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Born as orthodox catholic in 1700 in Leyden, Gerard van Swieten was orphaned as a child in 1712. He studied medicine under Herman Boerhaave in Leyden from 1720, recording the lectures of his mentor and publishing them after his death. Following his graduation in 1715, van Swieten practiced medicine and pharmacy in Leyden, giving private lectures to students in both fields. Van Swieten became known as a brilliant doctor, and it was expected that he might succeed to Boerhaave’s position after his death in 1738; however, his catholic faith was an obstacle for the protestant State University. These very beliefs, however, contributed to his instatement as the personal physician of the Austrian Empress Maria Theresia (1717–1780) in October 1744. In the summer of 1745 he was appointed physician to Maria Theresa in Vienna by Franz I. and at the same time appointed prefect of the court library. In addition to taking care of the library, other tasks he received from Maria Theresia included reformation of the medical faculty, improving the quality of Vienna’s clinics and promoting healthcare in the empire. Van Swieten is seen as one of the founders of the so-called First Wiener Medical School (Erste Wiener Medizinische Schule) in 1745, and was at the founding of the first modern clinic in 1754. Van Swieten died June 18, 1772.

Descriptions of endometriosis in 18th century monographs and manuscripts are rare and the recorded macroscopic features of endometriosis seldom support this attribution to the described cases. Recently, we became aware of an anonymous German autopsy report from the 18th century. After transcription, the manuscript was assessed by pathologists with historical expertise. This revealed that the patient died because of a malignant tumor, most probably of a gynecological origin. Furthermore, the described ovarian pathologic findings strongly support the diagnosis endometriotic ovarian cyst. Like Giovanni Battista Morgagni (1668–1772) in his landmark publication De Sedibus et Causis Morborum per Anatomen Indagatis (1761), the author correlated the pathological findings at autopsy with the symptoms of the patient. The identity of the patient could, with high probability, be established as being the Countess of Reitzenstein, the wife of a Prussian general major in the army of Friedrich the Great: Karl Erdmann von Reitzenstein (1722–1789).

The purpose of medical autopsy has changed to issues of quality assurance today. In addition, autopsies are considered valuable in medical education, e.g., delivering cases for problem-based learning for students. Many studies underscore the need for autopsies also in the era of technical progress emphasizing the continuing discrepancies between antemortem and post mortem diagnoses. Despite these important tasks, we face a decline of autopsy for several reasons with complex interactions. The role of all persons involved in this decline is evaluated and suggestions for changes are proposed. Last but not least, the future of the autopsy is in the hands of pathology itself.

IntroductionCurrently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient’s prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged≤40 years.Methods and analysisAll young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle.Ethics and disseminationObservational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a ‘non-WMO’ declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

An important indication for bone marrow investigation is the presence of bone marrow failure, which manifests itself as (pan)cytopenia. The causes of cytopenia are varied and differ considerably between childhood and adulthood. In the paediatric age group inherited bone marrow failure syndromes are important causes of bone marrow failure, but they play only a minor role in later life. This review gives a comprehensive overview of bone marrow failure disorders in children and adults. We classified the causes of bone marrow failure according to the main presenting haematological abnormality, i.e. anaemia, neutropenia, thrombocytopenia or pancytopenia. The following red cell disorders are discussed: red cell aplasia, sideroblastic anaemia, congenital dyserythropoietic anaemia, haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, iron deficiency anaemia, anaemia of chronic disease and megaloblastic anaemia. The neutropenias occur in the context of Shwachman-Diamond syndrome (SDS), severe congenital neutropenia, cyclic neutropenia, immune-related neutropenia and non-immune neutropenia. In addition, the following causes of thrombocytopenia are discussed: congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, immune-related thrombocytopenia and non-immune thrombocytopenia. Finally, we pay attention to the following pancytopenic disorders: Fanconi anaemia, dyskeratosis congenita, aplastic anaemia, myelodysplastic syndromes and human immunodeficiency virus (HIV) infection.

With the free movement of people in the European Union, medical mobility has increased significantly. This is notably the case for disciplines for which shortage of well-trained staff has occurred. Pathology is among those specialties and effectively the discipline is confronted with a striking increase in mobility among trainees and qualified specialists. The presumption underlying unlimited mobility is that the competencies of the medical specialists in the European countries are more or less equal, including significant similarities in the postgraduate training programs. In order to assess whether reality corresponds with this presumption, we conducted a survey of the content and practice requirements of the curricula in the EU and affiliated countries. The results indicate a striking heterogeneity in the training program content and practice requirements. To name a few elements: duration of the training program varied between 4 and 6 years; the number of autopsies required varied between none at all and 300; the number of biopsies required varied between none at all and 15,000. We conclude that harmonization of training outcomes in Europe is a goal that needs to be pursued. This will be difficult to reach through harmonization of training programs, as these are co-determined by political, cultural, and administrative factors, difficult to influence. Harmonization might be attained by defining the general and specific competencies at the end of training and subsequent testing them through a test to which all trainees in Europe are subjected.

Killer cell immunoglobulin-like receptors (KIRs) expressed on donor natural killer (NK) cells are important for induction of NK cell alloreactivity in haematopoietic stem cell transplantation (HSCT). Current criteria in the selection procedure of an unrelated donor do not account for this potential NK alloresponse. In this study the KIR gene repertoire of 21 HSCT patients and all their potential, unrelated donors (N = 64) has been identified by the sequence-specific priming (SSP) procedure. KIR genotype characteristics are correlated with HLA and clinical data. These data show that for 16 cases an HLA compatible alternative donor was available. Among those 16 were 8 donors with a favourable predicted NK alloreactivity directed against the leukaemic cells. In conclusion, it is feasible and clinically relevant to add the KIR repertoire to the unrelated donor selection procedure.

After left ventricular assist device (LVAD) support in patients with end-stage cardiomyopathy, cardiomyocytes decrease in size. We hypothesized that during this process, known as reverse remodeling, the basement membrane (BM), which is closely connected to, and forms the interface between the cardiomyocytes and the extracellular matrix, will be severely affected. Therefore, the changes in the myocardial BM in patients with end-stage heart failure before and after LVAD support were studied. The role of MMP-2 in this process was also investigated. Transmission electron microscopy showed that the BM thickness decreased post-LVAD compared to pre-LVAD. Immunohistochemistry indicated a reduced immunoreactivity for type IV collagen in the BM after LVAD support. Quantitative PCR showed a similar mRNA expression for type IV collagen pre- and post-LVAD. MMP-2 mRNA almost doubled post-LVAD (P

Most of the 119 human leukocyte antigen (HLA)-DPB1 alleles are defined by polymorphism in six hypervariable regions (HVRs) in exon 2 of the HLA-DPB1 gene. We investigated how DPB1 polymorphism is represented in the entire coding region. An RNA sequencing-based typing (SBT) approach was developed for the identification of HLA-DPB1 polymorphism from the 5' untranslated region (UTR) through the 3'-UTR. B-cell lymphoblastoid cell lines, encoding 16 different DPB1 alleles, were studied. Results show additional HLA-DPB1 polymorphism in exons 1, 3, 4 and 5 and the 5' and 3'-UTR. Four new HLA-DPB1 alleles were identified, DPB1*0502, DPB1*0602, DPB1*0802 and DPB1*0902, which have exon 2 sequences identical to other DPB1 alleles but differ in the extended region. The additional polymorphism represents two main polymorphic lineages in the DPB1 alleles. Among the HVRs in exon 2, only HVR F correlates with these two main lineages.

A new variant of the HLA-A*010101 allele designated as HLA-A*0111N, previously known as HLA-A*010101var, was identified in a patient requiring a stem-cell transplantation. The patient was typed by serologic methods as HLA-A2 homozygous and by sequence-based typing (SBT) as A*010101,020601. Flow-cytometric (FCM) analysis with 11 human monoclonal antibodies (mAbs) for the A1 molecule confirmed lack of any cell membrane expression of the A*0111N allele. One-dimensional isoelectric focusing (1D-IEF) of total cell lysate from the patient’s cells revealed no cell surface and cytoplasmic A1 protein expression, whereas the HLA-A2 molecule was identified by both FCM analysis and 1D-IEF. DNA sequence analysis showed the presence of a synonymous substitution from G to T at position 597 in codon 175. RNA SBT revealed a deletion of 24 bp in exon 3, position 596 through 619, encoding codons 175 through 182 of the HLA-A*0111N allele. The synonymous substitution introduced a new splice site, resulting in an efficient splicing, because no classical A1 protein could be detected in the patient. This alternative splicing prevented the translation into a correct and stable class I molecule expression on the cell surface.

Chronic graft-versus-host disease (cGVHD) is an important determinant of long-term morbidity and mortality in allogeneic stem cell transplantation patients. Because cGVHD has clinical, histologic, and laboratory findings of autoimmune diseases and anti–B-cell therapy has shown efficacy in autoimmune diseases, we hypothesized that monoclonal anti-CD20 antibody therapy might improve patients with cGVHD. We treated 5 men and 1 woman with therapy-refractory extensive cGVHD with anti-CD20 monoclonal antibody. Intravenous infusion was given at a weekly dose of 375 mg/m2 for 4 weeks. In case of incomplete clinical response, additional courses of 4 weeks were given. Five patients responded to treatment with marked clinical, biochemical, and histologic improvement. One patient failed to respond. Anti-CD20 monoclonal antibody seems to be effective in cGVHD. A controlled trial is mandatory to confirm these results. The outcome of this study suggests a participating role of B cells in the pathogenesis of cGVHD.

Left ventricular assist device (LVAD) implantation in patients with end-stage heart failure results in impressive hemodynamic improvement. The effects on myocardial apoptosis and its mediators are unknown.Myocardial biopsies from 17 patients at the time of LVAD implantation and after explantation, at the time of heart transplantation (HTx), were examined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) reaction and with antibodies against Fas ligand (FasL), Fas, tumor necrosis factor (TNF)-alpha receptor 1 (TNF-R1), TNF-alpha receptor 2 (TNF-R2), TNF-alpha, TNF-alpha-converting enzyme (TACE), poly(ADP-ribose) polymerase (PARP), poly(ADP-ribose) (PAR), caspase-3 and FLICE inhibitory protein (FLIP).Apoptosis incidence was low: 0.8% (range 0% to 3%) positive cardiomyocytes nuclei before support, and 0.1% (range 0% to 0.6%) after support (p0.01). This was accompanied by low expression of caspase-3 and high expression of the DNA repair enzyme, PARP. Its product, PAR, increased after support. Mediators and receptors inducing apoptosis as well as FLIP were widely present before and after support.Despite the abundant presence of mediators and receptors inducing apoptosis, the incidence of apoptosis itself was low before and after mechanical support. The abundant expression of FLIP may suggest an important role for this protein in the inhibition of cardiomyocyte death.

Background: The cytokine interleukin-4 (IL-4) is secreted mainly by activated T lymphocytes and characterizes the T-helper 2 (Th2) sub-type. In transplantation Th2 cells are believed to induce graft tolerance. Previous studies revealed that patients with a relatively high frequency of IL-4 producing helper T lymphocytes (HTL) before heart transplantation (HTX) had no or less rejection episodes compared with patients with a low frequency of IL-4 producing HTL. Three single nucleotide polymorphisms (SNPs) have been identified in the promoter region of the IL-4 gene, which influence promoter strength. We investigated whether there was a correlation between SNP genotypes in the IL-4 promoter and heart failure, and rejection after HTX. Methods: Seventy HTX patients, 61 donors, and 36 controls were genotyped for the 3 SNPs by sequencing. Results: Of the SNPs at −285 and −81, only the C and A alleles, respectively, were found in this study. Both alleles were found for the −590 SNP. No relation between patient genotype of the SNP at −590 and heart failure and rejection was found. However, incidence of rejection was significantly lower in patients that received a donor heart with the T-positive genotype compared with patients that received a heart from a T-negative donor. Patients who had the T-negative genotype and received a heart from a T-positive donor, suffered significantly less from rejection than T-negative patients that received a T-negative donor heart. This was not significant in the T-positive patient group. Conclusions: This indicates that IL-4 production within the donor heart and by cells from the donor is important for reducing incidence of episodes of rejection.

Neural network-based screening (NNS) of cervical smears can be performed as a so-called "hybrid screening method," in which parts of the cases are additionally studied by light microscope, and it can also be used as "pure" NNS, in which the cytological diagnosis is based only on the digital images, generated by the NNS system. A random enriched sample of 985 cases, in a previous study diagnosed by hybrid NNS, was drawn to be screened by pure NNS. This study population comprised 192 women with (pre)neoplasia of the cervix, and 793 negative cases. With pure NNS, more cases were recognized as severely abnormal; with hybrid NNS, more cases were cytologically diagnosed as low-grade. For a threshold value > or = HSIL (high-grade squamous intraepithelial lesions), the areas under the receiver operating characteristic (ROC) curves (AUC) were 81% (95% CI, 75-88%) for pure NNS vs. 78% (95% CI, 75-81%) for hybrid NNS. For low-grade squamous intraepithelial lesions (LSIL), the AUC was significantly higher for hybrid NNS (81%; 95% CI, 77-85%) than for pure NNS (75%; 95% CI, 70-80%). Pure NNS provides optimized prediction of HSIL cases or negative outcome. For the detection of LSIL, light microscopy has additional value.

HLA class I and beta-2-microglobulin (β2m) expression in a moderately differentiated laryngeal squamous cell carcinoma appeared to be downregulated when analyzed by immunohistochemical procedures using the monomorphic anti-HLA class I monoclonal antibody (mAb; W6/32), locus-specific (HCA2 and HC10) and allele-specific (LT129.11 and KRE501) mAbs and anti-β2m mAbs. To reveal the molecular basis of downregulated HLA class I expression, HLA-A typing was performed on DNA derived from peripheral blood lymphocytes (PBL) and the tumor. Sequencing-based typing (SBT) revealed HLA-A*02011, 31012. In addition to HLA-A*02011, 31012 alleles, the tumor contained an HLA-A*31012 allele, which lacked all introns when sequenced from the initiation codon through exon eight. The 3′ UTR region was intact up to at least 200 bp downstream. The mutant HLA-A*31012 is restricted to laryngeal tumor tissue since it was not amplified in flanking tumor-free laryngeal tissue. The mutant HLA-A*31012 shares structural characteristics with processed pseudogenes, i.e., absence of introns and an intact 3′ UTR. This indicates that the mutant HLA-A*31012 allele resulted from a retroposition (reverse transcription and integration) from the processed transcript of the wild-type HLA-A*31012 allele within a clonal tumor cell. Genes Chromosomes Cancer 27:26–34, 2000. © 2000 Wiley-Liss, Inc.

In cryostat sections of 84 head and neck squamous cell carcinomas (HNSCC) HLA class I and beta 2m expression was analysed using monomorphic and locus specific monoclonal antibodies. Loss of expression was heterogeneous and none of the tumours tested showed a total loss of HLA class I and/or beta 2m when analysed with W6/32, which recognises HLA class I determinants and anti-beta 2m MoAbs. Weak HLA class I and beta 2m expression was found in 9 tumours (11%) and heterogeneous expression was found in 2 tumours (2%). When analysed with locus-specific antibodies (HCA2 and HC10, anti-HLA-A and anti-HLA-B/C, respectively) 37 tumours (44%) showed a loss, weak or heterogeneous expression of one or both loci. Tumours showing a down-regulated HLA class I expression were analysed for mutations in either allele of the beta 2m gene by sequencing based mutation analysis (SBMA). Exon 1 and exons 2 and 3 were amplified separately by PCR using M13-tailed intron-specific primers. PCR products were sequenced in two directions. In none of the tumours mutations in the beta 2m gene were detected. In 59% of the tumours with down-regulated HLA class I expression, lost or down-regulated TAP 1 expression was found when analysed with anti-TAP 1 antibodies. This indicates an important role for TAP in down-regulation of HLA class I expression in HNSCC.

ABSTRACT: Sequencing Based Typing (SBT) is a generic approach for the identification of HLA-A polymorphism. This approach includes the high resolution typing of the HLA-A broad reacting groups, HLA-A subtypes and will identify new alleles directly. The SBT approach described here uses a locus specific amplification of DNA from exon 1 to exon 5. The resulting 2,022 bp PCR product serves as a template for the subsequent sequencing reactions. Amplification is followed by direct sequencing of exons 2, 3 and 4 in both orientations with fluorescently labeled primers to define all polymorphic positions leading to a high resolution typing result. In this study the sequence of exons 2 and 3 of a panel of 49 cell lines was determined. In addition, the exon 4 region of 35 cell lines was also sequenced to evaluate the exon 4 polymorphism. The HLA-A type of most of the cells could be identified by sequencing only exons 2 and 3. However, the sequence of exon 4 was required to discriminate A∗0201 from A∗0209 and A∗0207 from A∗0215N. In this panel, an identical new “HLA-A∗0103” was identified in two Caucasian samples.

Many patients with exocrine pancreatic cancer develop diabetes mellitus due to insulin resistance. This may relate to concurrent over-production of islet amyloid polypeptide (IAPP) by the pancreatic beta cells. We investigated the effects of pancreatic cancer on circulating IAPP and glucose homeostasis in azaserine-treated rats (developing acinar pancreatic tumours) and BOP-treated hamsters (developing ductular pancreatic tumours). Glucose, insulin and IAPP levels in plasma were neither affected in azaserine-only treated rats nor in animals with enhanced carcinogenesis after chronic caerulein treatment. Azaserine-treated rats on a high-fat diet had decreased insulin levels and enhanced IAPP/insulin ratios in plasma, without hyperglycaemia. All BOP-treated hamsters showed pancreatic carcinogenesis at 6 months post-treatment. Supranormal plasma glucose levels in animals on a low-fat diet were the only change observed. After a second 6-month period, subnormal plasma glucose levels, at least 4-fold decreased plasma insulin and up to 2-fold decreased plasma IAPP levels were present in all hamsters. Remarkably, both in azaserine-treated rats on high-fat and in BOP-treated hamsters, decreased insulin levels and elevated IAPP/insulin ratios are not associated with hyperglycaemia. In contrast to humans with pancreatic cancer, IAPP over-production and hyperglycaemia do not develop in rats and hamsters with (pre-)neoplastic pancreatic lesions. Int. J. Cancer 72:637–641, 1997. © 1997 Wiley-Liss, Inc.

BACKGROUND Hypoplastic myelodysplastic syndrome (MDS) is characterized by dysplasia and hypocellularity. The treatment of choice for young patients is bone marrow transplantation. METHODS This report describes the effect of immunosuppressive therapy in two patients with hypoplastic MDS for whom no suitable bone marrow donors were available. RESULTS Both patients had no human lymphocyte antigen-identical siblings and no suitable matched unrelated donor could be found. They received cyclosporin A (CsA), antithymocyte globulin (ATG), or a combination of the two. Treatment with CsA, ATG, or the combination led to clinical improvement (resolution of transfusion requirement), increase of bone marrow cellularity, and the disappearance of dysplastic characteristics in the two patients with hypoplastic MDS. At the time of recurrence, this disease was still responsive to immunosuppressive therapy. CONCLUSIONS Treatment with ATG and CsA can be an attractive alternative for patients with hypoplastic MDS for whom there is no possibility of bone marrow transplantation. Cancer 1997; 79:1548-51. © 1997 American Cancer Society.

Here we report two cases in which healthy young patients died during surgery because ventilation was impossible by a clinical picture of massive subcutaneous emphysema. The probable diagnosis was tracheal rupture. This diagnosis was not confirmed during coroner's autopsy, but there had been no systematic search for a puncture in the trachea or the main bronchial tubes. Immediate recognition of this situation, and implementation of ventilation of one lung by pushing a narrower endobronchial tube beyond the tracheal rupture, is potentially life-saving.

Objective To examine the reliability of clinical examination and in vivo confocal microscopy (IVCM) in distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions. Design Case-control study. Participants Sixty individuals with conjunctival lesions (OSSN and benign) and 60 age-matched controls with normal conjunctiva presenting to Kilimanjaro Christian Medical Centre, Moshi, Tanzania. Methods Participants were examined and photographed, and IVCM was performed. Patients with conjunctival lesions were offered excisional biopsy with histopathology and a human immunodeficiency virus (HIV) test. The IVCM images were read masked to the clinical appearance and pathology results. Images were graded for several specific features and given an overall categorization (normal, benign, or malignant). A group of 8 ophthalmologists were shown photographs of conjunctival lesions and asked to independently classify as OSSN or benign. Main Outcome Measures Comparison of the histopathology diagnosis with the clinical and IVCM diagnosis. Results Fifty-two cases underwent excisional biopsy with histopathology; 34 were on the OSSN spectrum, 17 were benign, and 1 was lymphoma. The cases and controls had comparable demographic profiles. Human immunodeficiency syndrome infection was more common in OSSN compared with benign cases (58.8% vs. 5.6%; odds ratio, 24.3, 95% confidence interval [CI], 2.8–204; P = 0.003). Clinically, OSSN lesions more frequently exhibited feeder vessels and tended to have more leukoplakia and a gelatinous appearance. Overall, the ophthalmologists showed moderate agreement with the histology result (average kappa = 0.51; 95% CI, 0.36–0.64). The masked grading of IVCM images reliably distinguished normal conjunctiva. However, IVCM was unable to reliably distinguish between benign lesions and OSSN because of an overlap in their appearance (kappa = 0.44; 95% CI, 0.32–0.57). No single feature was significantly more frequent in OSSN compared with benign lesions. The sensitivity and specificity of IVCM for distinguishing OSSN from benign conjunctival lesions were 38.5% and 66.7%, respectively. Conclusions In East Africa, conjunctival pathology is relatively common and can present significant diagnostic challenges for the clinician. In this study, neither clinical examination nor IVCM was found to reliably distinguish OSSN from benign conjunctival pathology because of an overlap in the features of these groups. Therefore, IVCM cannot currently replace histopathology, and management decisions should continue to rely on careful clinical assessment supported by histopathology as indicated.

Migration patterns of leukemic cells in bone marrow are largely regulated by cell contacts between leukemic cells and stromal cells or extra-cellular matrix. The mechanism of this interaction with bone-marrow stromal cells was studied in a human in vitro model. Migration behavior of erythroleukemia cell line K562, derived from a patient with chronic myeloid leukemia, was compared with that of the erythroleukemia cell line HEL92.1.7 and the promyelocytic leukemia cell line HL60 from acute leukemias. Interaction varied between low binding affinity (K562) to intensive cell interaction (HEL92.1.7) followed by invasion into the stromal cell monolayer. Some of the HL60 cells adhered to stromal cells, while the remainder migrated into the stromal cell monolayer. The role of adhesion molecules in these cell interactions was determined. Distinct expression of beta1-integrins ICAM-1, CD44 and VCAM-1 was detected on the different cell lines. Inhibition studies pointed to a dominant role of VLA-4- and VLA-5-mediated interactions. K562 lacked VLA-4 and a low binding affinity of the VLA-5 on these cells resulted in an absence of binding to the bone-marrow stroma. These results indicate the VLA-5/fibronectin, VLA-4/fibronectin and the VLA-4/VCAM-1 interaction pathways between leukemic cells and bone-marrow stroma.

In a retrospective study of ductal carcinoma in situ (DCIS) of the breast, the expression of the neu oncogene was determined immunohistochemically in 76 women treated by local excision or mastectomy. The histopathological features, including the extent of the lesion, histological subtype, cell type, and number of mitoses, were related to neu overexpression. Immunopositivity was found only in DCIS of large cell type, where it correlated with extent of disease but not with mitotic rate. Our findings, together with previous experimental evidence, suggest that this relationship is a consequence of the effect of the neu protein on cell motility.

For the past 150 years the most constant factor in the pathologist's histopathological diagnostic work-up has been haematoxylin staining. This technique, in combination with later additional staining techniques, determined knowledge on a cellular level for a long time. The invention of the transmission electron microscope added an ultrastructural dimension, and for many decennia in the middle of the twentieth century this was an important diagnostic tool. Enzyme histochemistry and morphometry came next, but these techniques never really became important as they were largely overtaken by immunohistochemistry and molecular diagnostics. These, in their turn, will face competition from proteomics and other forms of genomics. It seems likely that the trusty light microscope will lose out to digital microscopy, which is developing rapidly and offers the possibility to make a diagnosis at a distance. Pathology will continue to be a specialty on the move.

Background The only realistic way to improve harmonisation of European pathology training is to define the generally accepted competencies and to test them periodically during the training programme (progress test). The European Association of Pathology Chairs and Program Directors therefore decided to implement an annual on-line test using virtual slides in addition to static jpeg images and theoretical MCQ’s. The EU supported this endeavour as EUROPALS (EUROpean Pathology Assessement & Learning System). Methods To address the challenges of large scale digital testing EUROPALS teamed up with i-Path Diagnostics Ltd, a company specialising in utilisation of virtual slides in histology/pathology education and examination. Specific examination software was used in the test system. Results In the first 2 years we provided at five occasions progress tests, including 2 proctored tests, attracting hundreds of participants. The accessibility varied from suboptimal to good and improved with each subsequent test. It was influenced both by the hosting server capacity and the internet bandwidth at the user’s location. Conclusion On-line testing using virtual slides is possible but requires a good collaboration between the provider and the user. Both should be aware of the requirements and threads of large scale testing with hundreds of simultaneous users.

Recognition of HLA-C molecules by killer cell immunoglobulin-like receptors (KIRs) is an important mechanism in the regulation of natural killer (NK) cell activity. Eradication of residual leukaemic cells by alloreactive donor NK cells after haematopoietic stem cell transplantation (HSCT) fulfils a crucial role in the control of relapse. This retrospective study evaluates 83 patients and their related donors. All individuals were typed at low-resolution level to determine their HLA repertoire. KIR genotyping data were obtained by the use of sequence-specific oligonucleotide (SSO) analysis. All data were combined with patient and donor characteristics and post-transplant clinical data. A higher overall survival was seen when KIR2DS1 in the donor was mismatched with the HLA-C group 2 ligand in the patient (p=0.03). The number of activating KIRs either in the patient or in the donor was significantly correlated with the occurrence of relapse (p=0.003 and p=0.02, respectively). In addition, the presence of KIR2DS5 in the patient alone or in both the patient and donor was significantly correlated with the occurrence of relapse (p=0.004 and p=0.005, respectively). In conclusion, significant correlations were found for activating KIRs with overall survival and relapse.

Dear Editor, To say that autopsy rates are declining is like kicking an open door. For more than three decades, hundreds of articles have been written to discuss this phenomenon [6]. No matter the background of the authors, clinicians and pathologists alike regret this decline and are of the opinion that this situation should be reversed in order to assure high quality medical practice [3–5, 7, 9]. However, all these papers have not had the desired effect of reversing this process. It appears that these papers served mainly to benefit the curriculum vitae of the respective authors and their list of citations. In strong contrast with this supposed lack of interest is the fact that a PubMed search for the term “autopsy” over the years 2000–2006 shows more than 10,000 links, indicating that the autopsy is still an important technique to study (mechanisms of) disease. The reasons for this decline are well known and extensively described [3]. Relatives now are more hesitant than in the past and refuse approval for an autopsy more frequently; or, perhaps, we should say that relatives in the past were as hesitant as relatives are at present but were less likely to contradict the then-well-known (and almighty) doctor. This independence has to be accepted as a fact, there is no reason to believe that this tide will change. Clinicians share some of the blame. Today, they are, perhaps, less persistent and even less interested in pursuing an autopsy because contacts with recently bereaved families are difficult, and many clinicians believe that modern imaging techniques supply them with enough critical information. Moreover, in today’s specialty and clinic orientated practice, the clinicians have less personal contacts with the patient and the relatives, and the chance that a patient dies in the presence of his own doctor is not what it was in the past. This situation will not change in the near future. Therefore, this looser relationship has to be accepted as a fait accompli, and no drastic changes can be foreseen that will influence the autopsy numbers in this respect. Finally, the various ‘medical authorities’ are also not very helpful. Requirements for specified numbers of autopsies for certification of hospitals and for residency training programmes were abolished long ago, often followed by the withdrawal of funding to perform autopsies. So what are we left with? Do we have to accept the situation as it is, or is there something that we, as pathologists, can do? It is strange that pathologists, although we must share responsibility for the waning of the autopsy, often are left in the shadow. Sometimes, long delays in the reporting of autopsy findings is mentioned as a cause of clinical dissatisfaction, but the professional competence of pathologists is almost never an issue. Yet a lot can be gained here. What are the facts? Many pathologists are not interested in autopsies and/or see them as a burden. Many pathologists lack sufficient clinicopathological background to adequately answer the questions of their clinical colleagues. Reports are often so delayed that the critical features of the case have been lost from memory, and interest therefore, is low. Reports often do not contain the relevant answers. In some occasions, the reported results are evidently wrong. Let us examine these facts one by one. Many pathologists are not interested in autopsies There is nothing wrong with the fact that some, or even many, pathologists have little direct interest. We accept that we have among our colleagues dermatopathologists, GI pathologists, etc. But for some reason, there is a widely held perception that every pathologist should be able to perform, or at least supervise, autopsies “to equally share the burden”, as is often said. This is a very strange and illogical perception. Nobody expects a general pathologist to diagnose a difficult myeloproliferative disorder or an unusual neurodegenerative disease or recognize a Sanderson’s polster, when they see one. But we nevertheless expect him/her to perform with aplomb an autopsy on a complicated intensive care unit (ICU) patient with multiorgan disease. The same problem is also seen at resident level. The UK already offers pathology training programmes without autopsy training. At a recent course for first year pathology residents in the Netherlands, I asked the 25 residents how many of them would choose such a training if offered. Five answered positively and six indicated that they would prefer never to do autopsies as a pathologist. Worse is the situation when pathologists openly put the value of autopsies up for debate. Unfortunately, this happens with increasing frequency. Many pathologists lack sufficient pathophysiological knowledge Performing autopsies not only requires a solid basis in the field of general pathology but also in the common problems of clinical medicine and in basic anatomy and physiology. The pathophysiology of the circulatory, respiratory and renal system, in addition to that of the clotting system, should be well known. Familiarity with ICU complications and their treatment is mandatory for adequate interpretation of what may be encountered in many autopsy cases. Also, the interpretation of the pathology of shock versus post mortem changes requires special training. We cannot expect that every pathologist has the time and interest to keep his competencies updated in such a broad and complex field, certainly if he/she, with the declining autopsy rates, will only occasionally be responsible for an autopsy. Reports are often delayed The fact that autopsies are often reported after many weeks or even months (and sometimes not at all) is well known and constitutes a complaint in various articles discussing autopsy decline. The responsible clinician has, in the meantime, often moved to another rotation or has forgotten the details of the disease history and has also sent the final report about the patient to the GP of the patient; thus, the case is ‘closed’ in his/her mind. This type of disconnect certainly is a source for irritation and will contribute to reluctance in asking another autopsy approval. Many autopsy reports do not contain relevant answers to the questions raised during life. It must be said that the autopsy request forms often contain marginal and/or incomplete information [2]. However, the questions raised should be answered and in an epilogue the morphological findings should be interpreted in the clinical context and vice versa. Only then the patient’s file can be closed with confidence. In some instances, the reports provide wrong information These types of errors can be due to misinterpretation of findings, often because of lack of detailed knowledge of the clinical course leading up to death, coupled with lack of insight in pathophysiological phenomena or due to hurry or even neglect [2]. The circumstances surrounding Dr. Shipman’s cases are a good example of this situation, where deaths were reported as cardiac events without sufficient evidence for such a diagnosis [8]. Similar situations might happen everywhere. This type of publicity, certainly when combined with tissue retrieval problems, will most certainly influence the attitude towards autopsies of the general public and medical professionals. These facts taken together raise real concern as to the contribution of ‘Pathology’ and pathologists in the decline in autopsy rates and, in effect, cry out for another approach by our profession to the performance of autopsies. Moreover, we cannot close our eyes to such new approaches as limited autopsies, CT and MRI procedures followed by needle biopsies and so on [1, 3]. Certainly, in the light of the declining autopsy rates, where it is difficult to acquire sufficient experience in performing, interpreting and reporting autopsies, it is necessary that the pathologists who perform autopsies are enthusiastic, interested, competent and respected for their knowledge in this field. Only then are they good sparring partners for the clinicians and good teachers for our residents. The only way to achieve this goal is to accept Clinical Autopsy Pathology as a recognised subspecialty within our profession, in the same way as other subspecialties. A period of additional training in intensive care medicine would be desirable—to learn the language of the intensive care unit which, because of the critical condition of many ICU patients, is the source of a significant number of autopsies and certainly the most complicated ones. Or possibly, there is even a case for incorporating a year of clinical experience in Medicine and Surgery into the training of a Clinical Autopsy Pathologist, an experience that surely contributed to the high level of competence that many of our illustrious predecessors displayed in autopsy pathology. Of course, there should be room for subspecialists who will usually perform their own autopsies, e.g. paediatric pathologists and neuropathologists. In conclusion, the decline in autopsy rates is a progressive one. It is time for us, the pathologists, to finally do something constructive other than to weep and wail. We have to bring our best men and women in the frontline and respect their work as highly as any other recognised subspecialty. It is that or the end of the autopsy. What if our attempts do not work, and the decline continues? In that case, we have already anticipated some of the measures that must be adopted anyway. There is no way to escape the future; it is coming. But we can reshape it by acting now. I, therefore, sincerely hope that this letter will not prove to be just an addition to my list of publications.

Background: To evaluate whether the morphology of the contractile filaments in cardiomyocytes of patients with end-stage heart failure, treated with a left ventricular assist device (LVAD), is identical in the left- and right ventricle (LV, RV) and in the interventricular septum (IVS) and can be monitored by biopsies taken with a bioptome. The application of an LVAD as a bridge to recovery of cardiac function requires monitoring of myocyte recovery. The use of RV biopsies for this purpose might be feasible, if morphologic findings in the RV coincide with those in the LV. Methods and results: At the time of heart transplantation, myocardial biopsies of LV, RV and IVS from 13 patients after LVAD support were compared using immunohistochemistry with monoclonal antibodies against contractile proteins. Additionally, in five of these patients, small biopsies obtained with a diagnostic bioptome were compared with large transmural biopsies of the same region. Hemodynamic monitoring was performed when the patients were fully recovered from the implantation, to rule out persistent RV failure. The staining pattern of actin, myosin, tropomyosin, troponin T and C was identical in the biopsies of LV, RV and IVS. Small biopsies taken with a bioptome appeared to be representative for the larger biopsies. Hemodynamic monitoring showed absence of RV failure in our study group. Conclusion: In the absence of RV failure, morphology of the contractile myofilaments after LVAD support for 215±143 days is identical in LV, RV and IVS. This may allow monitoring of the possible occurrence of LV reverse remodeling by RV biopsies.

In this issue Lehr et al. describe the compulsory examination used by the Swiss Society of Pathology to assess senior residents, and thereby assure the professional competence of its future qualified members [1]. With this examination, Switzerland is, with Britain, one of the few European countries with a comprehensive examination (lasting several days) that tests the full range of theoretical and practical competencies required of a medical specialist-pathologist. There is considerable variation across Europe in the way that the final competencies of pathology trainees are assessed [2]. The reason for this variation is the fact that European countries are all entirely autonomous with regard to training, licensing and the issuing of specialty diplomas in postgraduate medical education. For example, in pathology six countries do not require any form of testing at all at the end of specialty training. In the remaining 26 there is considerable heterogeneity of testing [2], with autopsy competency tested in 11, gross specimen examination and sampling in 9 and cytology in 18. No exact data about the duration of these examinations are known. Harmonization of training and the assessment of its effectiveness in producing competent specialists has proven to be very difficult because very few countries are willing to give up their autonomy to decide on the competencies of their medical specialists, to be acquired during residency training. This is in stark contrast to many countries where obligatory specialty examinations, sometimes with considerable failure rates, are the norm. Examples include the North American specialty boards and the examinations of the British Royal Colleges [3, 4]. For the Royal College of Pathologists, examinations are one of the principal benchmarks by which trainees are judged to have reached professional competence. The British examinations are still copied in one form or another by their old colonies (e.g. Australia, Canada, many African countries). When one of us (JGvdT) was an external examiner in Zimbabwe in the 90’s it was much more difficult to become a pathologist there (or indeed a specialist in any medical discipline) than in the Netherlands and many other European countries. The same applies e.g. to Tanzania where, to progress further in the specialty, residents have to pass a general pathology examination already after 6 months of training. To tackle this diversity in training and testing in 1997 the European Board of Pathology (EBP) of the European Union of Medical Specialists (UEMS), introduced an annual voluntary examination for senior pathology residents, based upon a similar examination successfully introduced by the European Board of Urology. Although introduction of the examination was supported by a large majority of the members of EBP, due to the lack of any consequence of failing, and poor support by senior pathologists, the test never really got off the ground and is currently taken by only a handful of people, mainly those from outside the EU hoping to increase their prospect of finding work as pathologist in Europe. The only exception is Malta where since 2011 the UEMS examinations are officially recognized for all medical specialisms. With support of a grant from the EU, the European Association of Pathology Chairs and Program Directors (EAPCP) developed a voluntary progress test (EUROPALS) [5], comparable to the American RISE (Resident In Service Examination). The latter test is given for all medical specialties in the USA and is for pathology a good outcome predictor for the American Board Examination [6]. This EUROPALS test had a high participation rate and is now, thanks to the support of the European Society of Pathology being developed as an official progress test, not only for residents but also for specialised pathologists and subspecialists. The relevant question here of course is why trainee medical specialists, including in pathology, in so many countries in Europe are not thoroughly tested at the end of their training. This is relevant in view of the results of the American and British examinations, showing that a proportion of advanced residents do not have the core competencies, as defined by senior members of the profession, considered necessary for practicing safely. As there is no suggestion that the training in the UK or USA is substandard, the question is relevant whether introduction of similar assessments across Europe would demonstrate lacunar competencies in some of the examined residents. That is not to suggest that trainees across Europe might be less competent than their North American or UK homologues, merely that as the experience in the e.g. USA and UK indicates, assessment stimulates learning. Creating a knowledgeable, thoughtful and competent pool of specialists is surely the fundamental goal of any postgraduate medical training programme.