants and determination of additive effects of multiple variants as key issues to be addressed by future studies.

    National Category
    Surgery
    Identifiers
    urn:nbn:se:uu:diva-212875 (URN)10.1530/EC-13-0009 (DOI)23781326 (PubMedID)
    Available from: 2013-12-16 Created: 2013-12-16 Last updated: 2016-12-21Bibliographically approved
  • 11.
    Delgado Verdugo, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Starker, Lee F
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Global DNA methylation patterns in small intestinal neuroendocrine tumors (SI-NETs)2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 1, p. L5-L7Article in journal (Refereed)
    Abstract [en]

    Small intestinal neuroendocrine tumors (SI-NETs) are rare hormone producing tumors and are often diagnosed at advanced stage. The genetic and epigenetic background of SI-NETs are poorly understood, but several reports have indicated chromosomal losses at 18.21-qter and 11q22-q23. The aim of this study was to characterize CpG DNA methylation status of primary SI-NETs and the corresponding lymph node metastases. We used the commercially available HumanMethylation27 Beadchip array (Illumina), which covers 27578 CpG sites spanning over 14495 genes, and analyzed a discovery cohort of 10 primary SI-NETs with matched metastases. Messenger- mRNA, were determined for selected genes in a 47 tumors. In comparison to the primary tumors, the metastases showed 2697 statistically significant differentially genes. Metastases were generally less methylated than primary tumors. The relative mRNA expression level of the differentially methylated genes AXL, CRMP1, FGF5, and APOBEC3C largely reflected the methylation status. MAPK4, RUNX3, TP73, CCND1, CHFR, AHRR, and Rb1 known to be hypermethylated in other cancer types, displayed overall high methylation level (β-value ≥ 0.9). Methylation (β -value >0,7) at 18q21-qter and 11q22-q23 were detected in genes SETBP1, ELAC1, MBD1, MAPK4, TCEB3C and ARVC1, MMP8, BTG4, APOA1, FAM89B, HSPB1, respectively. Furthermore unsupervised clustering of the tumors identified three distinct clusters, one with a highly malignant behavior. Our data supports involvement of CpG DNA methylation in metastatic progression of SI-NETs and this could present a possibility to identify more aggressive tumors based on DNA methylation.

  • 12.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Andersson, Tommy
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.;AZ Groeninge, Dept Med Imaging, Kortrijk, Belgium..
    Delgado, Anna Falk
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden..
    Clinical outcome after surgical clipping or endovascular coiling for cerebral aneurysms: a pragmatic meta- analysis of randomized and non- randomized trials with short- and long- term follow- up2017In: JOURNAL OF NEUROINTERVENTIONAL SURGERY, ISSN 1759-8478, Vol. 9, no 3, p. 264-+Article in journal (Refereed)
    Abstract [en]

    Background Two randomized trials have evaluated clipping and coiling in patients with ruptured aneurysms. Aggregated evidence for management of ruptured and unruptured aneurysms is missing. Objective To conduct a meta- analysis evaluating clinical outcome after aneurysm treatment. Methods PubMed, Cochrane Central Register of Controlled Trials, and Clinicaltrials. gov were searched for studies evaluating aneurysm treatment. The primary outcome measure was an independent clinical outcome ( modified Rankin scale 0- 2, Glasgow Outcome Scale 4- 5, or equivalent). Secondary outcomes were poor outcome and mortality. ORs were calculated on an intention- to- treat basis with 95% Cls. Outcome heterogeneity was evaluated with Cochrane's Q test ( significance level cut- off value at < 0.10) and l(2) ( significance cut- off value > 50%) with the Mantel-Haenszel method for dichotomous outcomes. A p value < 0.05 was regarded as statistically significant. Results Searches yielded 18 802 articles. All titles were assessed, 403 abstracts were evaluated, and 183 full-text articles were read. One- hundred and fifty articles were qualitatively assessed and 85 articles were included in the meta- analysis. Patients treated with coiling ( randomized controlled trials ( RCTs)) had higher independent outcome at short- term follow- up ( OR= 0.67, 95% Cl 0.57 to 0.79). Independent outcome was favored for coiling at intermediate and long- term follow-up ( RCTs and observational studies combined-OR= 0.80, 0.68 to 0.94 and OR= 0.81, 0.71 to 0.93, respectively). Independent outcome and lower mortality was favored after coiling in unruptured aneurysms ( database registry studies) at short- term follow- up ( OR= 0.34, 0.29 to 0.41 and OR= 1.74, 1.52 to 1.98, respectively). Conclusions This meta- analysis evaluating clinical outcome after coiling or clipping for intracranial aneurysms, indicates a higher independent outcome and lower mortality after coiling.

  • 13.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Andersson, Tommy
    Karolinska Institute, Department of Clinical Neuroscience; Karolinska University Hospital, Department of Neuroradiology; AZ Groeninge, Department of Medical Imaging, Kortrijk.
    Falk Delgado, Anna
    Karolinska Institute, Department of Clinical Neuroscience; Karolinska University Hospital, Department of Neuroradiology.
    Ruptured carotid-ophthalmic aneurysm treatment: a non-inferiority meta-analysis comparing endovascular coiling and surgical clipping2017In: British Journal of Neurosurgery, ISSN 0268-8697, E-ISSN 1360-046X, Vol. 31, no 3, p. 345-349Article in journal (Refereed)
    Abstract [en]

    Introduction: Aneurysms of the carotid-ophthalmic segment are relatively rare, comprising only five percent of all intracranial aneurysms. There is no consensus regarding the optimal management for ruptured carotid-ophthalmic aneurysms, whether endovascular coiling or surgical clipping provide the most favourable patient outcome. The aim of this meta-analysis is to analyse these two treatment modalities for ruptured carotid-ophthalmic aneurysms with respect to independent clinical outcome.

    Methods: We performed a systematic literature search in PubMed, Cochrane Central Registry of Controlled Trials and Clinicaltrials.gov for treatment of ruptured carotid-ophthalmic aneurysms, comparing endovascular coiling and surgical clipping. Primary outcome in the study was independent clinical patient outcome at follow up (defined as Glasgow Outcome Scale four–five). Secondary outcomes were poor clinical patient outcome, mortality and total angiographic occlusion. The meta-analysis was performed using the Mantel–Haenszel method for dichotomous outcome.

    Results: Four studies met the inclusion criteria and were included in the meta-analysis. In total, 152 patients were included. Sixty-seven of these patients were treated with endovascular coiling and 85 patients were treated with microsurgical clipping. The proportion of patients with an independent clinical outcome after coiling and clipping was comparable, OR 1.04 (95% CI: 0.40, 2.71). The proportion of patients with an independent outcome in the endovascular group was 76% and in the surgical group 71%. Mortality between the two treatment arms was equal.

    Conclusion: Clinical outcome after endovascular coiling and surgical clipping for ruptured carotid-ophthalmic aneurysms was comparable between surgical clipping and endovascular coiling. There was no proven difference in clinical outcome after endovascular coiling and surgical clipping for ruptured carotid-ophthalmic aneurysms but the evidence was based on few studies of moderate to low quality and we cannot rule out the possibility of a difference in clinical outcome between the two treatment modalities.

  • 14.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    De Luca, Francesca
    Univ G dAnnunzio, Fac Med & Surg, Sch Med & Hlth Sci, Chieti, Italy.
    van Westen, Danielle
    Skane Univ Hosp, Image & Funct, Lund, Sweden;Lund Univ, Inst Clin Sci Lund, Diagnost Radiol, Lund, Sweden.
    Delgado, Anna Falk
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Arterial spin labeling MR imaging for differentiation between high- and low-grade glioma: a meta-analysis2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 11, p. 1450-1461Article in journal (Refereed)
    Abstract [en]

    Background. Arterial spin labeling is an MR imaging technique that measures cerebral blood flow (CBF) noninvasively. The aim of the study is to assess the diagnostic performance of arterial spin labeling (ASL) MR imaging for differentiation between high-grade glioma and low-grade glioma.

    Methods. Cochrane Library, Embase, Medline, and Web of Science Core Collection were searched. Study selection ended November 2017. This study was prospectively registered in PROSPERO (CRD42017080885). Two authors screened all titles and abstracts for possible inclusion. Data were extracted independently by 2 authors. Bivariate random effects meta-analysis was used to describe summary receiver operating characteristics. Trial sequential analysis (TSA) was performed.

    Results. In total, 15 studies with 505 patients were included. The diagnostic performance of ASL CBF for glioma grading was 0.90 with summary sensitivity 0.89 (0.79-0.90) and specificity 0.80 (0.72-0.89). The diagnostic performance was similar between pulsed ASL (AUC 0.90) with a sensitivity 0.85 (0.71-0.91) and specificity 0.83 (0.690.92) and pseudocontinuous ASL (AUC 0.88) with a sensitivity 0.86 (0.79-0.91) and specificity 0.80 (0.65-0.87). In astrocytomas, the diagnostic performance was 0.89 with sensitivity 0.86 (0.79 to 0.91) and specificity 0.79 (0.63 to 0.89). Sensitivity analysis confirmed the robustness of the findings. TSA revealed that the meta-analysis was adequately powered.

    Conclusion. Arterial spin labeling MR imaging had an excellent diagnostic accuracy for differentiation between high-grade and low-grade glioma. Given its low cost, non-invasiveness, and efficacy, ASL MR imaging should be considered for implementation in the routine workup of patients with glioma.

  • 15.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Delgado, Anna Falk
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Self-declared stock ownership and association with positive trial outcome in randomized controlled trials with binary outcomes published in general medical journals: a cross-sectional study2017In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 18, article id 354Article in journal (Refereed)
    Abstract [en]

    Background: Describe the prevalence and types of conflicts of interest (COI) in published randomized controlled trials (RCTs) in general medical journals with a binary primary outcome and assess the association between conflicts of interest and favorable outcome. Methods: Parallel-group RCTs with a binary primary outcome published in three general medical journals during 2013-2015 were identified. COI type, funding source, and outcome were extracted. Binomial logistic regression model was performed to assess association between COI and funding source with outcome. Results: A total of 509 consecutive parallel-group RCTs were included in the study. COI was reported in 74% in mixed funded RCTs and in 99% in for-profit funded RCTs. Stock ownership was reported in none of the non-profit RCTs, in 7% of mixed funded RCTs, and in 50% of for-profit funded RCTs. Mixed-funded RCTs had employees from the funding company in 11% and for-profit RCTs in 76%. Multivariable logistic regression revealed that stock ownership in the funding company among any of the authors was associated with a favorable outcome (odds ratio = 3.53; 95% confidence interval = 1.59-7.86; p < 0.01). Conclusion: COI in for-profit funded RCTs is extensive, because the factors related to COI are not fully independent, a multivariable analysis should be cautiously interpreted. However, after multivariable adjustment only stock ownership from the funding company among authors is associated with a favorable outcome.

  • 16.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Complete Lymph Node Dissection in Melanoma: A Systematic Review and Meta-Analysis2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 12, p. 6825-6829Article, review/survey (Refereed)
    Abstract [en]

    Background: The aim of this meta-analysis was to estimate the survival after immediate complete lymph node dissection (CLND) compared to observation only (OO) or delayed CLND in patients with melanoma and lymph node metastasis.

    Materials and Methods: A systematic search was performed in: PubMed, Web of Science, Cochrane Library, CINAHL, Clinical trials and Embase. Eligible studies were randomized controlled trials (RCTs) comparing: CLND with OO, or immediate CLND with delayed CLND.

    Results: Four RCTs were included. There was no difference in melanoma-specific survival (MSS) (HR=0.91, 95% CI=0.77-1.08, p=0.29). In a sensitivity analysis, MSS was higher after immediate CLND compared to delayed CLND in patients with nodal metastasis (HR=0.63, 95% CI=0.35-0.74, p=0.0004) without evidence of heterogeneity.

    Conclusion: CLND appears to have no additional survival benefit after SNB compared to OO. However, subgroup analysis suggests a time-dependent benefit for early surgical lymph node removal compared to delayed or none.

  • 17.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Home institution bias in the New England Journal of Medicine?: A noninferiority study on citation rates2018In: Scientometrics, ISSN 0138-9130, E-ISSN 1588-2861, Vol. 115, no 1, p. 607-611Article in journal (Refereed)
    Abstract [en]

    Recently, in the four top journals of humanities, an institutional bias towards publication of authors from Harvard and Yale was shown. The New England Journal of Medicine (NEJM) is today the highest ranked general medical journal. It is unknown if there exists institutional bias favoring publication of articles originating from Harvard University, since the NEJM is produced by the Massachusetts Medical Society with close connections to the Harvard University. We examined if studies originating from the Harvard University published in the NEJM were noninferior in terms of citation rates compared to articles with an origin outside Harvard University. We evaluated original research articles published in the NEJM in 2000 up until June 2001. A two-sample noninferiority test based on the primary endpoint of citations was performed. Twenty-two studies were affiliated to the Harvard University and 280 studies were not affiliated to the Harvard University. The mean number of citations for Harvard affiliated studies was 625 (95% CI 358-952, median 354) and for non-Harvard affiliated studies 493 (95% CI 421-569, median 303). The mean difference was not statistically different between affiliations, but fulfilled the requirements for noninferiority [132 (95% CI - 138-402, P = 0.343), Delta 200]. In summary, citation rates were comparable between studies origination from the Harvard University compared to non-Harvard Institutions. Based on these results there appears to be low risk of institutional bias in the publishing process of original studies in the NEJM.

  • 18.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Karolinska Institute, Department of Clinical Neuroscience.
    Inconsistent Reporting Between Meta-analysis Protocol and Publication – A Cross-Sectional Study2017In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, no 9, p. 5101-5107Article in journal (Refereed)
    Abstract [en]

    Background: Inconsistent reporting in published meta-analyses compared to registered protocol are poorly understood. The aim of the study was to assess inconsistencies between registered protocols and published reports among oncology drug meta-analyses.

    Materials and Methods: A cross-sectional study was performed including oncology drug meta-analyses published between January 1st and November 14th 2016 with a published protocol. Two investigators extracted data on: selection criteria, outcome(s) and statistical plan in protocol and manuscript, plus self-acknowledgement of inconsistent reporting between protocol and publication.

    Results: Protocol registration was present in 19% (23/119) of all oncology drug meta-analyses. In meta-analyses with protocol (n= 23), 70% (16/23) had issues with inconsistent reporting between protocol and published report concerning; inclusion criteria, comparator group, intervention, outcome (PICO) or statistical analysis. Self-acknowledgement of changes between protocol and publication was found in 50% (8/16).

    Conclusion: In meta-analyses with protocol, discrepancies between registered protocols and publications are frequent.

  • 19.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Melanoma Sentinel-Node Metastasis.2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 9, p. 891-2Article in journal (Refereed)
  • 20.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Karolinska Inst, Stockholm, Sweden..
    Melanoma Sentinel-Node Metastasis2017In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 9, p. 891-892Article in journal (Other academic)
  • 21.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Anna
    Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
    Outcome switching in randomized controlled oncology trials reporting on surrogate endpoints: a cross-sectional analysis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 9206Article in journal (Refereed)
    Abstract [en]

    Inconsistent reporting of clinical trials is well-known in the literature. Despite this, factors associated with poor practice such as outcome switching in clinical trials are poorly understood. We performed a cross-sectional analysis to evaluate the prevalence of, and the factors associated with outcome switching. PubMed and Embase were searched for pharmaceutical randomized controlled trials (RCTs) in oncology reporting on a surrogate primary outcome published in 2015. Outcome switching was present in 18% (39/216). First-author male sex was significantly more likely associated with outcome switching compared to female sex with an OR of 3.05 (95% CI 1.07-8.64, p = 0.04) after multivariable adjustment. For-profit funded RCTs were less likely associated with outcome switching compared to non-profit funded research with an OR of 0.22 (95% CI 0.07-0.74, p = 0.01). First author male sex was more likely associated with outcome switching compared to female sex in drug oncology RCTs reporting on a primary surrogate endpoint. For-profit funded research was less likely associated with outcome switching compared to research funded by non-profit organizations. Furthermore, 18 percent of drug oncology trials reporting on a surrogate endpoint could have a higher risk of false positive results due to primary outcome switching.

  • 22.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery. Univ Uppsala Hosp, Akad Sjukhuset, S-75185 Uppsala, Sweden..
    Falk Delgado, Anna
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Neuroradiol, Stockholm, Sweden..
    The association of funding source on effect size in randomized controlled trials: 2013-2015-a cross-sectional survey and metaanalysis2017In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 18, article id 125Article in journal (Refereed)
    Abstract [en]

    Background: Trials financed by for-profit organizations have been associated with favorable outcomes of new treatments, although the effect size of funding source impact on outcome is unknown. The aim of this study was to estimate the effect size for a favorable outcome in randomized controlled trials (RCTs), stratified by funding source, that have been published in general medical journals. Methods: Parallel-group RCTs published in The Lancet, New England Journal of Medicine, and JAMA between 2013 and 2015 were identified. RCTs with binary primary endpoints were included. The primary outcome was the OR of patients' having a favorable outcome in the intervention group compared with the control group. The OR of a favorable outcome in each trial was calculated by the number of positive events that occurred in the intervention and control groups. A meta-analytic technique with random effects model was used to calculate summary OR. Data were stratified by funding source as for-profit, mixed, and nonprofit. Prespecified sensitivity, subgroup, and metaregression analyses were performed. Results: Five hundred nine trials were included. The OR for a favorable outcome in for-profit-funded RCTs was 1.92 (95% CI 1.72-2.14), which was higher than mixed source-funded RCTs (OR 1.34, 95% CI 1.25-1.43) and nonprofit-funded RCTs (OR 1.32, 95% CI 1.26-1.39). The OR for a favorable outcome was higher for both clinical and surrogate endpoints in for-profit-funded trials than in RCTs with other funding sources. Excluding drug trials lowered the OR for a favorable outcome in for-profit-funded RCTs. The OR for a favorable surrogate outcome in drug trials was higher in for-profit-funded trials than in nonprofit-funded trials. Conclusions: For-profit-funded RCTs have a higher OR for a favorable outcome than nonprofit-and mixed source-funded RCTs. This difference is associated mainly with the use of surrogate endpoints in for-profit-financed drug trials.

  • 23.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Lang, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Hakelius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Skoog, Valdemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Nowinski, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery. Uppsala Univ, Plast Surg, Dept Surg Sci, Uppsala, Sweden.
    The Skoog Lip Repair for Unilateral Cleft Lip Deformity: The Uppsala Experience2018In: Plastic and reconstructive surgery (1963), ISSN 0032-1052, E-ISSN 1529-4242, Vol. 141, no 5, p. 1226-1233Article in journal (Refereed)
    Abstract [en]

    Background: The Uppsala Craniofacial Center has been treating patients with unilateral cleft lip deformity using the lip repair technique described by Tord Skoog. The aim of this study was to determine complications after lip surgery and the incidence and indications for lip revisions in all patients born with unilateral cleft lip from 1960 to 2004.

    Methods: All patients who were born from 1960 to 2004 with unilateral cleft lip, cleft lip and alveolus, or cleft lip and palate and underwent lip repair were studied retrospectively. The timing, indication, complications of the primary procedure, and type of secondary surgery were recorded. Kruskal-Wallis and Fisher’s exact tests were used, with Bonferroni correction.

    Results: The study included 443 patients. The total rate of early surgical complications was 6 percent (n = 26). Secondary surgery for short upper lip was performed in 3.8 percent (n = 17), 8.4 percent (n = 37) underwent reduction of excess vermillion, 8.6 percent (n = 38) underwent scar revision, 11 percent (n = 51) underwent revision for incongruent vermillion-cutaneous border, and 10 percent (n = 45) underwent revision for other indications. Altogether, 45 percent had no secondary revisions.

    Conclusion: In conclusion, the Skoog lip repair is associated with a low total revision rate, and a short-lip deformity is rare.

    CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

  • 24.
    Falk Delgado, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Zommorodi, Sayid
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Dept Plast Surg, Stockholm, Sweden.
    Delgado, Anna Falk
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden.
    Sentinel Lymph Node Biopsy and Complete Lymph Node Dissection for Melanoma2019In: Current Oncology Reports, ISSN 1523-3790, E-ISSN 1534-6269, Vol. 21, no 6, article id 54Article, review/survey (Refereed)
    Abstract [en]

    Purpose of Review: The main surgical treatment for invasive malignant melanoma consists of wide surgical and examination of the sentinel node and in selected cases complete lymph node dissection. The aim of this review is to present data for the optimal surgical management of patients with malignant melanoma.

    Recent Findings: A surgical excision margin of 1-2cm is recommended for invasive melanoma depending on the thickness of the melanoma. Sentinel node biopsy may be considered for patients with at least T1b melanomas thickness 0.8 to 1.0mm or less than 0.8mm Breslow thickness with ulceration, classified as T1b lesion, per recent AJCC guidelines. Two randomized controlled trials have been publishedDeCOG (German Dermatologic Cooperative Oncology Group Selective Lymphadenectomy) and MSLT-2 (Multicenter Selective Lymphadenectomy Trial) comparing the complete lymph node dissection (CLND) with observation after positive sentinel node biopsy. In the MSLT-2 study, the disease control rate was improved in the immediate CLND group compared with observation but there was no difference in 3-year melanoma specific survival (86%1.3% and 86%+/- 1.2%, respectively; p=0.42). Isolated limb perfusion (ILP) or isolated limb infusion (ILI) with melphalan and actinomycin D is recommended for large and multiple in-transit metastases and satellite metastases in the extremities when local excision is considered ineffective or too extensive.

    Summary: In light of new adjuvant treatment options and new indications for checkpoint inhibitors, and the lack of survival benefit after CLND, we can expect open surgery to decrease in melanoma disease.

  • 25.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    [In Process Citation].2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112Article in journal (Refereed)
    Abstract [sv]

    Systemic thrombolysis is an established treatment in acute ischemic stroke. Endovascular treatment to reperfuse occluded vessels has been in clinical practice the last decade. The role of neurointervention in acute ischemic stroke has been questioned. Within the last year, several randomized controlled trials have been published, comparing endovascular treatment and systemic thrombolysis with systemic thrombolysis alone. A meta-analysis, using data from six trials treating 1569 patients, was recently published. In this meta-analysis, patients treated with endovascular therapy in addition to IV thrombolysis had a more favourable clinical outcome compared to patients receiving IV thrombolysis alone, after 3 months. Compared to the individ-ual studies, a decreased mortality in the intervention group was shown. Assessing the safety of endovascular treatment, there was no increased risk of intracranial bleed-ing, compared to IV thrombolysis alone. This meta-analysis highlights and summar-izes the scientific evidence for endovascular treatment in acute ischemic stroke.

  • 26.
    Falk-Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kuntze Söderqvist, Åsa
    Fransén, Jian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Improved clinical outcome 3 months after endovascular treatment, including thrombectomy, in patients with acute ischemic stroke: a meta-analysis2016In: Journal of neurointerventional surgery, ISSN 1759-8486, Vol. 8, no 7Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Intravenous thrombolysis with tissue plasminogen activator is standard treatment in acute stroke today. The benefit of endovascular treatment has been questioned. Recently, studies evaluating endovascular treatment and intravenous thrombolysis compared with intravenous thrombolysis alone, have reported improved outcome for the intervention group. The aim of this study was to perform a meta-analysis of randomized controlled trials comparing endovascular treatment in addition to intravenous thrombolysis with intravenous thrombolysis alone.

    METHODS: Databases were searched for eligible randomized controlled trials. The primary outcome was a functional neurological outcome after 90 days. A secondary outcome was severe disability and death. Data were pooled in the control and intervention groups, and OR was calculated on an intention to treat basis with 95% CIs. Outcome heterogeneity was evaluated with Cochrane's Q test (significance level cut-off value at <0.10) and I(2) (significance cut-off value >50%) with the Mantel-Haenszel method for dichotomous outcomes. A p value <0.05 was regarded as statistically significant.

    RESULTS: Six studies met the eligibility criteria, and data from 1569 patients were analyzed. A higher probability of a functional neurological outcome after 90 days was found for the intervention group (OR 2, 95% CI 2 to 3). There was a significantly higher probability of death and severe disability in the control group compared with the intervention group.

    CONCLUSIONS: Endovascular treatment in addition to intravenous thrombolysis for acute ischemic stroke leads to an improved clinical outcome after 3 months, compared with patients receiving intravenous thrombolysis alone.

  • 27. Lai, Enyin
    et al.
    Pettersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Verdugo, Alberto Delgado
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Bodin, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Källskog, Örjan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persson, Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandberg, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Blood lipids affect rat islet blood flow regulation through beta(3)-adrenoceptors2014In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 307, no 8, p. E653-E663Article in journal (Refereed)
    Abstract [en]

    Pancreatic islet blood perfusion varies according to the needs for insulin secretion. We examined the effects of blood lipids on pancreatic islet blood flow in anesthetized rats. Acute administration of Intralipid to anesthetized rats increased both triglycerides and free fatty acids, associated with a simultaneous increase in total pancreatic and islet blood flow. A preceding abdominal vagotomy markedly potentiated this and led acutely to a 10-fold increase in islet blood flow associated with a similar increase in serum insulin concentrations. The islet blood flow and serum insulin response could be largely prevented by pretreatment with propranolol and the selective beta(3)-adrenergic inhibitor SR-59230A. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester prevented the blood flow increase but was less effective in reducing serum insulin. Increased islet blood flow after Intralipid administration was also seen in islet and whole pancreas transplanted rats, i.e., models with different degrees of chronic islet denervation, but the effect was not as pronounced. In isolated vascularly perfused single islets Intralipid dilated islet arterioles, but this was not affected by SR-59230A. Both the sympathetic and parasympathetic nervous system are important for the coordination of islet blood flow and insulin release during hyperlipidemia, with a previously unknown role for beta(3)-adrenoceptors.

  • 28.
    Starker, Lee F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Delgado-Verdugo, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Udelsman, Robert
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Carling, Tobias
    Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism2010In: Endocrine, ISSN 0969-711X, Vol. 38, no 3, p. 397-401Article in journal (Refereed)
    Abstract [en]

    To investigate the SDHAF2 gene and its effect on primary hyperparathyroidism. Parathyroid tumors causing primary hyperparathyroidism (pHPT) are one of the more common endocrine neoplasias. Loss of heterozygosity at chromosome 11q13 is the most common chromosomal aberration in parathyroid tumors occurring in about 40% of sporadic tumors. Only 15-19% display somatic mutations in the MEN1 gene, which suggest that this chromosomal region may harbor additional genes of importance in parathyroid tumor development. The SDHAF2 (formerly SDH5) gene is a recently identified neuroendocrine tumor suppressor gene at this locus, and inherited mutations of the SDHAF2 gene has been linked to familial paraganglioma. We demonstrate that the SDHAF2 gene is expressed in parathyroid tissue using RT-PCR. Because detection of inactivating mutations is the major criterion for validating a candidate tumor suppressor, we used automated sequencing of the coding region and intron/exon boundaries in 80 sporadic parathyroid adenomas from patients with pHPT. A known polymorphisms (A to G substitution; rs879647) was identified in 9/80 parathyroid tumors but no tumor-specific somatic mutational aberrations, such as nonsense, frameshift, or other inactivating mutations were identified. The SDHAF2 gene is expressed in parathyroid tissue. However, somatic mutations of the SDHAF2 tumor suppressor gene are unlikely to frequently contribute to parathyroid tumor development in sporadic pHPT.

  • 29.
    Starker, Lee F.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Åkerström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Long, William D
    Delgado-Verdugo, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Donovan, Patricia
    Udelsman, Robert
    Lifton, Richard P
    Carling, Tobias
    Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism2012In: Hormones & Cancer, ISSN 1868-8497, Vol. 3, no 1-2, p. 44-51Article in journal (Refereed)
    Abstract [en]

    Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

  • 30.
    Svee, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Mani, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Sandquist, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Audolfsson, T.
    Oslo Univ Hosp, Dept Plast & Reconstruct Surg, Oslo, Norway.
    Folkvaljon, Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Univ Uppsala Hosp, Dept Surg, Uppsala, Sweden.
    Isern, A. E.
    Norwegian Univ Sci & Technol, Dept Clin & Mol Med, Trondheim, Norway;Volvat Stokkan, Trondheim, Norway.
    Ringberg, A.
    Lund Univ, Skane Univ Hosp Malmo, Dept Plast & Reconstruct Surg, Malmo, Sweden.
    Manjer, J.
    Lund Univ, Skane Univ Hosp Malmo, Dept Surg, Malmo, Sweden.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Univ Uppsala Hosp, Dept Surg, Uppsala, Sweden.
    Survival and risk of breast cancer recurrence after breast reconstruction with deep inferior epigastric perforator flap2018In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 105, no 11, p. 1446-1453Article in journal (Refereed)
    Abstract [en]

    Background: Women who undergo autologous breast reconstruction have been reported to have an increased risk of breast cancer recurrence compared with those who have mastectomy alone. It has been suggested that more extensive surgery possibly activates dormant micrometastases. The aim of this study was to evaluate whether delayed unilateral deep inferior epigastric perforator (DIEP) flap reconstruction after mastectomy increases the risk of breast cancer recurrence or affects mortality among women previously treated for breast cancer.

    Methods: This was a matched retrospective cohort study including women with a previous unilateral invasive breast cancer who received a delayed DIEP flap breast reconstruction and a control cohort of individually matched women with unilateral breast cancer who underwent mastectomy but no autologous breast reconstruction. Matching criteria comprised: year of diagnosis (+/-3years), age at diagnosis (+/-5years), type of cancer and demographic region. The primary endpoints were local recurrence or distant metastasis, and overall mortality was a secondary endpoint. Absolute risk of recurrent disease and mortality was analysed, and relative risks were estimated using Cox proportional hazards analysis.

    Results: There were 225 women in the DIEP cohort and 450 in the no-DIEP cohort. The median follow-up time was 125months. There was no difference in absolute risk of recurrence between the cohorts. The hazard ratio for breast cancer recurrence in DIEP versus no-DIEP cohorts was 0·76 (95 per cent c.i. 0·47 to 1·21).

    Conclusion: There is no increased risk in breast cancer recurrence after delayed DIEP flap reconstruction compared with mastectomy alone. As above

  • 31.
    Åkerström, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Verdugo, Alberto Delgado
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Starker, Lee F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Cupisti, Kenko
    Willenberg, Holger S.
    Knoefel, Wolfram T.
    Saeger, Wolfgang
    Feller, Alfred
    Ip, Julian
    Soon, Patsy
    Anlauf, Martin
    Alesina, Pier F.
    Schmid, Kurt W.
    Decaussin, Myriam
    Levillain, Pierre
    Wangberg, Bo
    Peix, Jean-Louis
    Robinson, Bruce
    Zedenius, Jan
    Backdahl, Martin
    Caramuta, Stefano
    Iwen, K. Alexander
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Kraimps, Jean-Louis
    Dralle, Henning
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sidhu, Stan
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lehnert, Hendrik
    Walz, Martin K.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Carling, Tobias
    Choi, Murim
    Lifton, Richard P.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41926-Article in journal (Refereed)
    Abstract [en]

    Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.

    Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.

    Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p < 0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p < 0.005).

    Discussion: Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

1 - 31 of 31
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