A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: The European experience.

BACKGROUND: The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system. METHODS: The hematoxylin-eosin-stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics. RESULTS: The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR. CONCLUSIONS: Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the 1990 ISHLT classification to the "new" 2005 ISHLT classification. Morphologic suspicion of AMR in the 2004 system on hematoxylin-eosin-stained slides only was poor, highlighting the need for better standardization of morphologic criteria for AMR. Ongoing educational programs are needed to ensure standardization of diagnosis of both acute cellular and antibody-mediated rejection.

Proliferating cell nuclear antigen (PCNA) in non-Hodgkin's lymphomas: Correlation with working formulation and Kiel classification in formalin-fixed paraffin-embedded material

PCNA is a 36-KD proliferating cell nuclear antigen associated with the cell cycle. The immunocytochemical detection of PCNA represents a useful tool for the study of tumor proliferation activity. This study documents the detection of PCNA, using antibody PC 10 in formalin-fixed, paraffin-embedded tissue, and correlates the proliferative activity of the non-Hodgkin's lymphomas (NHL) with histological grading assessed by the International Working Formulation (WF) and Kiel classification. In 92 cases of NHLs we found a strong correlation between the PCNA index and lymphoma grading. Statistically significant differences were also found between the proliferative index (PI) in low and high grade lymphomas according to the Kiel classification (t = 9.519; p < 0.001) and between low, intermediate and high grade lymphomas according to the WF classification (F = 79.01; p < 0.001). In the Kiel classification the mean of low grade lymphomas was 39.5% and of high grade 75.7%. In the WF the average of low grade lymphomas was 29.7%, intermediate 53.1% and high 75.1%. Although the differences among the groups had been significant, we found variations inside each histological subgroup in both classifications. The intermediate lymphomas were the most heterogeneous group, with PI inside the same histologic subtypes coincident with low and high grade lymphomas. Since PCNA may be used as a marker of cell proliferation in clinical studies to estimate the biological aggressiveness of lymphomas, its determination in intermediate grade NHL could be very useful to evaluate individual cases in this group and determine prognosis and probably the appropriate therapy.

Primary spinal epidural lymphoma: patients' profile, outcome, and prognostic factors: a multicenter Rare Cancer Network study

RESUME Objectif : Les lymphomes épiduraux primaires représentent moins de 10% des tumeurs épidurales et de 0,1 à 3,3% de tous les lymphomes. Le but de cette étude a été d'évaluer le profil clinique de cette maladie rare, son traitement, ses résultats ainsi que ses facteurs de pronostic. Matériel et méthode : Entre 1982 et 2002, 52 patients présentant un lymphome épidural primaire ont été traités dans neuf institutions membres du Rare Cancer Network. Les critères d'inclusion comprenaient : une biopsie confirmant le lymphome non-hodgkinien, un stade IE et IIE selon la classification de Ann Arbor, un traitement à visée curative de radiothérapie combinée ou non à une chimiothérapie et un suivi d'au moins six mois. Selon la Working Formulation, 12 patients (23%) présentaient un lymphome de bas grade, 28 (54%) un grade intermédiaire et 12 (23%) un haut grade. Les hommes étaient atteints 1.9 fois plus fréquemment que les femmes. L'âge moyen était de 61 ans (intervalle : 21 à 96). Le bilan incluait un Ct-scan spinal (98%), une IRM (52%), un CT-scan thoraco-abdominal (77%) et une aspiration ou biopsie de moelle osseuse (96%). Les symptômes les plus fréquents comprenaient des douleurs dorsales (79% des patients), une faiblesse musculaire (92%) et des déficits sensoriels (71 %). Quarante-huit patients ont subi une laminectomie de décompression avec résection partielle ou complète (42% et 13% des cas respectivement), tous ont reçu une radiothérapie seule (20 patients) ou en combinaison avec une chimiothérapie (32 patients). La dose médiane totale était de 36 Gy (intervalle 6-50 Gy) avec une moyenne de 20 Gy par fraction (intervalle : 1-25). Le suivi moyen était de 71 mois (intervalle : 22-165 mois). Résultats : Suite au traitement, une progression locale a été observée chez 6 patients après un temps de latence moyen de 6 mois. Le taux de rechute systémique a été de 42% (22 patients) le plus souvent dans les ganglions lymphatiques (n=9) après un intervalle de temps moyen de 20 mois. Lors du dernier contrôle, 28 patients étaient vivants et 24 patients étaient décédés. Le taux de survie à 5 ans, le taux de survie sans maladie et le contrôle local étaient de 69%, 57% et 88% respectivement. En analyse univariée, les facteurs pronostics favorables statistiquement significatifs concernant la survie sans maladie étaient un âge inférieur à 63 ans, ainsi qu'une réponse neurologique complète. Pour la survie à 5 ans, les facteurs favorables étaient un âge inférieur à 63 ans. En analyse multivariée, les facteurs pronostics favorables pour la survie globale à 5 ans étaient une réponse neurologique complète, un traitement combiné, un volume de radiothérapie plus que focal, une dose totale de radiothérapie supérieure à 36 Gy et une résection partielle ou complète de la tumeur. En ce qui concerne la survie sans maladie, les facteurs pronostics favorables étáient un âge inférieur à 63 ans et un traitement combiné. Conclusion : Ce qui ressort de cette analyse est que le bilan diagnostic devrait inclure une IRM ou un CT-scan, un échantillon de tissu pour poser le diagnostic pathologique définitif de la lésion, une histoire médicale et un examen physique complet, une chimie sanguine, un CTscan thoraco-abdominal et une biopsie de la moelle osseuse, un PET-scan devrait également faire partie du bilan. Le traitement devrait consister, dans la phase aiguë, en une chirurgie de décompression avec ou sans résection, suivie d'une radiothérapie d'au moins 36Gy en 2 Gy par fraction et d'une chimiothérapie. Tous les patients présentant un lymphome de haut grade ou de grade intermédiaire devraient pouvoir bénéficier d'un traitement combiné.

Classificação citológica dos linfomas caninos

Lymphoma is among the most frequent canine neoplasia and share many similarities with human non-Hodgkin's lymphoma in respect of etiology, epidemiology, clinical, morphological and immunophenotipical aspects. Human classification schemes have been used in canine lymphoma. The aim of this work was apply Kiel, Working Formulation and Fournel-Fleury's et al. (1994) classification in Fine Needle Aspiration (FNA) cytology matherial. According to Kiel scheme 61.02% (36 cases) were high-grade lymphomas and 38.98% (23 cases) low grade. The Working Formulation, showed 11.86% (7 cases) of low grade, 61.02% (36 cases) intermediary grade and 27.12% (16 cases) high grade. In Fournel-Fleury's protocol revealed a predominance of high-grade lymphoma, with 61.02% (36 cases) over 38.98% (23 cases) of low grade. In conclusion, FNA can be used as a diagnostic method and in canine lymphoma cytological classification. Kiel's system showed the best results, once is based on cytologic basis.

Classificação citológica e imunocitoquímica dos linfomas caninos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Classificação citoistológica, imunoistoquímica, lesão de DNA, morfometria e índice de proliferação celular dos linfomas em cães

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Avaliação da proliferação celular, índice apoptótico e da expressão do P53 nos linfomas caninos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

The multicenter trial SAKK 37/95 of cladribine, cyclophosphamide and prednisone in the treatment of chronic lymphocytic leukemias and low-grade non-Hodgkin's lymphomas

A multicenter trial was performed to confirm the therapeutic efficacy and the toxicity profile of the combination of cladribine, cyclophosphamide and prednisone in low-grade non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Twenty-three adults with previously treated (61%) or untreated (39%) NHL International Working Formulation A or Binet B and C CLL were administered cladribine 0.1 mg/kg/day as a subcutaneous bolus for 5 days, intravenous cyclophosphamide 500 mg/m2 on day 1, and oral prednisone 40 mg/m2 on days 1-5, every 4 weeks. Unexpected early hematological toxicities led to dose modifications for pretreated patients who received cladribine for 3 days only up to a maximum of five courses. Responses were observed in 75%, with 7 patients obtaining a complete clinical and hematological response. Median duration of complete response was 9 months. Median time to progression or relapse was 31 months. Myelosuppression and infections were dose limiting whereas posttreatment complications, including fatalities, resulted from infections. Median overall survival time from trial entry was 60 months. Activity of the combination of cladribine, cyclophosphamide and prednisone was confirmed. However, in the specific setting of a multicenter trial, unexpected fatal infectious episodes occurred in pretreated patients. Great caution is thus required in these susceptible patients and the routine use of corticosteroids should probably be abandoned.

Lymphoproliferative disease of the ocular adnexa: A clinical and pathologic study with statistical analysis of 69 patients

Purpose: To evaluate the clinical features, treatment, and outcomes of a cohort of patients with ocular adnexal lymphoproliferative disease classified according to the World Health Organization modification of the Revised European-American Classification of Lymphoid neoplasms and to perform a robust statistical analysis of these data. Methods: Sixty-nine cases of ocular adnexal lymphoproliferative disease, seen in a tertiary referral center from 1992 to 2003, were included in the study. Lesions were classified by using the World Health Organization modification of the Revised European-American Classification of Lymphoid neoplasms classification. Outcome variables included disease-specific Survival, relapse-free survival, local control, and distant control. Results: Stage IV disease at presentation, aggressive lymphoma histology, the presence of prior or concurrent systemic lymphoma at presentation, and bilateral adnexal disease were significant predictors for reduced disease-specific survival, local control, and distant control. Multivariate analysis found that aggressive histology and bilateral adnexal disease had significantly reduced disease-specific Survival. Conclusions: The typical presentation of adnexal lymphoproliferative disease is with a painless mass, swelling, or proptosis; however, pain and inflammation occurred in 20% and 30% of patients, respectively. Stage at presentation, tumor histology, primary or secondary status, and whether the process was unilateral or bilateral were significant variables for disease outcome. In this study, distant spread of lymphoma was lower in patients who received greater than 20 Gy of orbital radiotherapy.

Is diagnosis enough to guide interventions in mental health? Using case formulation in clinical practice.

ABSTRACT: While diagnosis has traditionally been viewed as an essential concept in medicine, particularly when selecting treatments, we suggest that the use of diagnosis alone may be limited, particularly within mental health. The concept of clinical case formulation advocates for collaboratively working with patients to identify idiosyncratic aspects of their presentation and select interventions on this basis. Identifying individualized contributing factors, and how these could influence the person's presentation, in addition to attending to personal strengths, may allow the clinician a deeper understanding of a patient, result in a more personalized treatment approach, and potentially provide a better clinical outcome.

Real-time simulation of multibody systems with applications for working mobile vehicles

This dissertation describes an approach for developing a real-time simulation for working mobile vehicles based on multibody modeling. The use of multibody modeling allows comprehensive description of the constrained motion of the mechanical systems involved and permits real-time solving of the equations of motion. By carefully selecting the multibody formulation method to be used, it is possible to increase the accuracy of the multibody model while at the same time solving equations of motion in real-time. In this study, a multibody procedure based on semi-recursive and augmented Lagrangian methods for real-time dynamic simulation application is studied in detail. In the semirecursive approach, a velocity transformation matrix is introduced to describe the dependent coordinates into relative (joint) coordinates, which reduces the size of the generalized coordinates. The augmented Lagrangian method is based on usage of global coordinates and, in that method, constraints are accounted using an iterative process. A multibody system can be modelled as either rigid or flexible bodies. When using flexible bodies, the system can be described using a floating frame of reference formulation. In this method, the deformation mode needed can be obtained from the finite element model. As the finite element model typically involves large number of degrees of freedom, reduced number of deformation modes can be obtained by employing model order reduction method such as Guyan reduction, Craig-Bampton method and Krylov subspace as shown in this study The constrained motion of the working mobile vehicles is actuated by the force from the hydraulic actuator. In this study, the hydraulic system is modeled using lumped fluid theory, in which the hydraulic circuit is divided into volumes. In this approach, the pressure wave propagation in the hoses and pipes is neglected. The contact modeling is divided into two stages: contact detection and contact response. Contact detection determines when and where the contact occurs, and contact response provides the force acting at the collision point. The friction between tire and ground is modelled using the LuGre friction model, which describes the frictional force between two surfaces. Typically, the equations of motion are solved in the full matrices format, where the sparsity of the matrices is not considered. Increasing the number of bodies and constraint equations leads to the system matrices becoming large and sparse in structure. To increase the computational efficiency, a technique for solution of sparse matrices is proposed in this dissertation and its implementation demonstrated. To assess the computing efficiency, augmented Lagrangian and semi-recursive methods are implemented employing a sparse matrix technique. From the numerical example, the results show that the proposed approach is applicable and produced appropriate results within the real-time period.

Production under glass : working conditions and class-consciousness of the Niagara greenhouse workers

This study applies a Marxist theoretical paradigm to examine the working conditions of greenhouse workers in the Niagara Region, and the range of factors that bear upon the formation of their class-consciousness. The Niagara greenhouse industry represents one of the most developed horticultural regions in Canada and plays a prominent role in the local economy. The industry generates substantial revenues and employs a significant number of people, yet the greenhouse workers are paid one of the lowest rates in the region. Being classified as agricultural workers, the greenhouse employees are exempted from many provisions of federal and provincial labour regulations. Under the current provincial statutes, agricultural workers in Ontario are denied the right to organize and bargain collectively. Except for a few technical and managerial positions, the greenhouse industry employs mostly low-skilled workers who are subjected to poor working conditions that stem from the employer's attempts to adapt to larger structural imperatives of the capitalist economy. While subjected to these poor working conditions, the greenhouse workers are also affected by objectively alienated social relations and by ruling class ideological domination and hegemony. These two sets of factors arise from the inherent conflict of interests between wage-labour and capital but also militate against the development of class-consciousness. Semi-structured interviews were conducted with 12 greenhouse workers to examine the role played by their material circumstances in the formulation of their social and political views as well as the extent to which they are aware of their class location and class interests. The hegemonic notions of 'common sense' acted as impediments to formation of classconsciousness. The greenhouse workers have virtually no opportunities to access alternative perspectives that would address the issues associated with exploitation in production and offer solutions leading to 'social justice'. Fonnidable challenges confront any organized political body seeking to improve the conditions of the working people.

A BEM formulation for analysing the coupled stretching-bending problem of plates reinforced by rectangular beams with columns defined in the domain

In this work, a boundary element formulation to analyse plates reinforced by rectangular beams, with columns defined in the domain is proposed. The model is based on Kirchhoff hypothesis and the beams are not required to be displayed over the plate surface, therefore eccentricity effects are taken into account. The presented boundary element method formulation is derived by applying the reciprocity theorem to zoned plates, where beams are treated as thin sub-regions with larger rigidities. The integral representations derived for this complex structural element consider the bending and stretching effects of both structural elements working together. The standard equilibrium and compatibility conditions along interface are naturally imposed, being the bending tractions eliminated along interfaces. The in-plane tractions and the bending and in-plane displacements are approximated along the beam width, reducing the number of degrees of freedom. The columns are introduced into the formulation by considering domain points where tractions can be prescribed. Some examples are then shown to illustrate the accuracy of the formulation, comparing the obtained results with other numerical solutions.