Precursor lesions in testis and dysgenetic gonads.
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Biomedical subjects
Publications and source records attributed to Finn Edler von Eyben.
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The majority of non-small cell (NSC) lung cancers express epidermal growth factor receptor (EGFR). Many studies have evaluated the clinical effect from targeted therapy achieved by blocking EGFR in patients with NSC lung cancer. Treatment of biologically unselected patients with NSC lung cancer with two reversible quinazole EGFR inhibitors, gefitinib and erlotinib, gave negative results in all controlled trials but one. Ten percent to 20% of patients with NSC lung cancers have somatic mutations in EGFR, and these patients have a significantly higher response rate (73%) to treatment with EGFR inhibitors than patients with wild-type EGFR (10%). Patients with Asian background, women, non-smokers, and patients with adenocarcinoma had higher response rates than other patients, and the differences may be due to an association between the clinical characteristics and EGFR mutations. Further studies are needed to fully evaluate the effect of EGFR inhibitor-treatment for subgroups of patients with NSC lung cancer with favorable biological and clinical characteristics.
Microinvasive germ cell tumor (MGCT) consists of a limited number of malignant germ cells in the intertubular tissue of the testis. The cells have large nuclei, prominent nucleoli, abundant clear cytoplasm, and distinct cellular borders in hematoxylin and eosin staining. MGCT can be the first stage of malignancy in the development of testicular germ cell tumor (TGCT). Biopsies from men with maldescended testes have been reported to contain intratubular germ cell neoplasia, unclassified (IGCN) and MGCT in 1.8% of the examined cases (95% CI 0.5-4.6%). MGCT has also been found in testes of subfertile men and in the contralateral testis of patients with TGCT. MGCT is a frequent finding (19%) in the testicular tissue adjacent to an overt TGCT. Men with a high risk of TGCT may gain from screening for precursor lesions of TGCT with ultrasonography of the testes followed by a testicular biopsy if suspicious abnormalities are found: Treatment is high-voltage radiotherapy for intratubular germ cell neoplasia (IGCN), and orchidectomy for MGCT and germ cell tumor in situ, either intratubular seminoma or intratubular embryonal carcinoma. After local treatment, patients with precursor lesions can be followed with a surveillance program. The mRNA levels of invasion-related genes were evaluated based on a DNA microarray data set, and we found two gene abnormalities most relevant for the invasion of malignant germ cells: matrix metalloproteinase 9 (MMP9) and plasminogen activator, urokinase (PLAU) genes were up-regulated in a study comparing tissue samples of TGCT and IGCN.
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BACKGROUND: Male gender is an independent coronary risk factor. METHOD: Long-term follow-up of 989 Danish men who underwent legal castration between 1929 and 1968. RESULTS: The legally castrated men were unmarried and belonged to social class IV and V more often than were Danish men in general. During the follow-up until 2000, 835 of the 989 (85%) castrated men died, including 148 who died of myocardial infarction. In multiple Poisson regression analyses, the men had a standardized mortality rate (SMR) for all-cause mortality of 1.30 (95% CI: 1.26-1.36) and a SMR for mortality of myocardial infarction of 1.08 (95% CI: 1.04-1.16). Thus, the castrated men had a lower proportion of deaths of myocardial infarction (148/792, 18.7% (95% CI: 16.0-21.6%)) than was expected based on the mortality rates for the Danish male population (136/608, 22.4%). The castrated men had discordant changes for the SMR for all-cause mortality and mortality of myocardial infarction whereas subgroups of the Danish population previously has been found to have concordant changes for the two SMRs. CONCLUSION: The castrated men had fewer deaths of myocardial infarction than expected, so men may not have increased risk of coronary heart disease from unphysiologically low levels of endogenous androgens.
Because only some coronary risk factors have been evaluated for an association with plasma plasminogen activator inhibitor 1 (PAI-1) activity, this cross-sectional study examined the association between 27 coronary risk factors and PAI-1 in 24 healthy persons without coronary heart disease (control persons) and 22 patients who had survived myocardial infarction (cases). The coronary risk factors included major coronary risk factors such as age, anthropometric measures such as intraabdominal fat, and biochemical analytes such as serum concentration of triglyceride and plasma von Willebrand factor activity. The associations were analyzed in univariate and multiple linear regression analyses. For the control persons, triglyceride and von Willebrand factor were significantly associated with PAI-1 activity (p=0.0002, R(2)=0.55). In contrast for the 24 cases, age and intraabdominal adipose tissue were significantly associated with PAI-1 (p=0.0011, R(2)=0.51). Coronary risk factors explained more than half the variation of PAI-1 activity for both study groups. However, healthy persons and patients with previous myocardial infarction differed regarding coronary risk factors associated with PAI-1.
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A literature review found 265 articles on testicular germ cell tumors (TGCTs) detailing the copy number of chromosomal regions and expression of 245 genes. An initial precursor stage, intratubular germ cell neoplasia (IGCN), is characterized by triploidization and an upregulation of KIT, ALPP, CCDN2, and ZNF354A, and a downregulation of CDKN2D. TGCT regularly have a series of chromosomal aberrations: a decrease in copy number at 4q21 approximately qter and 5q14 approximately qter; an increase at 7p21 approximately pter, 7q21 approximately q33, and 8q12 approximately q23 (especially high increase in seminoma); a decrease at 11p11 approximately p15 and 11q14 approximately q24; an increase at 12p11 approximately pter; a decrease at 13q14 approximately q31; an increase of 17q11 approximately q21 (only for nonseminoma); a decrease of 18q12 approximately qter; and an increase at 21q21 approximately qter, 22q11 approximately qter (only for seminoma), and Xq. Macroscopically overt TGCT is associated with a characteristic series of abnormalities in the retinoblastoma pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and the cyclin-dependent kinase inhibitors p16, p18, p19, and p21. TGCT thus has a synergistic pattern in gene expressions of the retinoblastoma pathway that is rare in other malignancies.
Extent of intra-abdominal fat had significant linear relations with six metabolic coronary risk factors: systolic and diastolic blood pressure, fasting blood concentrations of glucose, high density lipoprotein (HDL) cholesterol, triglyceride, and plasminogen activator inhibitor-1. Tumor necrosis factor-alpha and adiponectin can be biological mediators from the intra-abdominal fat to the metabolic coronary risk factors. Complementarily, we describe a new study that will analyze the gene expression in intra-abdominal and subcutaneous fat on mRNA and protein level using high throughput methods. The study will elucidate further whether intra-abdominal obesity is the common denominator for the different components of the metabolic syndrome.
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In univariate analyses of patients with metastatic testicular germ cell tumours (TGCT), both the International Germ Cell Consensus Classification (IGCCC) and serum lactate dehydrogenase (S-LD) isoenzyme 1 catalytic concentration (S-LD-1) significantly predicted survival. In complementary analyses of 81 patients with metastatic TGCT, S-LD and S-LD-1 classified the prognosis differently for 23 patients. In multivariate Cox hazard analyses of risk factors, only IGCCC and S-LD-1 predicted the prognosis (p=0.036, and p=0.0007, respectively). A new prognostic model based on prognostic information from main histology, IGCCC, and S-LD-1 changed the prognostic prediction by IGCCC for 19 patients (24%). Judged by to the area under the curve for receiver operation characteristics curves, the new model predicted five-years survival for the patients better than IGCCC and a modified version of the third edition of the TNM classification (p=0.025, and p=0.01, respectively). However, new studies should validate the new model before it is recommended as a general classification system of patients with metastatic TGCT.
The International Germ Cell Consensus Classification (IGCCC) of testicular germ cell tumors (TGCT) in 1997 included three serum tumor markers, serum lactate dehydrogenase catalytic concentration (S-LD), serum alpha fetoprotein concentration (S-AFP), and serum human chorionic gonadotropin concentration (S-hCG). The recommendation should be implemented for all patients with TGCT and is also useful for patients with ovarian and extragonadal germ cell tumors. A fourth serum tumor marker for TGCT, S-LD isoenzyme 1 (S-LD-1), is also relevant for TGCT. Patients with seminoma have a raised S-LD-1 more often than a raised S-AFP and S-hCG, whereas patients with nonseminoma have a raised S-AFP more often than a raised S-LD-1 and S-hCG. A new model combining IGCCC and S-LD-1 predicts survival better than previous staging systems. LD-1 is related to a characteristic chromosomal abnormality in all types of TGCT, a high copy number of chromosome 12p. In contrast, AFP and hCG are found mainly in nonseminomatous germ cell tumors and they related to the histologic differentiation of the tumors. The different biologic background for the serum tumor markers may contribute to the difference in their clinical behavior.
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