| 51. |
- Falk Delgado, Anna, et al.
(author)
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Diffusion kurtosis imaging of gliomas grades II and III : a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation
- 2017
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In: Radiology and Oncology. - : Walter de Gruyter GmbH. - 1318-2099 .- 1581-3207. ; 51:2, s. 121-129
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Journal article (peer-reviewed)abstract
- Background. Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas).Patients and methods. Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student's t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves.Results. There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=< 0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003-0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011-0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657-0.815.Conclusions. Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.
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| 52. |
- Gatto, Francesco, 1987, et al.
(author)
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Plasma Glycosaminoglycans as Diagnostic and Prognostic Biomarkers in Surgically Treated Renal Cell Carcinoma
- 2018
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In: European Urology Oncology. - : Elsevier BV. - 2588-9311. ; 1:5, s. 364-377
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Journal article (peer-reviewed)abstract
- Plasma glycosaminoglycan (GAG) measurements, when aggregated into diagnostic scores, accurately distinguish metastatic clear-cell renal cell carcinoma (RCC) from healthy samples and correlate with prognosis. However, it is unknown if GAG scores can detect RCC in earlier stages or if they correlate with prognosis after surgery. Objective: To explore the sensitivity and specificity of plasma GAGs for detection of early-stage RCC and prediction of recurrence and death after RCC surgery. Design, setting, and participants: This was a retrospective case-control study consisting of a consecutive series of 175 RCC patients surgically treated between May 2011 and February 2014 and 19 healthy controls. Outcome measurements and statistical analysis: Plasma GAGs in preoperative and postoperative RCC and healthy samples were measured using capillary electrophoresis with laser-induced fluorescence in a single blinded laboratory. A discovery set was first analyzed to update the historical GAG score. The sensitivity of the new GAG score for RCC detection versus healthy subjects was validated using the remaining samples. The correlation of the new GAG score to histopathologic variables, overall survival, and recurrence-free survival was evaluated using nonparametric and log-rank tests and multivariable Cox regression analyses. Results and limitations: The RCC cohort included 94 stage I, 58 stage II–III, and 22 stage IV cases. In the first discovery set (n = 67), the new GAG score distinguished RCC from healthy samples with an area under the receiver operating characteristic curve (AUC) of 0.999. In the validation set (n = 108), the GAG score achieved an AUC of 0.991, with 93.5% sensitivity. GAG scores were elevated in RCC compared to healthy samples, irrespective of and uncorrelated to stage, grade, histology, age, or gender. The total chondroitin sulfate concentration was an independent prognostic factor for both overall and recurrence-free survival (hazard ratios 1.51 and 1.25) with high concordance when combined with variables available at pathologic diagnosis (C-index 0.926 and 0.849) or preoperatively (C-index 0.846 and 0.736). Limitations of the study include its retrospective nature and moderate variability in GAG laboratory measurements. Conclusions: Plasma GAGs are highly sensitive diagnostic and prognostic biomarkers in surgically treated RCC independent of stage, grade, or histology. Prospective validation studies on GAG scores for early detection, prediction, and surveillance for RCC recurrence are thus warranted. Patient summary: In this study, we examined if a new molecular blood test can detect renal cell carcinoma in the early stages and predict if the cancer might relapse after surgery. The trial is registered on ClinicalTrial.gov as NCT03471897. Plasma glycosaminoglycan measurements aggregated into scores had higher sensitivity for the detection of any-stage renal cell carcinoma and high concordance with survival after surgery.
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| 53. |
- Glimelius, Bengt, et al.
(author)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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In: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Journal article (peer-reviewed)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 54. |
- Hu, Min, et al.
(author)
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Endometrial progesterone receptor isoforms in women with polycystic ovary syndrome
- 2018
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In: American Journal of Translational Research. - 1943-8141. ; 10:8, s. 2696-2705
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Journal article (peer-reviewed)abstract
- Context: Polycystic ovary syndrome (PCOS) affects approximately 4%-18% of all reproductive-aged women and is often accompanied by endometrial progesterone (P4) resistance. Endometrial cells from PCOS patients display increased progesterone receptor (PGR) expression; however, in vivo knockout studies and in vitro experiments indicate the two PGR isoforms are not functionally equivalent. Objective: We aimed to compare endometrial PGR iso-form expression between non-PCOS and PCOS patients during the proliferative phase. Design: A case-control study. The expression of PGR isoforms (PGRA and PGRB), estrogen receptor alpha (ERα), and markers of cell proliferation was determined by qRT-PCR, Western blot, immunohistochemistry, and immunofluorescence assays. Patient(s): Patients were recruited and diagnosed with PCOS according to the Rotterdam criteria provided by the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology. Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia (n = 11) and from PCOS patients with or without hyperplasia (n = 14). Result(s): Although the alteration of PGRB mRNA and protein expression was different, we found that PGRA mRNA and protein expression was higher in PCOS patients than non-PCOS patients. PGRA/B and PGRB were localized in both epithelial and stromal cells, with notable changes in the nuclei of epithelial and stromal cells. A similar expression pattern of ERα, vimentin and Ki-67, in association with an increased PGR expression, was observed in PCOS patients. Conclusion(s): These results demonstrated that elevated both PGR isoform expression depends on the presence of PCOS, and our data suggest that abnormal regulation of PGR isoforms is a pathological outcome of defective endometrium in PCOS patients.
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| 55. |
- Manojlovic-Gacic, Emilija, et al.
(author)
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Histopathological classification of non-functioning pituitary neuroendocrine tumors
- 2018
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In: Pituitary. - : Springer Science and Business Media LLC. - 1386-341X .- 1573-7403. ; 21:2, s. 119-129
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Research review (peer-reviewed)abstract
- 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.
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| 56. |
- Marcisauskas, Simonas, 1988, et al.
(author)
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Univariate and classification analysis reveals potential diagnostic biomarkers for early stage ovarian cancer Type 1 and Type 2
- 2019
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In: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 196, s. 57-68
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Journal article (peer-reviewed)abstract
- Biomarkers for early detection of ovarian tumors are urgently needed. Tumors of the ovary grow within cysts and most are benign. Surgical sampling is the only way to ensure accurate diagnosis, but often leads to morbidity and loss of female hormones. The present study explored the deep proteome in well-defined sets of ovarian tumors, FIGO stage I, Type 1 (low-grade serous, mucinous, endometrioid; n = 9), Type 2 (high-grade serous; n = 9), and benign serous (n = 9) using TMT–LC–MS/MS. Data are available via ProteomeXchange with identifier PXD010939. We evaluated new bioinformatics tools in the discovery phase. This innovative selection process involved different normalizations, a combination of univariate statistics, and logistic model tree and naive Bayes tree classifiers. We identified 142 proteins by this combined approach. One biomarker panel and nine individual proteins were verified in cyst fluid and serum: transaldolase-1, fructose-bisphosphate aldolase A (ALDOA), transketolase, ceruloplasmin, mesothelin, clusterin, tenascin-XB, laminin subunit gamma-1, and mucin-16. Six of the proteins were found significant (p <.05) in cyst fluid while ALDOA was the only protein significant in serum. The biomarker panel achieved ROC AUC 0.96 and 0.57 respectively. We conclude that classification algorithms complement traditional statistical methods by selecting combinations that may be missed by standard univariate tests. Significance: In the discovery phase, we performed deep proteome analyses of well-defined histology subgroups of ovarian tumor cyst fluids, highly specified for stage and type (histology and grade). We present an original approach to selecting candidate biomarkers combining several normalization strategies, univariate statistics, and machine learning algorithms. The results from validation of selected proteins strengthen our prior proteomic and genomic data suggesting that cyst fluids are better than sera in early stage ovarian cancer diagnostics.
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| 57. |
- Nilsson, Jonas, 1970, et al.
(author)
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Synthetic standard aided quantification and structural characterization of amyloid-beta glycopeptides enriched from cerebrospinal fluid of Alzheimer's disease patients
- 2019
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Journal article (peer-reviewed)abstract
- An early pathological hallmark of Alzheimer's disease (AD) is amyloid-beta (A beta) deposits in the brain, which largely consist of up to 43 amino acids long A beta peptides derived from the amyloid precursor protein (APP). We previously identified a series of sialylated Tyr-10 O-glycosylated A beta peptides, 15-20 residues long, from human cerebrospinal fluid (CSF) and observed a relative increase of those in AD vs non-AD patients. We report here on the synthesis and use of an isotopically double-labeled A beta 1-15 glycopeptide, carrying the core 1Gal beta 3GalNAc alpha 1-O-Tyr-10 structure, to (1) identify by HCD LC-MS/MS the definite glycan core 1 structure of immunopurified and desialylated A beta glycopeptides in human CSF and to (2) establish a LC-MS/MS quantification method for desialylated A beta 1-15 (and A beta-17) glycopeptides and to (3) compare the concentrations of these A beta glycopeptides in CSF from 20 AD patients and 20 healthy controls. Although we unambiguously identified the core 1 structures and Tyr-10 attachment sites of the glycopeptides, we did not observe any quantitative differences, determined through both peptide and oxonium ion fragments, of the desialylated A beta 1-15 or A beta 1-17 glycopeptides between the AD and non-AD group. The new quantitative glycoproteomic approach described, using double-labeled glycopeptide standards, will undoubtedly facilitate future studies of glycopeptides as clinical biomarkers but should also embrace sialylated A beta standards to reveal specific sialylation patterns of individual A beta glycopeptides in AD patients and controls.
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| 58. |
- Bondeson, Marie-Louise, 1960-, et al.
(author)
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A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.
- 2017
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In: Clinical Genetics. - : Wiley. - 0009-9163 .- 1399-0004. ; 92:5, s. 510-516
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Journal article (peer-reviewed)abstract
- Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.
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| 59. |
- Dehlin, Mats, 1968, et al.
(author)
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Validity of gout diagnosis in Swedish primary and secondary care - a validation study
- 2015
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In: Bmc Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 16:149
-
Journal article (peer-reviewed)abstract
- Background: The diagnostic golden standard for gout is to detect monosodium urate (MSU) crystals in synovial fluid. While some gout classification criteria include this variable, most gout diagnoses are based on clinical features. This discrepancy between clinical practice and classification criteria can hinder gout epidemiological studies. Here, the objective was to validate gout diagnoses (International Classification of Diseases (ICD)-10 gout codes) in primary and secondary care relative to five classification criteria (Rome, New York, ARA, Mexico, and Netherlands). The frequency with which MSU crystal identification was used to establish gout diagnosis was also determined. Methods: In total, 394 patients with >= 1 ICD-10 gout diagnosis between 2009 and 2013 were identified from the medical records of two primary care centers (n = 262) and one secondary care center (n = 132) in Gothenburg, Sweden. Medical records were assessed for all classification criteria. Results: Primary care patients met criteria cutoffs more frequently when >= 2 gout diagnoses were made. Even then, few primary care patients met the Rome and New York cutoffs (19 % and 8 %, respectively). The ARA, Mexico, and Netherlands cutoffs were met more frequently by primary care patients with >= 2 gout diagnoses (54 %, 81 %, and 80 %, respectively). Mexico and Netherlands cutoffs were met more frequently by the rheumatology department patients (80 % and 71 %, respectively), even when patients with only 1 gout diagnosis were included. Analysis of MSU crystals served to establish gout diagnoses in only 27 % of rheumatology department and 2 % of primary care cases. Conclusions: If a patient was deemed to have gout at >= 2 primary care center or >= 1 rheumatology-center visits according to an ICD-10 gout code, the positive predictive value of this variable in relation with the Mexico and Netherlands classification criteria was >= 80 % for both primary care and rheumatology care settings in Sweden. MSU crystal identification was rarely used to establish gout diagnosis.
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| 60. |
- Ekman, Bertil, et al.
(author)
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Urine oligosaccharide pattern in patients with hyperprolactinaemia
- 2015
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In: Glycoconjugate Journal. - : Springer. - 0282-0080 .- 1573-4986. ; 32:8, s. 635-641
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Journal article (peer-reviewed)abstract
- Free milk-type oligosaccharides are produced during pregnancy and lactation and may have an impact on several cells in the immune system. Our aim was to investigate if patients with isolated hyperprolactinaemia, not related to pregnancy, also have increased synthesis and urinary excretion of milk-type oligosaccharides and to compare the excretion pattern with that found during pregnancy. Urine samples were collected as morning sample from 18 patients with hyperprolactinaemia, 13 healthy controls with normal prolactin levels and four pregnant women. After purification, lactose and free oligosaccharides were analysed and quantified by high-performance anion-exchange chromatography with pulsed amperometric detection. The identity of peaks was confirmed by exoglycosidase treatment and comparison with oligosaccharide standards. Prolactin was measured in serum collected between 09 and 11 a.m. by a standardized immunochemical method. Patients with hyperprolactinaemia had higher urinary excretion of lactose than normoprolactinemic controls and urinary lactose correlated positively to prolactin levels (r = 0.51, p < 0.05). Increased levels of the fucosylated oligosaccharides 2-fucosyl lactose and lacto-di-fucotetraose were found in urine from three and two patients, respectively. The acidic oligosaccharide 3-sialyl lactose was found in high amount in urine from two patients with prolactin of >10,000 mU/l. However, pregnant women in their third trimester had the highest concentration of all these oligosaccharides and excretion increased during pregnancy. This study is first to show that both lactose and certain fucosylated and sialylated milk-type oligosaccharides are increased in some patients with hyperprolactinaemia. It remains to elucidate the functional importance of these findings.
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