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PubMed1988

Prostaglandins, leukotrienes, and other arachidonic acid metabolites in the pathogenesis of otitis media.

Among the various inflammatory mediators of otitis media (OM), metabolites of arachidonic acid (AA) such as prostaglandins (PGs) and leukotrienes (LTs) appear to play an important role in the pathogenesis of otitis media. In an effort to investigate the role of AA metabolites on the pathogenesis of otitis media, concentrations of AA metabolites were measured in middle ear effusion (MEE) from human and paralleling animal models of otitis media and the effects of inhibitors of AA metabolism, antibiotics, and tympanostomy tube (TT) on the outcome of animal models of OM were studied. Concentrations of AA metabolites in MEE were higher in the younger age group. Levels of PGE2 and LTB4 in MEE seem to represent the degree of inflammation of OM best. Lipoxygenase products seem to be associated with the mucoid type of MEE. In the study of animal models of OM, combined models and ears with TT showed more inflammation than single models and ears without TT. Study of the therapeutic use of inhibitors of AA metabolism, penicillin, and TT showed that lipoxygenase products may be more important in the pathogenesis of OM than the cyclo-oxygenase products, and that the use of a combination of penicillin and corticosteroid produces the best results. It is clear from these studies that arachidonic acid metabolites are important inflammatory mediators in the pathogenesis of otitis media.

6-Ketoprostaglandin F1 alpha↗

PubMed1994

Pathogenesis of peritonsillar abscess.

The pathogenesis of peritonsillar abscess is described in textbooks as being a direct communication and progression of acute exudative tonsillitis. Little study has been done on the true etiology and pathogenesis of peritonsillar abscess. This paper focuses on the pathogenesis of peritonsillar abscess. A group of salivary glands (Weber's glands) proven to be located in the supratonsillar space have been shown to be implicated in the pathogenesis of peritonsillar abscess. A review of peritonsillar abscess has been undertaken, and evidence has been presented to support the premise that the true cause for peritonsillar abscess is not necessarily an extension of an acute exudative tonsillitis, but an abscess formation of Weber's salivary glands in the supratonsillar fossa.

Adolescent↗

PubMed1983

Pathogenesis of human urinary bladder cancer.

The pathogenesis of bladder cancer is being analyzed at several levels of biological organization, i.e., population groups, individual whole animal, tissue, cell, molecule, etc. Each of these levels provides opportunities for mechanistic studies. Yet the integration of these several levels into a cohesive fabric is incomplete. From a clinical point of view, the following seem of importance to human bladder cancer pathogenesis. The initiation, promotion, and progression of bladder cancer involves several factors acting concurrently or sequentially. These factors appear to be naturally occurring or synthetically created chemicals present in the external environment. Human exposures to these agents may begin in utero, and varying, dynamic qualitative and quantitative exposure patterns continue through developmental and adult life. Apparent latent periods of development of clinical bladder cancer may be as short as one, or as long as 50 years or more. Individuals may exhibit differential susceptibility to vesical carcinogens, perhaps through phenotypic differences in quantitative biotransformation routes. Differences in bladder epithelial cell susceptibilities probably also occur, as well as varying local tissue and generalized resistance to neoplasia formation. Older individuals do not appear to be more resistant to bladder carcinogenesis. A number of animal model systems have been developed for the study of the in vivo, cellular, and molecular pathogenesis of bladder cancer. These models replicate many of the known salient features of human bladder cancer. Through use of appropriate whole animal models in conjunction with investigations of human and animal bladder cells and tissues in culture, controlled mechanistic and quantitative studies of bladder cancer pathogenesis should rapidly develop.

Amines↗

PubMed2007

Accumulation of viroid-specific small RNAs and increase in nucleolytic activities linked to viroid-caused pathogenesis.

Strong viroid-caused pathogenesis was achieved in tomato cv. Rutgers by biolistic transfer of severe or lethal potato spindle tuber viroid (PSTVd) strains, while other tomato genotypes (e.g., Moneymaker) were tolerant. With reciprocal hybrids between sensitive and tolerant genotypes, we show that plant depression dominates over tolerance. Biolistic transfer of the most pathogenic PSTVd strain AS1 to Nicotiana benthamiana, which is considered to be a symptomless PSTVd host, led to a strong pathogenesis reaction and stunting, suggesting the presence of specific viroid pathogenesis-promoting target(s) in this plant species. Total levels of small siRNA-like PSTVd-specific RNAs were enhanced in strongly symptomatic tomato and N. benthamiana plants after biolistic infection with AS1 in comparison to the mild QFA strain. This indicates association of elevated levels of viroid-specific small RNA with production of strong symptoms. In symptom-bearing tomato leaves in comparison to controls, an RNase of approximately 18 kDa was induced and the activity of a nuclease of 34 kDa was elevated by a factor of seven in the vascular system. Sequence analysis of the nuclease cDNA designated TBN1 showed high homology with plant apoptotic endonucleases. The vascular-specific pathogenesis action is supported by light microscopic observations demonstrating a certain lack of xylem tissue and an arrest of the establishment of new vascular bundles in collapsed plants.

Amino Acid Sequence↗

PubMedDate not supplied

Comparison of a putative second serotype of chicken infectious anemia virus with a prototypical isolate I. Pathogenesis.

CIAV-7 is a virus with similar pathogenic and physicochemical characteristics to, but antigenically distinct from, chicken infectious anemia virus (CIAV). The pathogenesis of CIAV-7 was evaluated in a comparative study with a representative isolate of CIAV, the Del-Ros strain. The pathogenesis of CIAV-7 was similar to Del-Ros on the basis of the clinical disease induced and gross and microscopic lesions, although CIAV-7 produced fewer and less severe lesions overall. A second comparative pathogenesis study was performed with Del-Ros and CIAV-7, both alone and in combination with infectious bursal disease virus (IBDV). In this study, the pathogenesis of CIAV-7 was similar to Del-Ros in clinical, gross, and microscopic lesions in the bone marrow. However, thymic lesions were less severe in CIAV-7-inoculated birds. The interaction between Del-Ros and IBDV was synergistic, whereas there was no observed potentiation of CIAV-7-induced disease by IBDV. Progeny from breeder flocks from several geographic locations in the eastern United States were challenged with CIAV-7 or Del-Ros to assess protection by maternal antibodies. Some progeny from all flocks had protection against CIAV-7 challenge, providing evidence for the presence of CIAV-7 in the field. Additionally, the number of birds protected against CIAV-7 or Del-Ros challenge varied within flocks, demonstrating that the agents are serologically distinct.

Animals↗

PubMed2004

Quinone formation as dopaminergic neuron-specific oxidative stress in the pathogenesis of sporadic Parkinson's disease and neurotoxin-induced parkinsonism.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by dopaminergic neuron-specific degeneration in the substantia nigra. A number of gene mutations and deletions have been reported to play a role in the pathogenesis of familial PD. Moreover, a number of pathological and pharmacological studies on sporadic PD and dopaminergic neurotoxin-induced parkinsonism have hypothesized that mitochondrial dysfunction, inflammation, oxidative stress, and dysfunction of the ubiquitin-proteasome system all play important roles in the pathogenesis and progress of PD. However, these hypotheses do not yet fully explain the mechanisms of dopaminergic neuron-specific cell loss in PD. Recently, the neurotoxicity of dopamine quinone formation by auto-oxidation of dopamine has been shown to cause specific cell death of dopaminergic neurons in the pathogenesis of sporadic PD and dopaminergic neurotoxin-induced parkinsonism. Furthermore, this quinone formation is closely linked to other representative hypotheses in the pathogenesis of PD. In this article, we mainly review recent studies on the neurotoxicity of quinone formation as a dopaminergic neuron-specific oxidative stress and its role in the etiology of PD, in addition to several neuroprotective approaches against dopamine quinone-induced toxicity.

Animals↗

PubMed2004

Matrix metalloproteinases in the pathogenesis of asthma and COPD: implications for therapy.

While asthma is an inflammatory disorder of the airways involving mediators released from mast cells and eosinophils, inflammation alone is insufficient to explain the chronic nature of the disease. Recent progress in the understanding of disease pathogenesis has revealed that airway remodeling, which is at least in part due to an excess of extracellular matrix (ECM) deposition in the airway wall, plays a significant role in airflow obstruction. Matrix metalloproteinases (MMPs) have been suggested to be the major proteolytic enzymes to induce airway remodeling in asthma and COPD. It has been widely accepted that different inflammatory processes are involved in asthma and COPD with different inflammatory cells, mediators, and responses to treatments. Despite these different processes, airflow obstruction and airway remodeling characterize these two diseases. MMP-2 and -9 have been reported to be involved in the pathogenesis of airway remodeling in both diseases and MMP-12, in addition to these MMPs, in the pathogenesis of COPD. In this review, we discuss the current views on the role of MMPs in the pathogenesis of bronchial asthma and COPD. Anti-MMP therapy could theoretically be useful to prevent airway remodeling in asthma and COPD. However, to date no clinical data are available regarding the efficacy of anti-MMP therapies in the treatment of patients with asthma and COPD.

Asthma↗

PubMed2004

The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity.

Interactions between members of the TNF ligand superfamily with their cognate TNF receptors play a crucial role in maintaining immune homeostasis in normal individuals, while dysregulation of certain TNF-ligands and receptors contributes to the pathogenesis of autoimmunity. Identification of novel members of the TNF ligand and receptor families will promote our understanding of the pathogenesis of systemic autoimmune diseases, thus facilitating the development of novel therapeutic approaches. TNF-like weak inducer of apoptosis (TWEAK), a recently identified member of the TNF ligand family, induces PGE2, MMP-1, IL-6, IL-8, RANTES, and IP-10 in fibroblasts and synoviocytes, and upregulates ICAM-1, E-selectin, IL-8, and MCP-1 in endothelial cells. The receptor for TWEAK, Fn14, is expressed in various organs including the kidney; it is intriguing that some of these chemokines induced by TWEAK are crucial in the pathogenesis of lupus nephritis. Furthermore, others have described upregulated TWEAK expression on the surface of T cells in human lupus. In this paper we review the possible roles of TWEAK/TWEAK receptor interactions in the pathogenesis of inflammatory and systemic autoimmune diseases, with particular focus on systemic lupus erythematosus. TWEAK blockade may be helpful therapeutically in restoration of tolerance, but is more likely to modify inflammatory damage in target organs.

Animals↗

PubMed1998

Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease.

OBJECT: Prominent features of moyamoya disease are intimal thickening of the cerebral arterial trunks and abundant angiogenesis for collateral blood supplies, but its pathogenesis is still unknown. The aim of this study was to test the possibility that transforming growth factor-beta1 (TGFbeta1) may play a role in the pathogenesis of moyamoya disease. METHODS: The authors used reverse transcription-polymerase chain reaction to analyze the expression level of TGFbeta1 in smooth-muscle cells cultured from the superficial temporal arteries (STAs) and measured the serum level of TGFbeta1 by using enzyme-linked immunosorbent assay. Although the STA is not predominantly involved with moyamoya disease, it has been used in studies of the pathogenesis of this disease. In this report, the STAs from six patients with moyamoya disease and four with arteriosclerotic cerebrovascular disease, along with sera from 14 patients with moyamoya disease and 10 normal healthy volunteers, were studied. The expression of TGFbeta1 was significantly higher in cultured smooth-muscle cells derived from the STAs of patients with moyamoya disease than in those derived from the STAs of patients with arteriosclerotic cerebrovascular disease (p < 0.05). The serum level of TGFbeta1 was also significantly higher in patients with moyamoya disease than in controls (p < 0.0005). CONCLUSIONS: Taking into account the functional roles of TGFbeta1 in the expression of connective tissue genes and angiogenesis, these investigators suggest that TGFbeta1 is associated with the pathogenesis of moyamoya disease, including abundant neovascularization, although their findings do not necessarily mean that TGFbeta1 is a causative factor in this disease.

Adolescent↗

PubMed1998

Free radicals in viral pathogenesis: molecular mechanisms involving superoxide and NO.

The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide (O2-) and hydroxyl radical (.OH) have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical [nitric oxide (NO)] in the host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular, the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-gamma. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS (i.e., neuronal NOS and endothelial NOS). Recent studies indicate that NO and O2- are produced in excess during the host's defense responses against various intruding microbes. Reactive nitrogen oxide species such as peroxynitrite (ONOO-) and NOx (NO2 and N2O3) are produced in biological systems through the reaction of NO with either O2- or O2. Among these reactive nitrogen species, ONOO- and its biological actions are of considerable interest in that ONOO- causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. Because the ONOO- is formed via a diffusion-limited fast reaction of NO and O2-, it may be a dominant nitrogen oxide species during the host's defense reactions, when both NO and O2- are produced in excess. Thus, understanding the role of NO and oxygen radical generation in virus infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.

Animals↗

PubMed2006

Pathogenesis of primary biliary cirrhosis: a unifying model.

Primary biliary cirrhosis (PBC) is a disease of unknown etiology leading to progressive destruction of small intrahepatic bile ducts and eventually to liver cirrhosis and failure. It is characterised by female predominance and serum auto-antibodies to mitochondrial antigens targeting the E2 components of the 2-oxoacid dehydrogenase complex. Although they are associated with disease pathogenesis, no concrete evidence has been presented so far. Epidemiological data indicate that a geographical clustering of cases and possible environmental factors are implicated in pathogenesis. A number of genetic factors play a role in determining disease susceptibility or progression, although no definitive conclusion has been reached so far. A key factor to immune pathogenesis is considered to be the breakdown of immune tolerance, either through molecular mimicry or through the so called determinant density model. In this review, the available data regarding the pathogenesis of primary biliary cirrhosis are described and discussed. A new unifying hypothesis based on early endothelin overproduction in primary biliary cirrhosis (PBC) is presented and discussed.

Apoptosis↗

PubMed2000

Variable expression of pathogenesis-related protein allergen in mountain cedar (Juniperus ashei) pollen.

Allergic diseases have been increasing in industrialized countries. The environment is thought to have both direct and indirect modulatory effects on disease pathogenesis, including alterating on the allergenicity of pollens. Certain plant proteins known as pathogenesis-related proteins appear to be up-regulated by certain environmental conditions, including pollutants, and some have emerged as important allergens. Thus, the prospect of environmentally regulated expression of plant-derived allergens becomes yet another potential environmental influence on allergic disease. We have identified a novel pathogenesis-related protein allergen, Jun a 3, from mountain cedar (Juniperus ashei) pollen. The serum IgE from patients with hypersensitivity to either mountain cedar or Japanese cedar were shown to bind to native and recombinant Jun a 3 in Western blot analysis and ELISA. Jun a 3 is homologous to members of the thaumatin-like pathogenesis-related (PR-5) plant protein family. The amounts of Jun a 3 extracted from mountain cedar pollen varied up to 5-fold in lots of pollen collected from the same region in different years and between different regions during the same year. Thus, Jun a 3 may contribute not only to the overall allergenicity of mountain cedar pollen, but variable levels of Jun a 3 may alter the allergenic potency of pollens produced under different environmental conditions.

Allergens↗

PubMed2000

[The probability of assessing the pathogenesis of ischemic stroke. Study of 81 patients].

81 patients with ischemic stroke were studied in order to assess the pathogenesis, the accuracy of the pathogenetic diagnosis and the relationship between pathogenesis and infarct site. The pathogenetic mechanisms were grouped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system. TOAST system settles five pathogenetic diagnosis: 1) Large artery atherosclerosis (LM); 2) Cardioembolism (CE); 3) Small artery occlusion (SAO); 4) Other etiologies (SOE); 5) Undetermined pathogenesis. As regards the site, the patients were divided into the following groups: Posterior Circulation Infarcts (POCI) 8.6%, Total Anterior Circulation Infarcts (TACI) 19.8%, Partial Anterior Circulation Infarcts (PACI) 29.6%, Lacunar Anterior Circulation Infarcts (LACI) 30.9%, Multiple Site Infarcts 11.1%. A probable or certain diagnosis was issued only in 33.3%. The diagnosis was not complete in 22.2%. That was due either to the severe clinical status or the patient and his relatives' refusal. Most of the incomplete diagnosis occurred in TACI patients. The undetermined pathogenesis due to absent clues occurred in 18.5%. CE often brought about TACI, whereas LM was likely to provoke PACI. SOE, like systemic hypotension, brought about Multiple Site Infarcts. Unfortunately assessing the pathogenetic diagnosis is still a controversial issue and TOAST method itself is not satisfactory as an overall classification system.

Adult↗

PubMed2000

Genetic and molecular pathogenesis of hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The pathogenesis regarding heterogeneity of vascular malformations in patients with HHT has been obscure, although it has become possible to partially explain the pathogenesis from the identification of two distinct genes, endoglin and ALK-1. Endoglin and ALK-1 are type III and type I TGF-beta receptors, respectively, and are exclusively expressed on vascular endothelial cells. Binding of TGF-beta to the type II TGF-beta receptor on endothelial cells, which is accelerated in the presence of endoglin, phosphorylates type I TGF-beta receptors, ALK-5 and ALK-1, and phosphorylated ALK-5 and ALK-1 activate the downstream proteins Smad2/3 and Smad1/5, respectively. These activated Smad proteins dissociate from the type I TGF-beta receptor, bind to Smad4, and enter the nucleus to transmit TGF-beta signaling by regulating transcription from specific gene promoters involved in angiogenesis. Therefore, a balance between these two signaling pathways via ALK-5 and ALK-1 plays an important role in determining the properties of endothelial cells during angiogenesis. Mutations of endoglin and ALK-1 genes are genetic pathogenesis of HHT type 1 and HHT type 2, respectively. To date, at least 29 and 17 different kinds of mutations in endoglin and ALK-1, respectively, have been found, including missense, nonsense, frameshift, and deletion mutations. The precise mechanisms of vascular abnormalities elicited by these mutations observed in HHT patients are still uncertain, although elucidation of the mechanism of intracellular signal transduction and the change in targeted gene expressions using mutant recombinant endoglin or ALK-1 proteins and knockout mice will enable us to understand the genetic and molecular pathogenesis of HHT and to effectively treat patients with HHT.

Activin Receptors↗

PubMedDate not supplied

An alternative hypothesis from veterinary science for the pathogenesis of noncarious cervical lesions.

An alternative hypothesis to abrasion and erosion for the pathogenesis of noncarious cervical lesions was put forward in 1984; the so-called occlusal theory suggested that tensile stresses from occlusal overload could be involved in the pathogenesis of noncarious cervical lesions and that bending stresses applied to teeth could cause disruption of the surface enamel, resulting in increased susceptibility to dissolution and abrasion at the affected sites and in the development of wedge-shaped lesions. This theory has gained increased acceptance in recent years, although absolute scientific evidence has been scant. These lesions also occur in animals, in particular, the domestic cat, in which they are called feline odontoclastic resorptive lesions. A variety of theories about pathogenesis of these lesions have been put forward, but there is some evidence that occlusal overload may be a contributory factor in the development of an inflammatory response in the periodontal membrane and the presence of enzymes associated with resorption in the gingival crevice. Further investigation may help define a common etiology between the pathogenesis of feline odontoclastic resorptive lesions and noncarious cervical lesions.

Acid Phosphatase↗

PubMed2003

[Pathogenesis of osteoporosis--overview].

Pathogenesis of osteoporosis was overviewed from standpoints of individual level, organ level and cellular level, respectively. As for the individual level, it is important to discriminate the pathogenetic factors related to low BMD or fractures. Independent from BMD, age, previous fractures, bone geometry, microstructure of the bone are related to fractures by influencing the bone quality. As for the organ level, pathogenesis of osteoporosis should be discussed from the view point of bone remodeling and its controlling factors. However, details of this process are still unclear. As for the cellular level, clarification of the roles of osteoblast, osteoclast and their interactions are essential in understanding the pathogenesis of osteoporosis. Recent discovery of Cbfa1, RANK/RANKL signaling and osteoprotegerin may open the new insight in the pathogenesis of osteoporosis.

Animals↗

PubMed2003

[The pathogenesis of vitreoretinal diseases from the standpoint of molecular biology].

It is important to study the pathogenesis in vitreoretinal diseases to develop new medical therapy. We investigated the molecular mechanisms underlying the genesis of idiopathic macular hole, exudative age-related macular degeneration (AMD), and diabetic retinopathy. We observed high levels of chymase and tryptase activity in the vitreous humor of patients with idiopathic macular hole. This activity was significantly higher than in other vitreoretinal diseases. Immunohistochemical study using monkey eyes showed the possibility that Müller cells in foveal lesions have properties similar to retinal stem cells. Intravitreal injection of chymase induced apoptosis of foveal retinal cells and fibrous change of vitreoretinal interface in the macular area. Biochemical study using cultured human Müller cells revealed that chymase caused the inhibition of growth and the induction of apoptosis in dedifferentiated Müller cells treated with basic fibroblast growth factor (bFGF). These findings show that increased production of chymase and tryptase in mast cells could be related to the pathogenesis of idiopathic macular hole. Oxidative stress and arterosclerosis may be the major causes of exudative AMD. Paraoxonase (PON) is a polymorphic protein known to prevent oxidation of low-density lipoprotein (LDL). We analyzed PON genotypes and found that two types of polymorphism were significantly different between patients with AMD and control subjects. We also investigated serum oxidized low-density lipoprotein(oxLDL) levels, PON activity, and extracellular superoxide dismutase(EC-SOD) levels. All these factors were significantly higher in patients with AMD than in controls. Titers of IgA and IgG antibodies against chlamydia pneumoniae in the serum of AMD patients were also significantly higher than in controls. These results indicate that genetic factors related to PON polymorphisms, vascular damage caused by increment of serum oxLDL and malfunction of EC-SOD, and chronic inflammation provoked by clamydia pneumoniae infection may be involved in the pathogenesis of AMD. Excess accumulation of advanced glycation end products(AGEs) has a causative role in the development of diabetic complications. We determined the concentrations of three AGEs (pentosidine, carboxy-methyllysine, and crossline) and two cytokines (VEGF, IL-6) using ELISA. The levels of the three AGEs and two cytokines in the vitreous of patients with proliferative diabetic retinopathy(PDR) were significantly higher than in controls. The concentrations of VEGF and IL-6 were strongly correlated with the level of these AGEs. Cultured human Müller cells expressed both VEGF and IL-6 mRNA and these expressions were augmented after the treatment of AGEs, while also acting as photosensitizers and accelerating the degradation of hyaluronic acid in vitro. AGEs may consequently play an important role in the pathogenesis of diabetic retinopathy by inducing the production of VEGF and IL-6 in retinal Müller cells and the acceleration of vitreous liquefaction.

Animals↗

PubMed2004

[Malignant trophoblastic tumors (MTT) treated in the years 1955-2004 in trophoblastic disease center in the Czech Republic (TDC-CZ): clinical-pathological features, curability, typing, pathogenesis].

OBJECTIVE: Clinical- pathological features, typing, curability and pathogenesis of malignant tumors of trophoblast (MTT). DESIGN: A retrospective analysis. SETTING: Trophoblastic Disease Center in the Czech Republic (TDC-CZ), Mother and Child Care Institute, 3rd Medical Faculty, Charles University, Prague. METHODS: Revision of 379 MITT cases treated at TDC-CZ and comparison of their histological picture with developmental stages of orthologic trophoblast from the standpoint of MTT typing and pathogenesis. The determination of curability of different histological types and risk stages (RS) used in TDC-CZ and a comparison with RS axccording to FIGO, WHO and NIH. Differentiation of undifferentiated choriocarcinoma (CH-Und) alias Epitheloid Trophoblastic Tumor (ETT) from the given cohort of MIT and establishment of its clinical and biological properties, curability and formal pathogenesis. RESULTS: Three hundred and seventy nine MTT cases were classified into 5 histological types onthe basis of analogy with developmental stages of 7 to 14 days old trophoblast. 1: typical "classical" choriocarcinoma - No Special Type (CH-NST), which forms more than 80% of MTT. Moreover, the degree of differentiation of tumorous trophoblast and its prevailing (cytological) type made it possible to define other 4 types, i.e.: 2: CH-syncytio-trophoblastic (CH-Syn), representing 3.8%; 3: CH-cytotrophoblastic CH-Cyt with 3.3%; 4: CH-dissociated (CH-Dis), representing 6%; 5: CH-undifferentiated (CH-Und) with 6.8%. Mortality due to MIT of all mentioned types reached 94% until 1963, decreased to 43% until 1980 and has been 5.8% in the period of 1981-2004. In the latter period of time (1981-2004), mortality due to CH-Cyt proved to be 40%, that due to CH-Dis being 11%, and CH-Und 18%, though. Mortality of s.c. Placental Site Trophoblastic Tumor, which includes our CH-Cyt and CH-Dis therefore forms 21.4%. We have been using four RS in TDC-CZ. The following outline includes only the main features: 1st RT includes CH-NST < 30mm limited to uterus in connection with mole. 2nd RS includes CH-NST > 30mm after birth. 3rd RS includes CH-NST with multiple metastases outside GIT and CNS and MTT with the CH-Cyt, Dis, Und component < 75%. 4th RS includes CH-NST with metastases in CNS or GIT. MTT with CH-Cyt Dis, Ned component < 75% with metasteses and MTT with the same components > 75% In the last 23 years 1st RS and 2nd RS includes 85 % of all MTT in the TDC-CZ and curability is 100%. In the 3rd RS curability decreases to 64.3% and decreases to 55.6% in the 4th RS. According to FIGO classification the 1st RS forms 48%, 2nd RT represents 17% and 100% curability applies for both of them. 3rd a RS includes 20% of 100% curability, 3rd bc RS forms 10% with 67% curability and 4th abc RS includes 5 % with 50% curability. In using the WHO classification with four RS, their percentage representation is similar to our classification with similar curability; nevertheless the 1st RS and 2nd RS did not detect almost 8% of MTT, which ended with exitus. 3rd RS according to FIGO is overestimated in view of 100% curability and the abc degree in 1st and 2nd RS are only of theoretical significance and irrelevant for the choice of treatment. The closest results comparable with our classification were those of NIH. A very careful clinical-pathological analysis of 25 CH-Und-ETT, detected among 379 MTT revealed that CH-Und-ETT is anaggressive malignant form of CH, which is best derived from undifferentiated 7-8 days old trophoblast. It is insidious for its seemingly primary extragenital symptomatology in seven out of 25 cases, low hCG values and poor sensitivity to chemotherapy. CONCLUSION: 1) The comparison of histological pictures of 379 MTT with developmental stages of orthologic trophoblast of 7-14 days old embryo was the basis for classification of 5 types of choriocarcinoma (CH): 1. Differentiated CH "No Special Type" (CH-NST), 2. Syncytiotrophoblastic CH (CH-Syn), 3. Cytotrophoblastic CH (CH-Cyt), 4. Dissociated CH (CH-Dis), and 5. Non-differentiated CH (CH-Und); 2) We have determined their percentual (and absolute) occurrence in the group of 379 MTT treated in CTN in the years 1955-2004. 3) We have described biological properties of individual types of CH and established the way they influence curability. 4) Four degrees of risk (RS) were specified in relation to 7 types of risk factors observed (1. size of tumor, 2. type of preceding pregnancy, 3. interval from pregnancy to the diagnosis, 4. histological type of CH, 5. number of metastases, 6. localization of metastases, 7. values of hCG). It has become obvious how RS influenced curability of CH (1st and 2nd RS forms 85% of all CH's and their curability is 100% (!), 3rd and 4th RS are represented in 15% and their curability is 64% in the 3rd RS and 55% in the 4th RS. 6) The curability reached in CTN was compared with that determined according to FIGO, WHO and NIH, respectively. The results proved to be similar, but in case of FIGO the 3rd degree was overestimated and the degrees abc in the 1st and 2nd RS were of theoretical importance only, therefore being of no values for the choice of treatment. Low and medium score according to WHO did not detect 8% of women who had died. The CH curability according to RS, having been recommended by NIH and used in the American Centers was virtually the same as our results. 7) It has been proved that the histological type of CH significantly influenced the determination of RS in the given patient. 8) CH-Und-ETT represents the least differentiated form of MTT, in other words choriocarcinoma. This is associated with a low production of HCG, mostly between 10(1) and 10(3) mIU/ml. 9) Pathogenesis of CH-Und ETT-ETT we derive from the earliest, undifferentiated stage of orthological trophoblast. The origin from the differentiated intermediate trophoblast chorion leeve we considerei improbable. 10) There are continuous transitions from CH-Und-ETT and PSTT to CH-NST, representing an analogy to grading in other malignant epithelial tumors.

Choriocarcinoma↗