ABSTRACT
Genome-scale high-throughput sequencing enables the detection of unprecedented numbers of sequence variants. Variant filtering and interpretation are facilitated by mutation databases, in silico tools, and population-based reference datasets such as ExAC/gnomAD, while variants are classified using the ACMG/AMP guidelines. These methods, however, pose clinically relevant challenges. We queried the gnomAD dataset for (likely) pathogenic variants in genes causing autosomal-dominant disorders. Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co-occurring variants in FBN1 and FBN2. In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal-dominant disorders, enabling the estimation of variant-filtering thresholds and disease predisposition/prevalence rates. In our database, we discovered two families with hitherto unreported co-occurrence of FBN1/FBN2 variants causing phenotypes with mixed or modified MFS/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co-occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.
Subject(s)
Arachnodactyly/genetics , Contracture/genetics , Fibrillin-1/genetics , Fibrillin-2/genetics , Marfan Syndrome/genetics , Adolescent , Adult , Aged , Alleles , Arachnodactyly/physiopathology , Child , Contracture/congenital , Contracture/physiopathology , Databases, Genetic , Female , Frameshift Mutation , Genetic Association Studies , Genetic Variation , Genotype , Humans , INDEL Mutation , Male , Marfan Syndrome/physiopathology , Middle Aged , Pedigree , Phenotype , Whole Genome SequencingABSTRACT
Although several pharmacogenetic (PGx) predispositions affecting drug efficacy and safety are well established, drug selection and dosing as well as clinical trials are often performed in a non-pharmacogenetically-stratified manner, ultimately burdening healthcare systems. Pre-emptive PGx testing offers a solution which is often performed using microarrays or targeted gene panels, testing for common/known PGx variants. However, as an added value, whole-genome sequencing (WGS) could detect not only disease-causing but also pharmacogenetically-relevant variants in a single assay. Here, we present our WGS-based pipeline that extends the genetic testing of Mendelian diseases with PGx profiling, enabling the detection of rare/novel PGx variants as well. From our in-house WGS (PCR-free 60× PE150) data of 547 individuals we extracted PGx variants with drug-dosing recommendations of the Dutch Pharmacogenetics Working Group (DPWG). Furthermore, we explored the landscape of DPWG pharmacogenes in gnomAD and our in-house cohort as well as compared bioinformatic tools for WGS-based structural variant detection in CYP2D6. We show that although common/known PGx variants comprise the vast majority of detected DPWG pharmacogene alleles, for better precision medicine, PGx testing should move towards WGS-based approaches. Indeed, WGS-based PGx profiling is not only feasible and future-oriented but also the most comprehensive all-in-one approach without generating significant additional costs.
Subject(s)
Genetic Testing/methods , High-Throughput Nucleotide Sequencing/methods , Pharmacogenomic Variants , Whole Genome Sequencing/methods , Cytochrome P-450 CYP2D6/genetics , Genetic Testing/standards , High-Throughput Nucleotide Sequencing/standards , Humans , Whole Genome Sequencing/standardsSubject(s)
Genome , Sequence Alignment , High-Throughput Nucleotide Sequencing , Sequence Analysis, DNA , SoftwareABSTRACT
OBJECTIVE: Hereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers-Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models. MATERIAL AND METHODS: We used two mouse models (Fbn1C1041G and Fbn1mgR ) of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). One of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. RESULTS: The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice. CONCLUSION: Our read-out system can characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force-focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as antihypertensive drugs reducing aortic dilatation might not strengthen the weakened aortic wall. Our results may enable identification of improved medical therapies of hADs.
ABSTRACT
BACKGROUND: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection as the routine staging procedure in clinically node-negative breast cancer. False-negative SLN biopsy results in misclassification and may cause undertreatment of the disease. The aim of this study was to investigate whether serial sectioning of SLNs reveals metastases more frequently in patients with false-negative SLNs than in patients with true-negative SLNs. METHODS: This was a case-control study. Tissue blocks from patients with false-negative SLNs, defined as tumour-positive lymph nodes excised at completion axillary dissection or a subsequent axillary tumour recurrence, were reassessed by serial sectioning and immunohistochemical staining. For each false-negative node, two true-negative SLN biopsies were analysed. Tumour and node characteristics in patients with false-negative SLNs were compared with those in patients with a positive SLN by univariable and multivariable regression analysis. RESULTS: Undiagnosed SLN metastases were discovered in nine (18 per cent) of 50 patients in the false-negative group and in 12 (11.2 per cent) of 107 patients in the true-negative group (P = 0.245). The metastases were represented by isolated tumour cells in 14 of these 21 patients. The risk of a false-negative SLN was higher in patients with hormone receptor-negative (odds ratio (OR) 2.50, 95 per cent confidence interval 1.17 to 5.33) or multifocal tumours (OR 3.39, 1.71 to 6.71), or if only one SLN was identified (OR 3.57, 1.98 to 6.45). CONCLUSION: SLN serial sectioning contributes to a higher rate of detection of SLN metastasis. The rate of upstaging of the tumour is similar in false- and true-negative groups of patients.
Subject(s)
Breast Neoplasms/pathology , Lymph Nodes/pathology , Neoplasm Recurrence, Local/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/surgery , Case-Control Studies , False Negative Reactions , Female , Humans , Lymph Node Excision/methods , Lymphatic Metastasis , Middle Aged , Regression Analysis , Sentinel Lymph Node Biopsy/standards , Tumor BurdenABSTRACT
AIMS: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The ß-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. METHODS AND RESULTS: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. CONCLUSIONS: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.
Subject(s)
Adrenergic beta-1 Receptor Antagonists/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Aorta, Thoracic/drug effects , Aortic Aneurysm, Thoracic/prevention & control , Aortic Dissection/prevention & control , Aortic Rupture/prevention & control , Celiprolol/pharmacology , Ehlers-Danlos Syndrome/drug therapy , Losartan/pharmacology , Vascular Remodeling/drug effects , Aortic Dissection/pathology , Aortic Dissection/physiopathology , Animals , Aorta, Thoracic/pathology , Aorta, Thoracic/physiopathology , Aortic Aneurysm, Thoracic/pathology , Aortic Aneurysm, Thoracic/physiopathology , Aortic Rupture/pathology , Aortic Rupture/physiopathology , Collagen Type III/genetics , Doxycycline/pharmacology , Ehlers-Danlos Syndrome/pathology , Ehlers-Danlos Syndrome/physiopathology , Heterozygote , Matrix Metalloproteinase Inhibitors/pharmacology , Mice, Inbred C57BL , Mutation , Proof of Concept Study , Stress, MechanicalABSTRACT
The aim of this study was to compare the sensitivity of intraoperative frozen section with hematoxyllin-eosin (H&E) staining, immunohistochemistry (IHC) or imprint cytology (IC) in the analysis of sentinel node (SN) in breast cancer. Towards this end, a prospective study of 102 patients undergoing mastectomy or sector resection with SN biopsy was conducted. Frozen sections of SN with H&E, IHC staining and IC had sensitivities of 73.5%, 75.5% and 51.0%, respectively. The combination of H&E and IHC raised the overall sensitivity to 83.7%. Macrometastases (>2 mm) were detected in 100% of the cases with H&E, 92.6% with IHC and 81.5% with IC; and micrometastases (2 mm) in 35.0%, 45.0% and 5.0%, respectively. The combination of H&E and IHC staining raised the sensitivity to 55.0%. Frozen-section analysis with H&E staining showed high sensitivity in detecting macrometastases but not micrometastases. The sensitivity for detection of micrometastases was not substantially increased by the use of intraoperative IHC. Imprint cytology did not provide any additional information.
Subject(s)
Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/secondary , Carcinoma, Lobular/secondary , Adenocarcinoma, Mucinous/secondary , Adult , Aged , Aged, 80 and over , Axilla , Breast Neoplasms/surgery , Female , Frozen Sections/standards , Humans , Immunohistochemistry , Intraoperative Period , Middle Aged , Prospective Studies , Sensitivity and Specificity , Sentinel Lymph Node Biopsy/standardsABSTRACT
Human breast cancers are known to preferentially metastasize to skeletal sites, however, the mechanisms that mediate the skeletal preference (orthotropism) of specific types of cancers remains poorly understood. There is a significant clinical correlation between the expression of bone sialoprotein (BSP) and skeletal metastasis of breast cancers. Our laboratory, as well as others, have proposed the concept that skeletal selective metastasis and associated disease may be attributable to a mimicry of skeletal cellular phenotypes by metastasizing cancer cells. We hypothesize that breast cancer cell expression of phenotypic properties of skeletal cell types, including BSP as one component of that phenotype, is the result of ectopic expression or activity of one or more central transcriptional regulators of bone cell gene expression. To test this hypothesis, we examined the molecular mechanisms that regulate bsp expression in human breast cancer cell lines with previously characterized metastatic potentials. Our results demonstrate that the majority of the distal bsp promoter sequences act to repress BSP expression in cancer cells and that most of the promoter activity resides in the proximal -110 bp of the bsp promoter. In this region, we identified a putative Runx binding element providing a basis for a mechanism for skeletal gene activation. Our results demonstrate that Runx2 is ectopically expressed in breast cancer cells and that one isoform of Runx2 can activate bsp expression in these cells. In addition, we observe that bsp expression is additionally regulated by the homeodomain factor Msx2, another regulator of osteoblast-associated genes. Thus, this is the first report of osteoblast-related transcription factors being expressed in human breast cancer cells and provides a component of a mechanism that may explain the osteoblastic phenotype of human breast cancer cells that preferentially metastasize to bone.
Subject(s)
Breast Neoplasms/metabolism , DNA-Binding Proteins/physiology , Neoplasm Proteins , Sialoglycoproteins/biosynthesis , Transcription Factors/physiology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Core Binding Factor Alpha 1 Subunit , Core Binding Factor alpha Subunits , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Homeodomain Proteins/physiology , Humans , Integrin-Binding Sialoprotein , Neoplasm Metastasis , Promoter Regions, Genetic , Sialoglycoproteins/genetics , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transcriptional Activation , Transfection , Tumor Cells, CulturedABSTRACT
It is now widely recognised that classifying ductal carcinoma in situ (DCIS) of the breast and diagnosing atypical ductal hyperplasia are associated with significant interobserver variation. Two possible reasons for this inconsistency are differences in the interpretation of specified histological features and field selection where morphology is heterogeneous. In order to investigate the relative contribution of these two factors to inconsistent interpretation of intraductal proliferations, histological sections of 32 lesions were sent to 23 European pathologists followed 3 years later by images of small parts of these sections. Kappa statistics for diagnosing hyperplasia of usual type, atypical ductal hyperplasia and ductal carcinoma in situ were 0.54, 0.35 and 0.78 for sections and 0.47, 0.29 and 0.78 for images, respectively, showing that most of the inconsistency is due to differences in morphological interpretation. Improvements can thus be expected only if diagnostic criteria or methodology are changed. In contrast, kappa for classifying DCIS by growth pattern was very low at 0.23 for sections and better at 0.47 for images, reflecting the widely recognised variation in the growth pattern of DCIS. Higher kappa statistics were obtained when any mention of an individual growth pattern was included in that category, thus allowing multiple categories per case; but kappa was still higher for images than sections. Classifying DCIS by nuclear grade gave kappa values of 0.36 for sections and 0.49 for images, indicating that intralesional heterogeneity has hitherto been underestimated as a cause of inconsistency in classifying DCIS by this method. More rigorous assessment of the proportions of the different nuclear grades present could lead to an improvement in consistency.
Subject(s)
Breast Neoplasms/diagnosis , Breast/pathology , Carcinoma in Situ/diagnosis , Carcinoma, Ductal, Breast/diagnosis , Breast Neoplasms/classification , Carcinoma in Situ/classification , Carcinoma, Ductal, Breast/classification , Female , Humans , Hyperplasia/diagnosis , Observer VariationABSTRACT
The increased detection of ductal carcinoma in situ (DCIS) by mammographic screening, the greater use of breast-conserving surgery, and the recognition that certain histological subtypes are associated with a greater risk of local recurrence has led to the formulation of several new classifications of DCIS in recent years. There are, however, no data concerning the degree of consistency with which these schemes can be applied by reasonable numbers of pathologists. Thirty-three cases of DCIS were thus examined by a working group of 23 European pathologists who categorized them using five recently published classifications: (1) that of the European Pathologists' Working Group based on differentiation (a combination of nuclear grade and cell polarization) with categories of poorly, intermediately, and well differentiated; (2) one based entirely on nuclear grade with categories of high, intermediate, and low, currently in use in the UK national and EC-funded breast screening programs; (3) the same classification in which only two categories, high nuclear grade and other, were used; (4) the Van Nuys system in which lesions are divided into high grade, non-high grade with necrosis and non-high grade without necrosis; and (5) a two-category classification based entirely on the presence or absence of comedo necrosis. Of the three systems with three categories, Van Nuys gave the highest overall kappa statistic of 0.42. Others gave similar values of 0.37 and 0.35 showing that assessing cell polarization in addition to nuclear grade neither improves nor worsens consistency. In all three systems, the middle category was associated with the lowest value for kappa. Of the two systems with two categories, that based on nuclear grade gave the highest overall kappa of 0.46 and that based on comedo necrosis the lowest of 0.34. The most robust histological features were thus high- and low-grade nuclei and necrosis as long as the latter did not involve the recognition of a comedo growth pattern. These values probably represent the maximum achievable, at least by reasonable numbers of pathologists in everyday practice. They are better than those previously reported for classification based entirely on architecture, but further improvement is needed.
Subject(s)
Breast Neoplasms/classification , Carcinoma in Situ/classification , Carcinoma, Ductal, Breast/classification , Breast Neoplasms/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Europe , Female , Humans , Observer VariationABSTRACT
A detailed analysis of the consistency with which pathologists from 12 different European countries diagnose and classify breast disease was undertaken as part of the quality assurance programme of the European Breast Screening Pilot Network funded by the Europe against Cancer Programme. Altogether 107 cases were examined by 23 pathologists in 4 rounds. Kappa statistics for major diagnostic categories were: benign (not otherwise specified) 0.74, atypical ductal hyperplasia (ADH) 0.27, ductal carcinoma in situ (DCIS) 0.87 and invasive carcinoma 0.94. ADH was the majority diagnosis in only 2 cases but was diagnosed by at least 2 participants in another 14, in 9 of which the majority diagnosis was benign (explaining the relatively low kappa for this category). DCIS in 4 (all low nuclear grade) and invasive carcinoma (a solitary 1-mm focus) in 1. The histological features of these cases were extremely variable; although one feature that nearly all shared was the presence of cells with small, uniform, hyperchromatic nuclei and a high nucleo-cytoplasmic ratio. The majority diagnosis was DCIS in 33 cases; kappa for classifying by nuclear grade was 0.38 using three categories and 0.46 when only two (high and other) were used. When ADH was included with low nuclear grade DCIS there was only a slight improvement in kappa. Size measurement of DCIS was less consistent than that of invasive carcinoma. The majority diagnosis was invasive carcinoma in 57 cases, the size of the majority being 100% in 49. The remainder were either special subtypes (adenoid cystic, tubular, colloid, secretory, ductal/medullary) or possible microinvasive carcinomas. Subtyping was most consistent for mucinous (kappa, 0.92) and least consistent for medullary carcinomas (kappa, 0.56). Consistency of grading using the Nottingham method was moderate (kappa=0.53) and consistency of diagnosing vascular invasion, fair (kappa=0.38). There was no tendency for consistency to improve from one round to the next, suggesting that further improvements are unlikely without changes in guidelines or methodology.
Subject(s)
Breast Diseases/diagnosis , Breast Neoplasms/diagnosis , Breast Diseases/pathology , Breast Neoplasms/pathology , Carcinoma/diagnosis , Female , Guidelines as Topic , Humans , Hyperplasia , Neoplasm Invasiveness , PrognosisABSTRACT
To assess the variability of oestrogen receptor (ER) testing using immunocytochemistry, centrally stained and unstained slides from breast cancers were circulated to the members of the European Working Group for Breast Screening Pathology, who were asked to report on both slides. The results showed that there was almost complete concordance among readers (kappa=0.95) in ER-negative tumours on the stained slide and excellent concordance among readers (kappa=0.82) on the slides stained in each individual laboratory. Tumours showing strong positivity were reasonably well assessed (kappa=0.57 and 0.4, respectively), but there was less concordance in tumours with moderate and low levels of ER, especially when these were heterogeneous in their staining. Because of the variation, the Working Group recommends that laboratories performing these stains should take part in a external quality assurance scheme for immunocytochemistry, should include a tumour with low ER levels as a weak positive control and should audit the percentage positive tumours in their laboratory against the accepted norms annually. The Quick score method of receptor assessment may also have too many categories for good concordance, and grouping of these into fewer categories may remove some of the variation among laboratories.
Subject(s)
Breast Neoplasms/metabolism , Immunohistochemistry/standards , Receptors, Estrogen/metabolism , Staining and Labeling/standards , European Union , Female , Humans , Quality Control , Reproducibility of ResultsABSTRACT
To evaluate the accordance of size measurements of malignant breast lesions 65 women with 76 malignant lesions were preoperatively examined with triple diagnosis (mammography was performed in three views with additional views if necessary) and dynamic MR imaging using a subtraction technique with a 3D T1-weighted sequence. Maximum lesion size at histopathology was used as gold standard and compared with maximum lesion size at MRI and mammography. All measurements were made independently for each method. Histopathology verified 48 invasive, 5 in situ, and 23 mixed lesions. No significant difference was found for the pure invasive lesions ( p=0.366). In the mixed lesions a slightly better result for MRI was indicated ( p=0.116), although there was a great spread. Only five pure in situ lesions were assessed, too few to draw any statistical conclusions ( p>0.5). An overall difference indicated a slight superiority of MRI ( p=0.097). The MR imaging and mammography are both good at measuring the size of detected invasive breast malignancies. The total sizes of mixed lesions are frequently underestimated by both MRI and mammography, although the invasive parts were equally well described and measured with both methods.
Subject(s)
Breast Neoplasms/diagnosis , Breast/pathology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Carcinoma in Situ/diagnosis , Carcinoma in Situ/diagnostic imaging , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/diagnosis , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/diagnosis , Carcinoma, Intraductal, Noninfiltrating/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/pathology , Female , Humans , Magnetic Resonance Imaging , Mammography , Middle Aged , Subtraction TechniqueABSTRACT
BACKGROUND: Studies in patients with acute pancreatitis have shown a correlation between obesity and serious complications or a fatal outcome. However, the mechanisms by which obesity aggravates acute pancreatitis are not known. In the present study we used the sodium taurocholate model of pancreatitis to examine the effect of obesity on severity and outcome in acute experimental pancreatitis (AEP). METHODS: AEP was induced at two degrees of severity by retrograde infusion of sodium taurocholate (0.2 ml x 3% or 0.4 ml x 3.5%) into the pancreatic duct of rats with obesity induced by high-fat diet, genetically obese (GO) rats or lean control rats. Surviving animals were sacrificed 72 h after induction of pancreatitis. RESULTS: In the low-dose experiment, there were no significant differences in pancreatic histology or survival rate between the groups. In the high-dose experiment, the GO rats had a significantly lower 72-h survival rate than the high-fat obese (HFO) or lean control (LC) groups (GO 25% versus HFO 73%, P < 0.05; GO 25% versus LC 100%, P < 0.001). Survival rates in the high-dose experiment correlated strongly with basal liver fat content (R2 = 0.86). Pancreatic histology showed significantly more fat necrosis and a higher total pathological mean score in the HFO rats than in the LC animals (both P < 0.05). CONCLUSIONS: Obesity had a negative influence on the outcome of necrotizing pancreatitis that was related to the magnitude of the pancreatic insult. The sodium taurocholate model in obese rats would be useful for future mechanistic studies of the effect of obesity on pancreatitis.
Subject(s)
Obesity/complications , Pancreatitis, Acute Necrotizing/physiopathology , Animals , Dietary Fats/administration & dosage , Male , Obesity/genetics , Obesity/physiopathology , Pancreatitis, Acute Necrotizing/chemically induced , Rats , Rats, Zucker , Taurocholic AcidABSTRACT
PURPOSE: The aim of our prospective study was to determine the diagnostic accuracy of planar breast imaging with 99mTc-MIBI in detecting malignant disease. MATERIAL AND METHODS: Ninety-six consecutive patients with 121 clinically- and/or mammographically-detected breast lesions underwent preoperative planar scintimammography. Ten minutes after injection of 700 MBq 99mTc-MIBI, two lateral prone and one anterior supine projections with an acquisition time of 8 minutes each were obtained. Interpretation of scintimammographic results was made blindly and any focal accumulation of MIBI in the breasts was the criterion for an abnormal scintigram. All lesions were operated on and histologically verified. RESULTS: Histologically, 86 malignant and 35 benign lesions were found in 121 breast lesions. A sensitivity of 83.7% and a specificity of 74.2% for malignancy was achieved at planar scintimammography. CONCLUSION: Scintimammography with 99mTc-MIBI is an imaging modality of modest usefulness in the investigation of breast lesions. The method has a low sensitivity in lesions smaller than 10 mm in diameter, which decreases the clinical use of the method.
Subject(s)
Breast Neoplasms/diagnostic imaging , Carcinoma in Situ/diagnostic imaging , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Lobular/diagnostic imaging , Carcinoma, Papillary/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Sestamibi , Adult , Aged , Aged, 80 and over , Breast Neoplasms/surgery , Carcinoma in Situ/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , Carcinoma, Papillary/surgery , Female , Fibroadenoma/diagnostic imaging , Fibroadenoma/surgery , Follow-Up Studies , Humans , Mammography , Mastectomy , Middle Aged , Neoplasm Invasiveness , Observer Variation , Prospective Studies , Radionuclide Imaging , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
BACKGROUND: Obesity is associated with increased severity in patients with acute pancreatitis (AP). The underlying mechanisms are unknown. Genetically obese rats exhibit decreased survival rate in experimental AP, but the clinical relevance of this model of obesity may be questioned. It is proposed that development of organ failure in AP occurs in two stages: initial priming of leucocytes followed by a second inflammatory attack. The aim was to evaluate the impact of diet-induced obesity on outcome in a 'two-hit' model of AP. METHODS: Lipopolysaccharide (LPS) was injected i.p. 3 h after retrograde bile duct infusion of sodium taurocholate in rats. Three experiments were done: 1) an LPS dose-response experiment, 2) chronic high-fat feeding (HF) for 16 weeks, and 3) acute HF for 10 days. Control rats received normal chow. Obesity, morphology and survival rate were assessed. RESULTS: LPS dose-dependently decreased survival rate and increased morphological severity. HF increased weight, intra-abdominal and liver fat. Only acute HF induced hyperlipidaemia. In AP, acute obese rats exhibited less pancreatic inflammation, but total histological severity between groups was not different. In the chronic experiment only obese animals succumbed before 24 h of pancreatitis, but 72-h survival rate was not statistically different in either high-fat experiment. CONCLUSION: An addition of LPS to AP decreases survival rate and intensifies the peri-pancreatic processes. Despite significant obesity, neither hyperlipidaemia nor increased intra-abdominal or hepatic fat influenced local pancreatic injury or survival negatively. The amount of fat per se seems not to be responsible for the deleterious influence of obesity on acute pancreatitis.