ALAT
: alanine aminotransferase
ASAT
: aspartate aminotransferase
APAH
: associated pulmonary arterial hypertension
BAS
: balloon atrial septostomy
BMPR2
: bone morphogenetic protein receptor 2
BNP
: brain natriuretic peptide
BPA
: balloon pulmonary angioplasty
BREATHE
: Bosentan

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2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).

Guidelines and Expert Consensus Documents summarize and evaluate all currently available evidence on a particular issue with the aim to assist physicians in selecting the best management strategies for a typical patient, suffering from a given condition, taking into account the impact on outcome, as well as the risk/benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.

A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines and Expert Consensus Documents can be found on the ESC website (http://www.escardio.org/knowledge/guidelines).

In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition.

Unpublished clinical trial results are not taken into account. A critical evaluation of diagnostic and therapeutic procedures is performed including assessment of the risk/benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to predefined scales, as outlined in Tables 1 and 2 .

View this table:

Table 1 
Classes of recommendations



View this table:

Table 2 
Levels of evidence



The experts of the writing panels have provided disclosure statements of all relationships they may have which might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise …

/pdf/guidelines-for-the-diagnosis-and-treatment-of-pulmonary-4pfz1dw03n.pdf

Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT)

Stereology is a set of simple and efficient methods for quantitation of three-dimensional microscopic structures which is specifically tuned to provide reliable data from sections. Within the last few years, a number of new methods has been developed which are of special interest to pathologists. Methods for estimating the volume, surface area and length of any structure are described in this review. The principles on which stereology is based and the necessary sampling procedures are described and illustrated with examples. The necessary equipment, the measurements, and the calculations are invariably simple and easy.

Some new, simple and efficient stereological methods and their use in pathological research and diagnosis.

The extracellular matrix (ECM) is a highly dynamic structure that is present in all tissues and continuously undergoes controlled remodelling. This process involves quantitative and qualitative changes in the ECM, mediated by specific enzymes that are responsible for ECM degradation, such as metalloproteinases. The ECM interacts with cells to regulate diverse functions, including proliferation, migration and differentiation. ECM remodelling is crucial for regulating the morphogenesis of the intestine and lungs, as well as of the mammary and submandibular glands. Dysregulation of ECM composition, structure, stiffness and abundance contributes to several pathological conditions, such as fibrosis and invasive cancer. A better understanding of how the ECM regulates organ structure and function and of how ECM remodelling affects disease progression will contribute to the development of new therapeutics.

/pdf/remodelling-the-extracellular-matrix-in-development-and-4thd3cxc2p.pdf

Remodelling the extracellular matrix in development and disease.

Published on behalf of the European Society of Cardiology. All rights reserved. & 2015 European Society of Cardiology & European Respiratory Society. This article is being published concurrently in the European Heart Journal (10.1093/eurheartj/ehv317) and the European Respiratory Journal (10.1183/13993003.01032-2015). The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article. * Corresponding authors: Nazzareno Galiè, Department of Experimental, Diagnostic and Specialty Medicine–DIMES, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy, Tel: +39 051 349 858, Fax: +39 051 344 859, Email: nazzareno.galie@unibo.it.

/pdf/special-article2015-esc-ers-guidelines-for-the-diagnosis-and-22zaj14m7s.pdf

Special article2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension

Background Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. Methods We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. Results In the controls, endothelin-1-like immu...

Expression of Endothelin-1 in the Lungs of Patients with Pulmonary Hypertension

A practical methodology is proposed for the stereological analysis of lung and other organs using recently developed unbiased procedures. This study concentrates on the unbiased estimation of lung volume using Cavalieri's principle compared with the fluid displacement method and measurement of pleural surface area using vertical sections. Furthermore, the proposed design, in addition to the sampling of extensive slices for the initial steps, also allows sampling of vertical sections for light and electron-microscopical stereology. The procedures are described in detail by reference to biological data from the right lungs of four rabbits. We found excellent agreement between estimates of lung volume measured with Cavalieri's principle and those measured by fluid displacement. Pertinent details of the statistical analysis of the sources of variation (namely biological, systematic sectioning and point-counting variation) are given in an appendix.

Application of the Cavalieri principle and vertical sections method to lung: estimation of volume and pleural surface area

Idiopathic pulmonary fibrosis (IPF) is characterized by an alveolitis with epithelial and endothelial damage progressing to fibrosis. Numerous mediators have been implicated in this complex process. Studies in humans have shown that endothelin-1 (ET-1), a vasoconstrictor and mitogenic peptide, is a mediator in IPF. To determine the role of ET-1 and endothelin-converting enzyme (ECE)-1 and the effect of Bosentan, an ET receptor antagonist, in an animal model of IPF, we studied three groups of rats (n = 6 each): Group 1, control, received saline; Group 2, fibrosis, received 1.5 U bleomycin intratracheally; Group 3, fibrosis-Bosentan treated, received bleomycin and Bosentan daily by gavage. After 28 d, right upper lobes were fixed for immunohistochemistry (IHC) and sections were stained with antisera to ET-1 and ECE-1 and graded semiquantitatively. Sections from left lungs were embedded in paraffin and stained for light microscopic morphometry to quantitate the fibrosis. By IHC, we found increased ET-1 immunoreactivity (ir) in airway epithelium and inflammatory cells, and ECE-1-ir in airway epithelium, type II pneumocytes and endothelial cells (p < 0.05). By morphometry, the volume fraction (Vv) of connective tissue (CT) increased and the Vv of air decreased in the fibrosis group compared with that in the control group. Bosentan reduced the Vv of CT and increased the Vv of air compared with that in the fibrosis group (p < 0.05). These results indicate that ET-1 is involved in the pathogenesis of pulmonary fibrosis in the rodent model and that blockage of its receptors reduces the fibrosis.

Increased Endothelin-1 in Bleomycin-induced Pulmonary Fibrosis and the Effect of an Endothelin Receptor Antagonist

Background : Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. Purpose : We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. Methods : We conducted a study within a cohort that included 10 472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. Results : We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0 ; 95% CI = 1.1-3.6), procarbazine (RR = 4.9 ; 95% CI = 2.6-9.1), vinblastine (RR = 1.7 ; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8 ; 95% CI = 1.9-7.4). RRS were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9 ; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5 ; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0 ; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8 ; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7 ; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4 ; 95% CI = 1.1-5.4). Conclusions : Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. Implications : Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors. [J Natl Cancer Inst 87 :732-741, 1995]

Incidence of Second Cancers in Patients Treated for Hodgkin's Disease

BACKGROUND

Primary effusion lymphoma (PEL) is a human herpes virus-8 (HHV-8)-associated and very rare type of lymphoma usually confined to the body cavities and commonly observed in human immunodeficiency virus (HIV)-infected patients. A comparison was made between the cytologic and immunocytochemical features of 4 cases of PEL encountered in the authors' department with those reported to date in the literature.



METHODS

A comprehensive comparison of the cytologic and immunocytochemical features of the 4 cases with those reported in the literature was conducted.



RESULTS

Cytologically, the most consistent features of the 4 cases and those in the literature included large cell size, moderate to abundant cytoplasm, a single nucleus in most cells with occasional bi- or multinucleated giant cells, single to multiple prominent nucleoli, and coarse chromatin. Immunocytochemically, only 2 (50%) of the current cases were of the null-phenotype compared with 93% of cases in the literature; the other 2 cases had a T-cell phenotype. Activation markers were expressed in 50% and 78% of the current cases and the literature cases, respectively. Positivity for HHV-8 was proven in the 4 cases by immunocytochemistry.



CONCLUSIONS

Cytomorphologically, PEL exhibits features bridging large cell immunoblastic and anaplastic large cell lymphoma. Although it is usually of null-phenotype, it may occasionally express B-cell or T-cell markers, rendering its distinction difficult from other lymphomatous effusions on a cytologic and immunocytochemical basis alone. Therefore, HHV-8 detection is an essential confirmatory ancillary test in suspected cases of PEL. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.

Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis.

René P. Michel

Papers

Expression of Endothelin-1 in the Lungs of Patients with Pulmonary Hypertension

Application of the Cavalieri principle and vertical sections method to lung: estimation of volume and pleural surface area

Increased Endothelin-1 in Bleomycin-induced Pulmonary Fibrosis and the Effect of an Endothelin Receptor Antagonist

Incidence of Second Cancers in Patients Treated for Hodgkin's Disease

Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis.