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Background
The techniques of molecular biology are changing as we write. Here is a description of some of the most important diagnostic tools.
OUTLINE
Commonly Used Terms Internet Links Storage of Tissue
TECHNIQUE CHARACTERIZATION FILTER PAPER Use of FTA Gene Guard Filter Paper for the Storage and Transportation of Tumor Cells for Molecular Testing
Larry J. Dobbs, MD, PhD, Merle N. Madigan, DO, Alexis B. Carter, MD, and Lori Earls, BSMT(ASCP)
From the Brody School of Medicine at East Carolina University, Greenville, NC.
Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 56–63. Abstract quote
Context.—Efficient methods of storing tumor specimens for molecular testing are needed in the modern surgical pathology laboratory. The FTA Gene Guard system is a novel method for the collection and room temperature storage of blood samples for DNA testing. The method uses index card–sized filter papers that provide an ideal medium on which to store tumor specimens for DNA testing.
Objective.—To determine whether FTA filter paper can be used in the surgical pathology laboratory to store tumor cells for DNA testing.
Design.—Cell suspensions were prepared from 60 surgical specimens, and DNA was extracted either immediately or after storage on FTA paper. The DNA extracted by each method was tested by polymerase chain reaction (PCR) for the -globin and interferon gamma genes, and the results were compared. Fifteen lymph node specimens stored on FTA paper were then tested for immunoglobulin heavy chain (IgH) gene rearrangement by PCR, and these results were compared with those obtained for immediately extracted DNA.
Setting.—University medical center. Results.—The DNA extracted from cells stored on FTA paper performed as well in the PCR as the freshly extracted DNA in nearly all cases (>95%). The results of tests for IgH gene rearrangements showed 100% concordance between the 2 methods of DNA extraction.
onclusion.—Cells from surgical specimens can be stored on FTA paper for extended lengths of time, and DNA can be extracted from these cells for PCR-based testing. FTA filter paper is a reliable medium for the storage and/or transport of tumor cells for PCR-based DNA analysis.
Comparitive Genomic Hybridization
Enables one to obtain a scanning view of the genome of a tumor. DNA is extracted from a tumor and labeled with fluorochrome. DNA is extracted from normal tissue and labeled with fluorochrome of another color. Equal amounts of both DNA mixtures are allowed to react with a normal with a normal metaphase chromosome spread. Tumor DNA that contains extra copies of genetic material will bind to the corresponding chromosome on the metaphase spread. If the tumor DNA lacks a portion of normal DNA, more normal DNA will bind to the corresponding DNA on the metaphase spread. In both cases, the tumor DNA is distinguished from normal DNA by the different color fluorochrome tag.
TECHNIQUE CHARACTERIZATION Molecular cytogenetic analysis of a nontumorigenic human breast epithelial cell line that eventually turns tumorigenic: validation of an analytical approach combining karyotyping, comparative genomic hybridization, chromosome painting, and single-locus fluorescence in situ hybridization.
Nielsen KV, Niebuhr E, Ejlertsen B, Holstebroe S, Madsen MW, Briand P, Mouridsen HT, Bolund L.
Department of Medical Genetics, Panum Institute, University of Copenhagen, Denmark.
Genes Chromosomes Cancer 1997 Sep;20(1):30-7 Abstract quote
The immortalized, nontumorigenic human breast epithelial cell line HMT-3522 has been used as a model for premalignant and, eventually, malignant development. During cultivation, the karyotype evolution was followed. At an early stage, a very long constant phase showed a near-diploid karyotype, with only five marker chromosomes.
DNA from this phase was used for comparative genomic hybridization (CGH) analysis, confirming a previously known MYC amplification, and the integration sites were subsequently determined by single-locus fluorescence in situ hybridization (FISH). Furthermore, gains of 5q22-qter and 20q11-qter and deletion of most of chromosome 6 (6p23-qter) were detected by CGH. Because of uncertainty about some of the indicated changes, including a deletion of Ip35-pter, the CGH findings were investigated more closely by chromosome painting, leading to a revision of the karyotype: 45,XX,del(I)(p35),-6,dup(8)(pter-->qter::qter-->q24),der(12) t(6;12)(p23; p13),der(14)t(5;14)(q22;q32.3),der(17)t(8;17;20)(17pter-->17q25 ::8qter--> 8q23::8q24-->8qter::8q24-->8qter:: 8q23-->8q24.1::20q11-->20qter). Some karyotypic changes were confirmed by CGH; others had to be revised; and, in the Ip35 region, classical cytogenetics seems superior to CGH.
However, CGH revealed a karyotypically unsuspected dup(20q) that might be of special relevance to breast tumor initiation or progression.
Our study confirms that CGH is supplementary to current technologies, e.g., karyotyping and Southern analysis, but cannot replace them. In addition, our cell line turned out to be an excellent model for comparison among the different methods.
The results imply that future cytogenetic analyses of complex karyotypes should be based on a combination of karyotyping, CGH, and FISH.
High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays.
Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG.
Cancer Genetics Program, UCSF Cancer Center, University of California San Francisco, 94143-0808, USA.
Nat Genet 1998 Oct;20(2):207-11 Abstract quote
Gene dosage variations occur in many diseases. In cancer, deletions and copy number increases contribute to alterations in the expression of tumour-suppressor genes and oncogenes, respectively. Developmental abnormalities, such as Down, Prader Willi, Angelman and Cri du Chat syndromes, result from gain or loss of one copy of a chromosome or chromosomal region. Thus, detection and mapping of copy number abnormalities provide an approach for associating aberrations with disease phenotype and for localizing critical genes.
Comparative genomic hybridization (CGH) was developed for genome-wide analysis of DNA sequence copy number in a single experiment. In CGH, differentially labelled total genomic DNA from a 'test' and a 'reference' cell population are cohybridized to normal metaphase chromosomes, using blocking DNA to suppress signals from repetitive sequences. The resulting ratio of the fluorescence intensities at a location on the 'cytogenetic map', provided by the chromosomes, is approximately proportional to the ratio of the copy numbers of the corresponding DNA sequences in the test and reference genomes. CGH has been broadly applied to human and mouse malignancies. The use of metaphase chromosomes, however, limits detection of events involving small regions (of less than 20 Mb) of the genome, resolution of closely spaced aberrations and linking ratio changes to genomic/genetic markers. Therefore, more laborious locus-by-locus techniques have been required for higher resolution studies.
Hybridization to an array of mapped sequences instead of metaphase chromosomes could overcome the limitations of conventional CGH (ref. 6) if adequate performance could be achieved. Copy number would be related to the test/reference fluorescence ratio on the array targets, and genomic resolution could be determined by the map distance between the targets, or by the length of the cloned DNA segments.
We describe here our implementation of array CGH. We demonstrate its ability to measure copy number with high precision in the human genome, and to analyse clinical specimens by obtaining new information on chromosome 20 aberrations in breast cancer.
Minimal sizes of deletions detected by comparative genomic hybridization.
Bentz M, Plesch A, Stilgenbauer S, Dohner H, Lichter P.
Medizinische Klinik und Poliklinik V. Universitat Heidelberg, Germany.
Genes Chromosomes Cancer 1998 Feb;21(2):172-5 Abstract quote
Comparative genomic hybridization (CGH) has been used widely for the molecular cytogenetic analysis of tumors. Until now, the spatial resolution of this technique for diagnosing deletions of chromosomal sequences has not been assessed in detail.
In the present study, we performed CGH analyses on five DNA samples derived from B-cell leukemias with 11q deletions, the sizes of which ranged from 3 Mbp to 14-18 Mbp. CGH experiments were evaluated by two established commercial analysis systems. Deletions down to a size of 10-12 Mbp were diagnosed based on a diagnostic threshold value of 0.8, if the vast majority of cells carried the deletion.
For cases with smaller deletions, the ratio profiles were shifted toward underrepresentation at the respective chromosomal bands; however, the diagnostic threshold value was not reached. In all five cases, there was complete agreement between the two image analysis systems.
Applications of comparative genomic hybridisation in constitutional chromosome studies.
Breen CJ, Barton L, Carey A, Dunlop A, Glancy M, Hall K, Hegarty AM, Khokhar MT, Power M, Ryan K, Green AJ, Stallings RL.
National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin, Ireland.
J Med Genet 1999 Jul;36(7):511-7 Abstract quote
G band cytogenetic analysis often leads to the discovery of unbalanced karyotypes that require further characterisation by molecular cytogenetic studies. In particular, G band analysis usually does not show the chromosomal origin of small marker chromosomes or of a small amount of extra material detected on otherwise normal chromosomes.
Comparative genomic hybridisation (CGH) is one of several molecular approaches that can be applied to ascertain the origin of extra chromosomal material. CGH is also capable of detecting loss of material and thus is also applicable to confirming or further characterising subtle deletions.
We have used comparative genomic hybridisation to analyse 19 constitutional chromosome abnormalities detected by G band analysis, including seven deletions, five supernumerary marker chromosomes, two interstitial duplications, and five chromosomes presenting with abnormal terminal banding patterns.
CGH was successful in elucidating the origin of extra chromosomal material in 10 out of 11 non-mosaic cases, and permitted further characterisation of all of the deletions that could be detected by GTG banding. CGH appears to be a useful adjunct tool for either confirming deletions or defining their breakpoints and for determining the origin of extra chromosomal material, even in cases where abnormalities are judged to be subtle.
We discuss internal quality control measures, such as the mismatching of test and reference DNA in order to assess the quality of the competitive hybridisation effect on the X chromosome.
Comparative genomic hybridization: a new approach to screening for intrauterine complete or mosaic aneuploidy.
Lestou VS, Desilets V, Lomax BL, Barrett IJ, Wilson RD, Langlois S, Kalousek DK.
Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, Canada
Am J Med Genet 2000 Jun 5;92(4):281-4 Abstract quote
In the practice of clinical genetics chromosomal aneuploidy in both mosaic and nonmosaic forms has long been recognized as a cause of abnormal prenatal and postnatal development. Traditionally, cytogenetic analysis of cultured lymphocytes has been used as a standard test for detection of constitutional aneuploidies. As lymphocytes represent only one lineage, chromosomal mosaicism expressed in other tissues often remains undetected.
The purpose of this study was to assess the utilization of molecular cytogenetic analysis for detection of chromosomal aneuploidy in placental tissues. Using placentas from 100 pregnancies with viable nonmalformed livebirths, both trophoblast and chorionic stroma were analyzed using comparative genomic hybridization (CGH). In all cases with an indication of chromosomal imbalance by CGH, fluorescence in situ hybridization (FISH) analysis was performed to confirm the presence of aneuploidy.
To differentiate between constitutional aneuploidy and confined placental mosaicism (CPM), amniotic membrane was analyzed by CGH and FISH techniques. Our results demonstrated five placentas with CPM for chromosomes 2, 4, 12, 13, and 18, respectively, and two constitutional nonmosaic aneuploidies (47,XXX and 47,XXY). Molecular cytogenetic studies of human placental tissues enables easy analysis of both embryonic (amnion) and extraembryonic (chorion) cell lineages.
Detection at birth of chromosomal defects affecting intrauterine placental and fetal development is important because these chromosomal defects may continue to have an influence on postnatal development.
Science 1992;258:818-821
DNA MICROARRAYS
GENERAL CHARACTERIZATION
- DNA microarrays: from structural genomics to functional genomics. The applications of gene chips in dermatology and dermatopathology.
Sellheyer K, Belbin TJ.
Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
J Am Acad Dermatol. 2004 Nov;51(5):681-92; quiz 693-6. Abstract quote
The human genome project was successful in sequencing the entire human genome and ended earlier than expected. The vast genetic information now available will have far-reaching consequences for medicine in the twenty-first century. The knowledge gained from the mapping and sequencing of human genes on a genome-wide scale--commonly referred to as structural genomics--is prerequisite for studies that focus on the functional aspects of genes.
A recently invented technique, known as gene chip, or DNA microarray, technology, allows the study of the function of thousands of genes at once, thereby opening the door to the new field of functional genomics. At its core, the DNA microarray utilizes a unique feature of DNA known as complementary hybridization. As such, it is not different from Southern (DNA) blot or northern (RNA) blot hybridizations, or the polymerase chain reaction, with the exception that it allows expression profiling of the entire human genome in a single hybridization experiment. The article highlights the principles, technology, and applications of DNA microarrays as they pertain to the field of dermatology and dermatopathology. The most important applications are the gene expression profiling of skin cancer, especially of melanoma.
Other potential applications include gene expression profiling of inflammatory skin diseases, the mutational analysis of genodermatoses, and polymorphism screening, as well as drug development and chemosensitivity prediction. cDNA microarrays will shape the diagnostic approach of the dermatology and the dermatopathology of the future and may lead to new therapeutic options
Fluorescence In Situ Hybridization (FISH)
Fluorescent labeled DNA probes directed at specific DNA sequences bind to their complementary DNA. Thus, chromosomes as well as translocations and microdeletions may be found.
TECHNIQUE CHARACTERIZATION Multiplex-FISH for pre- and postnatal diagnostic applications.
Uhrig S, Schuffenhauer S, Fauth C, Wirtz A, Daumer-Haas C, Apacik C, Cohen M, Muller-Navia J, Cremer T, Murken J, Speicher MR.
Institut fur Anthropologie und Humangenetik, LMU Munchen, D-80336 Munchen, Germany.
Am J Hum Genet 1999 Aug;65(2):448-62 Abstract quote
For >3 decades, Giemsa banding of metaphase chromosomes has been the standard karyotypic analysis for pre- and postnatal diagnostic applications. However, marker chromosomes or structural abnormalities are often encountered that cannot be deciphered by G-banding alone.
Here we describe the use of multiplex-FISH (M-FISH), which allows the visualization of the 22 human autosomes and the 2 sex chromosomes, in 24 different colors. By M-FISH, the euchromatin in marker chromosomes could be readily identified.
In cases of structural abnormalities, M-FISH identified translocations and insertions or demonstrated that the rearranged chromosome did not contain DNA material from another chromosome. In these cases, deleted or duplicated regions were discerned either by chromosome-specific multicolor bar codes or by comparative genomic hybridization. In addition, M-FISH was able to identify cryptic abnormalities in patients with a normal G-karyotype.
In summary, M-FISH is a reliable tool for diagnostic applications, and results can be obtained in
Microdissection and Preservation of Tissues
TECHNIQUE CHARACTERIZATION Microdissection Is Essential for Gene Expression Profiling of Clinically Resected Cancer Tissues
Yuko Sugiyama, MD
Kazuo Sugiyama, MD, PhD
Yasuo Hirai, MD, PhD
Futoshi Akiyama, MD, PhD
Katsuhiko Hasumi, MD, PhDAm J Clin Pathol 2002;117:109-116 Abstract quote
The gene expression array method enables us to achieve expression profiling with thousands of genes. Clinically resected bulk cancer tissues, however, contain not only cancer cells but also stromal cells, which may affect gene expression profiling and hamper accurate analysis of the cancer cells per se.
Therefore, a procedure for dissecting specific cells, such as laser capture microdissection, is needed for the clinical application of a gene expression array. There has been no study actually comparing 2 gene expression profiles, one obtained using RNA extracted from cancer cells by laser capture microdissection and one obtained using RNA extracted from bulk cancer tissues.
We first demonstrated the difference in expression patterns between them, without any amplification procedures. In addition, differential expression analysis between tumor and nontumor tissue yielded quite different patterns between the 2 methods. We conclude that microdissection is essential for gene expression profiling of clinical specimens.
An efficient method for the assessment of DNA quality of archival microdissected specimens.Siwoski A, Ishkanian A, Garnis C, Zhang L, Rosin M, Lam WL.
British Columbia Cancer Research Centre (AS, AI, CG, MR, WLL), Vancouver.
Mod Pathol 2002 Aug;15(8):889-92 Abstract quote There will be an increasing need of methods for assessing the suitability of specimens for genetic-based assays as DNA markers become an integral part of molecular diagnosis. The targeting of specimens for specific analyses will require the ability to rapidly screen for DNA quality. Conventional methods such as Southern analysis and gene specific-polymerase chain reaction (PCR) often require quantities of material that represent a significant portion of the specimen, especially in microdissected samples.
Here we describe a novel application of a commonly used PCR-based DNA-fingerprinting technology that requires minimal quantities of DNA to simultaneously assess multiple regions throughout the genome for DNA quality. Randomly amplified polymorphic DNA (RAPD) PCR generates DNA fragments of a broad size range with the product size reflecting the degree of sample fragmentation. Fourteen DNA samples extracted from cells microdissected from seven formalin-fixed, paraffin-embedded oral cancer biopsies were assessed for DNA quality using gene-specific PCR and RAPD-PCR.
Although the more conventional assay required 2-ng DNA (or 300-cell equivalents) to examine DNA quality at a single locus, RAPD-PCR provided a more informative profile of DNA quality from the same microdissected archival specimens.
Analysis of the Molecular Quality of Human Tissues
An Experience From the Cooperative Human Tissue Network
Scott D. Jewell, PhD
Mythily Srinivasan, PhD
Linda M. McCart
Nita Williams
William H. Grizzle, MD, PhD
Virginia LiVolsi, MD
Greg MacLennan, MD,
and Daniel D. Sedmak, MDAm J Clin Pathol 2002;118:733-741 Abstract quote
The scientific usefulness of the data obtained from tissue analysis is related to specimen quality, which may be affected by conditions that may contribute to the degradation of the specimen before processing and analysis.
We determined the usability of nucleic acids extracted from banked human tissues for further molecular analyses. We assayed 151 tissue specimens, stored for various times at 4 divisions of the Cooperative Human Tissue Network, National Cancer Institute, Bethesda, MD, for DNA and RNA degradation. Simple electrophoresis, polymerase chain reaction (PCR), reverse-transcriptase (RT)-PCR, and Northern blot analysis were compared to determine the optimal quality control procedure. In addition, a time course degradation procedure was performed on human lung tissue.
Gel electrophoresis was as informative as PCR, RT-PCR, and Northern blot analysis in determining the molecular usefulness of the human tissues. Overall, 80% of the stored human tissues had good-quality DNA, and 60% had good-quality RNA. Electrophoresis procedures for DNA and RNA offer a quick and valuable measure of the molecular quality of stored human tissues. The DNA and RNA degradation of one tissue type (lung) was stable for both nucleic acids for up to 5 hours after excision.Polymerase chain reaction (PCR)
PCR can be performed upon formalin-fixed paraffin embedded tissues. Primers that are complementary to the sequences that one wishes to detect are used and a DNA polymerase enzyme is used. Thus, from one complementary sequence, the entire replication process is amplified and numerous copies of the DNA sequence can be obtained. There are now a number of separation methods that may also be applied to PCR.
SEPARATION TECHNIQUES DESCRIPTION Polyacrylamide Gel Electrophoresis (PGE) Separates DNA segments by size and length Denaturing Gradient Gel Electrophoresis (DGGE) Separates DNA by nucleotide sequence Single-strand Conformation Polymorphism analysis (SSCP) Separates DNA by nucleotide sequence Automated High-Resolution PCR fragment analysis PCR amplification is performed with fluorescent-labeled primers and separated by automated sequencing system
Analysis of fluorescent labeled DNA lengthmakers yields the exact size of each peak leading to differentiation of DNA segments differing by as little as one base pair
UTILITY CHARACTERIZATION IMMUNOGLOBULIN/T CELL RECEPTOR GENE REARRANGMENT Southern Blot analysis
PCRDETECTION OF CHROMOSOMAL TRANSLOCATION (GENE FUSION) Conventional cytogenetics
FISH
Southern Blot
PCR
FALSE POSITIVES OR NEGATIVES CHARACTERIZATION No detectable bands clonal Ig or TCR bands by PCR This does not rule out a lymphoma. There is an inherent false negative rate of ~30%.
Although very sensitive, it may fail to amplify the clonal Ig or TCR gene due to poor annealing of the primers with the rearranged Ig or TCR gene as a result of somatic hypermutations, differential annealing of primers with certain VH or JH families, interference from translocated gene segments (such as bcl-2 and bcl-6), unusual IgH or TCR gene rearrangements, and other uncharacterized moleculr or technical factorsClonal bands with a very small sample by PCR Small samples may yield pseudoclones which may be sufficient to give rise to a discrete band
Results can be considered significant only if repeatable in multiple separate DNA extractionsFORMALIN FIXATION
Effect of duration of fixation on quantitative reverse transcription polymerase chain reaction analyses.Macabeo-Ong M, Ginzinger DG, Dekker N, McMillan A, Regezi JA, Wong DT, Jordan RC.
Oral Pathology, Department of Stomatology (MM-O, ND, JAR, RCKJ).
Mod Pathol 2002 Sep;15(9):979-87 Abstract quote Increasingly, there is the need to analyze gene expression in tumor tissues and correlate these findings with clinical outcome. Because there are few tissue banks containing enough frozen material suitable for large-scale genetic analyses, methods to isolate and quantify messenger RNA (mRNA) from formalin-fixed, paraffin-embedded tissue sections are needed. Recovery of RNA from routinely processed biopsies and quantification by the polymerase chain reaction (PCR) has been reported; however, the effects of formalin fixation have not been well studied.
We used a proteinase K-salt precipitation RNA isolation protocol followed by TaqMan quantitative PCR to compare the effect of formalin fixation for 24, 48, and 72 hours and for 1 week in normal (2), oral epithelial dysplasia (3), and oral squamous cell carcinoma (4) specimens yielding 9 fresh and 36 formalin-fixed samples. We also compared mRNA and protein expression levels using immunohistochemistry for epidermal growth factor receptor (EGFR), matrix metalloproteinase (MMP)-1, p21, and vascular endothelial growth factor (VEGF) in 15 randomly selected and routinely processed oral carcinomas. We were able to extract RNA suitable for quantitative reverse transcription (RT) from all fresh (9/9) and formalin-fixed (36/36) specimens fixed for differing lengths of time and from all (15/15) randomly selected oral squamous cell carcinoma. We found that prolonged formalin fixation (>48 h) had a detrimental effect on quantitative RT polymerase chain reaction results that was most marked for MMP-1 and VEGF but less evident for p21 and EGFR. Comparisons of quantitative RT polymerase chain reaction and immunohistochemistry showed that for all markers, except p21, there was good correlation between mRNA and protein levels. p21 mRNA was overexpressed in only one case, but protein levels were elevated in all but one tumor, consistent with the established translational regulation of p21.
These results show that RNA can be reliably isolated from formalin-fixed, paraffin-embedded tissue sections and can produce reliable quantitative RT-PCR data. However, results for some markers are adversely affected by prolonged formalin fixation times.
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Taken from Chan JKC. Practical Lymphoma Diagnosis: A Simplified Approach. Presented at the 111th Semi-Annual California Tumor Tissue Registry. December 2001
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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
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Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Linkage Analysis-Gene mapping technique which identifies polymorphic DNA markers that closely border the gene of interest. This technique takes advantage of the fact that the chromome region surrounding the gene of interest usually remains in place during meiotic recombination. Smaller pieces of DNA are less likely to become separated. The polymorphic DNA markers have different variant or alleles and will occur only in patients with the defective variant of the known gene.
LOD Score-Acronym which stands for logarithm of odds. It is an estimate of the probability, compared to chance, that the chromosome region carrying the markers also carries the disease gene. Most studies accept a LOD score of 3 which indicates that the observed outcome is 1,000 times more likely to have occurred with a linked, rather than unlinked, marker and disease gene.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
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