Rapidly progressive primary undifferentiated ovarian carcinoma: presentation of a rare case.

Ovarian cancer is the second most common gynecologic malignancy and is one of the leading causes of death among women. The disease course and the accurate diagnosis are correlated with the early detection of the lesion. About 5% of ovarian cancers are poorly differentiated and difficult to be classified, and are referred to as undifferentiated carcinomas. They are usually large, solid with haemorrhage and necrosis, bilateral, and very difficult to be histologically classified. Generally, cases with undifferentiated components are very rare. The authors present a case of a young female patient with a rapidly progressive undifferentiated ovarian carcinoma and a final unfortunate clinical result.

Fine-needle aspiration cytology of primary renal angiosarcoma with histopathologic and immunocytochemical correlation: a case report.

Primary renal angiosarcoma is an extremely rare neoplasm, with fewer than 28 cases reported thus far in the English literature. We report for the first time the cytomorphology and immunocytochemistry of this tumor in liquid-based (ThinPrep) fine-needle aspiration (FNA) samples in correlation with the conventional cytologic and histopathologic findings. Conventional smears showed pleomorphic tumor cells focally arranged in structures suggesting anastomosing vascular channels, while ThinPrep smears were less cellular with fewer and smaller tumor cells arranged in clusters or rosette-like formations. Immunocytochemical staining demonstrated positive results for vimentin, CD31, and CD34 and negative staining for epithelial markers, thus supporting the diagnosis of a mesenchymal tumor of vascular origin. The diagnosis of primary renal angiosarcoma was established after histopathologic evaluation of a metastatic liver nodule. The cytological differential diagnosis of this neoplasm and the utility of the ThinPrep method as a diagnostic adjunct to conventional FNA cytology are further discussed.

VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2.

BACKGROUND: Vascular endothelial growth factor action in tumour angiogenesis is well characterised; nevertheless, it functions as a key element in the promotion of the immune system's evasion by tumours. We sought to investigate the possible direct effect of VEGF on T-cell activation and through which type of VEGF receptor it exerts this effect on cells isolated from ovarian cancer patients' ascites. METHODS: T cells isolated from the ascites of ovarian cancer patients were cultured with anti-CD3 and IL-2, with or without VEGF for 14 days and the number of viable T cells was counted. Cytotoxic activity of cultured T cells and expression of VEGF receptor-2 (VEGFR-2), was assayed. RESULTS: The addition of VEGF in cultures significantly reduced the number and proliferation rate of T cells in a dose-dependent manner and CD3(+) T cells expressed VEGFR-2 on their surface upon activation. Experiments with specific anti-VEGFR-2 antibodies revealed that the direct suppressive effect of VEGF on T-cell proliferation is mediated by VEGFR-2. We also showed that VEGF significantly reduced the cytotoxic activity of T cells. CONCLUSION: Our study showed that ascites-derived T cells secrete VEGF and express VEGFR-2 upon activation. Vascular endothelial growth factor directly suppresses T-cell activation via VEGFR-2.

Does hormone therapy, tibolone or raloxifene modify VEGF expression in cervical epithelial cells?

AIM: Vascular endothelial growth factor (VEGF) seems to be a critical molecule in cervical carcinogenesis. We aimed to investigate the possible associations between hormonal factors and VEGF expression in cervical epithelial cells from postmenopausal women. METHOD: A total of 105 healthy postmenopausal women (aged 45-68 years old) attending a university menopause clinic were enrolled in this cross-sectional study. Pap smears were derived from current users of 17ß-estradiol 1 mg + norethisterone acetate 0.5 mg (n = 28), tibolone 2.5 mg (n = 23), raloxifene HCl 60 mg (n = 21) and women not receiving treatment (n = 33). VEGF immunostaining was evaluated in squamous, glandular and metaplastic cells, using a semiquantitative method (rating scale: 0-3). RESULTS: Concerning endogenous hormones, higher Δ4-androstenedione levels were associated with more intense VEGF immunostaining in glandular (p = 0.041) and metaplastic cells (p = 0.004). Hormone therapy and raloxifene did not induce any changes in VEGF immunoreactivity in the examined cells. In contrast, tibolone administration was accompanied by diminished VEGF presence in metaplastic cells (p = 0.016 vs. controls). CONCLUSION: Our findings may in part reflect the molecular processes contributing to the safe profile of hormone therapy, tibolone and raloxifene in cervical carcinogenesis.

Fallopian tube cancer presenting as inflammatory breast carcinoma: report of a case and review of the literature.

Metastases of ovarian or fallopian tube carcinomas to the breast and axillary lymph nodes are quite uncommon and usually occur in advanced stages. These metastases may represent a pitfall for the pathologist, because they may mimic primary breast carcinoma. A 56-year-old woman was admitted to the hospital with a left-sided pelvic tumor, redness and swelling of the right breast and palpable right axillary nodes and left lower neck and supraclavicular lymphadenopathy. The imaging, surgical and pathologic findings were those of a papillary serous carcinoma of the fallopian tube with metastases to the breast, axillary and neck lymph nodes. It is important that metastasis to the breast be differentiated accurately from primary breast cancer, because prognosis and treatment differ significantly. Imaging, immunohistochemical analysis and pathology can help in making the correct diagnosis.

Prognostic impact of HER2/neu protein in urothelial bladder cancer. Survival analysis of 80 cases and an overview of almost 20 years' research.

PURPOSE: This study was conducted to evaluate the quantitative assessment of HER2/neu immunohistochemical expression in urothelial bladder cancer in order to determine its prognostic significance. MATERIALS AND METHODS: Archival tumor tissue from 80 patients with primary urothelial carcinoma were analysed for HER2/neu immunohistochemical expression. A highly reproducible standardized procedure on a Bond-X automated slide stainer was used. RESULTS: HER2 protein was overexpressed in 41 of 80 patients (51.25%), demonstrating an increase in the expression rate corresponding to progressively advanced tumor stage (p=0.032) and tumor grade (p=0.0001). Kaplan-Meier analyses showed that positive membranous expression of HER2/neu was not associated with an increased probability of tumor recurrence (p=0.362). In contrast, HER2 scores correlated strongly with specific survival probability (p=0.002) and overall survival (p=0.025). Multivariate analysis revealed that only stage was an independent predictor of specific survival (p=0.016). HER2 expression was an independent predictor of specific survival with borderline statistical significance (p=0.08). CONCLUSION: HER2 overexpression represents a prognostic factor for adverse disease outcome.

Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"?

Thyroid hormone receptor alpha1 (TRalpha1) is predominantly expressed in the myocardium but its biological function under physiological or pathological conditions remains largely unknown. The present study investigated possible interactions between alpha1 adrenergic and thyroid hormone signaling at the level of TRalpha1, potential underlying mechanisms and physiological consequences, as well as the role of TRalpha1 in cell differentiation. This may be of physiological relevance since both thyroid hormone and adrenergic signalling are implicated in the pathophysiology of cardiac remodelling. Neonatal cardiomyocytes obtained from newborn rats (2-3 days) were exposed to phenylephrine (PE, an alpha1 adrenergic agonist) for 5 days, in the absence or excess of T3 in the culture medium. PE, in the absence of T3, resulted in 5.0 fold increase in TRalpha1 expression in nucleus and 2.0 fold decrease in TRalpha1 expression in cytosol, P<0.05. As a result, a fetal pattern of myosin isoform expression with marked expression of beta-MHC was observed in PE treated vs the untreated cells, P<0.05. PD98059 (an ERK signalling inhibitor) abrogated this response. In the presence of T3 in the culture medium, TRalpha1 expression was increased 1.6 fold in nucleus and 2.0 fold in cytosol in PE-T3 vs PE treated cells, P<0.05, and the fetal pattern of myosin isoform expression was prevented. Parallel studies with H9c2 myoblasts showed that reduction of T3 binding to TRalpha1 receptor delayed cardiac myoblasts differentiation without affecting proliferation. In conclusion, in neonatal cardiomyocytes, nuclear TRalpha1 is overexpressed after prolonged activation of the alpha1- adrenergic signalling by PE. This response seems to be an ERK kinase dependent process. Over-expression of TRalpha1 may lead to fetal cardiac phenotype in the absence of thyroid hormone availability. Furthermore, TRalpha1 seems to be critical in cardiac myoblast differentiation.

Altered expression of adhesion molecules in inflammatory cervical smears.

OBJECTIVE: The aim of the present study was to evaluate the expression of pan-cadherin and beta-catenin in cervical smears with various types of infectious agents. PATIENTS AND METHODS: Cervical smears obtained from 53 women, aged 21-65 years, with a diagnosis of specific inflammation were examined in our study. Eighteen subjects were infected by Candida albicans, 18 by Gardnerella vaginalis, nine by Bacteroides spp. and eight by Chlamydia trachomatis. All infectious agents found in the smears were at the same time confirmed by the microbiological laboratory methods. We performed a biotin-streptavidin-peroxidase immunocytochemical method using anti-beta-catenin (Clone 12F7) and anti-pan-cadherin (pan, polyclonal) antibodies. RESULTS: Aberrant expression of pan-cadherin was found in the cytoplasmic membrane of glandular, metaplastic, superficial and intermediate squamous cells in all types of infections. With regard to beta-catenin, this was expressed in majority (90%) of glandular and metaplastic cells in all types of infections and in a small proportion (15%) of superficial and intermediate squamous cells in infections caused by C. albicans and G. vaginalis. CONCLUSION: Our data show that infectious agents may cause alterations in the expression and distribution of these adhesive molecules, which can be recognized in cervical smears. Additional studies in larger sets of patients should help clarify this issue further.

Epidermal growth factor receptor and proliferating cell nuclear antigen expression in urine ThinPrep specimens.

OBJECTIVE: To evaluate proliferating cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR) expression in urine ThinPrep (TP) specimens, to compare these findings with clinical and histological features and to determine whether these immunomarkers are predictive of clinical stage. PATIENTS AND METHODS: The TP processed urine samples and the corresponding tissue sections from 42 patients with newly diagnosed bladder cancer (18 non-muscle invasive and 24 muscle invasive) were included in our study. Urine was collected for cytological evaluation before transurethral resection. Tumour grade and clinical stage were assessed from the transurethral resection specimens. The EGFR and PCNA expression was obtained by an automated immunostainer. RESULTS: There was a remarkable concordance in the expression of both antibodies in TP smears and tissue sections. No significant association was detected for any of the immunomarkers examined with regard to tumour grade. The EGFR expression as well as grade of malignancy were significantly associated with stage of disease (P = 0.0001). PCNA was not found to be a significant predictor of stage (P = 0.210). CONCLUSION: Our data suggest that the evaluation of grade of malignancy and EGFR immunopositivity can be considered as reliable predictors of disease stage in urine TP specimens.

Association between polymorphisms of the atrial natriuretic peptide gene and proteinuria: a population-based study.

AIMS/HYPOTHESIS: In case-control studies, polymorphisms at the atrial natriuretic peptide gene (ANP) locus have been associated with presence of albuminuria in Type 1 and Type 2 diabetes. We evaluated the relationship between the ScaIand BstxI polymorphisms and albuminuria in the general population of the Mexico City Diabetes Study. METHODS: Allele/genotype frequencies were analysed by PCR-RFLP analysis using ScaI (wild, A(2) vs mutated, A(1)) and BstxI (wild, C(708) vs mutated, T(708)) enzyme. RESULTS: Among 1288 subjects, hypertension was present in 112 subjects, Type 2 diabetes in 191 and impaired glucose tolerance in 136; microalbuminuria was present in 464 subjects, and clinical proteinuria in 199. General frequencies were 0.93 and 0.96 for the wild alleles, and 0.07 and 0.04 for the mutated alleles, respectively for ScaI and BstxI. Frequency of A(1)was 0.08 in normoalbuminuric, 0.05 in microalbuminuric, and 0.05 in proteinuric patients (chi(2)=7.3, p=0.025). Frequency of T(708) was 0.06 in normoalbuminuric and 0.03 microalbuminuric and 0.03 in proteinuric subjects (chi(2)=8.1, p=0.017). By multivariate analysis, the associations between A(1)or T(708) allele and albuminuria were independent of age, sex, BMI, diabetes, and hypertension, (odds ratio (OR) 0.60, p=0.01, (OR) 0.51, p=0.004, respectively). CONCLUSION/INTERPRETATION: In the general population of Mexico City, both polymorphisms of ANP are associated with albuminuria independently of hypertension, and could play a role in protecting subjects against development of albuminuria.

A neural network approach to the outcome definition on first treatment with sertraline in a psychiatric population.

Therapy decision is one of the most important tasks clinicians have to perform in their clinical practice. The decision process requires taking into account many different factors. The Authors have proposed a neural computing approach for supporting clinical decision analysis. The mathematical model of artificial neural network (ANN) has been applied on a pool of clinical information gathered through case description freely filled by senior psychiatrists into 416 clinical charts. Sertraline, as drug for treatment, has been chosen since its clinical uses range from treatment of depression to that of many other psychiatric clinical conditions so that it has been thought to be a good candidate to this type of study. The ANN performance in forecasting successful and unsuccessful treatment cases showed an overall accuracy of classification of 97.35%. This result suggests a possible future application of this method to obtain a reliable prediction of a given psychiatric patient outcome during a specific psychopharmacological therapy, optimising the decisional making process.

Polycyclic aromatic hydrocarbons (PaHs) in subcutaneous biopsies of Mediterranean cetaceans.

The aim of the present study was to measure polycyclic aromatic hydrocarbon (PAH) levels in free-ranging Mediterranean cetaceans as they are likely to cause chemical stress in the organisms of this basin. Blubber samples were collected from live specimens of fin whales (Balaenoptera physalus) and striped dolphins (Stenella coeruleoalba) by means of biopsies, a non-destructive biological method. Fin whales were sampled in the Ligurian Sea, whereas striped dolphins were collected in the Ligurian and the Ionian Seas. A fingerprint of 14 PAHs was obtained for both species. In whales, the median value of total PAHs was 1970 ppb fresh weight (f.w.) while median carcinogenic PAH values were 89.80 ppb f.w.; in dolphins, the median values of total and carcinogenic PAHs were 29,500 and 676.00 ppb f.w., respectively. The different PAH values between the two species can be attributed to the different positions they take in the Mediterranean food web. The sampling period significantly influenced PAH concentrations of fin whales.

Hearing loss in progressive systemic sclerosis patients: a comparative study.

OBJECTIVE: To investigate the middle and inner ear involvement in patients with progressive systemic sclerosis (PSS). STUDY DESIGN AND SETTINGS: We prospectively evaluated 34 PSS patients. All patients underwent a complete ear-nose-throat physical examination and audiological evaluation with pure tone, impedance, and speech audiometry. In addition, systemic manifestations of the disease and drug therapy were recorded. Finally, all patients were tested for the presence of autoantibodies. The results were compared with those of 45 age-matched healthy subjects. RESULTS: We found a sensorineural hearing loss in 20% and mixed type hearing loss in 3.3% of the patients. There was no correlation of hearing loss with age, systemic manifestations of the disease, presence of autoantibodies, and drug therapy. Ten percent of the patients had patulous eustachian tubes. CONCLUSION: One fourth of PSS patients had a hearing loss affecting the middle and mainly the high frequencies. This is a lower percentage than that reported by other investigators. A significant prevalence of bilateral patulous eustachian tubes was noticed as well. Further investigation is needed for a better understanding of the mechanism of ear damage in PSS patients.

Outcome of lupus pregnancy: a controlled study.

OBJECTIVE: The reciprocal relationship between systemic lupus erythematosus (SLE) and pregnancy was investigated in a controlled study. METHOD: The outcome of 47 pregnant SLE patients with 59 pregnancies was compared with that of 57 healthy control women and 59 pregnancies. The results were also compared with those of 59 non-pregnant control SLE patients. RESULTS: All pregnant SLE patients but one were in remission at the onset of pregnancy and were being treated with low doses of prednisone (< or = 10 mg/day, 26 patients), hydroxychloroquine (200 mg/day, eight patients) or azathioprine (100 mg/day, one patient). Sixty-one per cent of SLE pregnancies were delivered at term and 5% had premature deliveries. The rates of spontaneous abortion and total fetal loss were significantly higher in the mothers with SLE than in the control population (P: < 0.001 and P: < 0.01 respectively). None of the 39 neonates from SLE mothers had neonatal lupus, anti-Ro(SSA) or anti-La(SSB) antibodies. Eight out of 59 pregnancies of SLE mothers (13.5%) were characterized by disease exacerbation. Arthralgias or arthritis, fever and skin lesions were observed more frequently in the mothers with SLE than in the non-pregnant group (P: < 0.001). Renal involvement was found in three SLE patients during pregnancy and in three after delivery. CONCLUSIONS: Pregnant women with SLE are at high risk of fetal loss and spontaneous abortion. Pregnancy does not cause life-threatening manifestations of the disease. Thus, for a better outcome of lupus pregnancy, it is essential to control disease activity and to achieve clinical remission.

Evaluation and characterization of micronuclei induced by the antitumour agent ASE [3beta-hydroxy-13alpha-amino-13, 17-seco-5alpha-androstan-17-oic-13, 17-lactam-p-bis(2-chloroethyl)amino phenylacetate] in human lymphocyte cultures.

3beta - Hydroxy - 13alpha - amino - 13, 17 - seco - 5alpha - androstan - 17 -oic-13,17-lactam-p-bis(2-chloroethyl)amino phenylacetate (ASE) is a homo-aza-steroidal ester of p-bis(2-chloroethyl) amino phenyl acetic acid and has been shown to display antineoplastic, mutagenic and genotoxic activity. In the present study an effort has been made to evaluate the ability of ASE to induce micronuclei (MN) in human lymphocytes treated in vitro using the cytokinesis-block assay. Lympocytes were treated with different concentrations of ASE (0.1, 0.25, 0.5, 1, 2.5, 5, 10 and 20 microg/ml) at two different cell culture times, 21 and 41 h after culture initiation. ASE treatment lasted until cell harvest, for 51 and 31 h, respectively. Two types of cultures were used, whole blood and isolated lymphocyte cultures. The content of induced MN was identified by FISH analysis, using an alpha-satellite DNA probe, in binucleate cells. Our results suggest that ASE is capable of increasing MN frequencies in human lymphocytes under both culture conditions. This increase is related to the concentration in a linear dose-dependent manner and is also dependent on the duration of treatment. FISH analysis has shown that the induced MN resulted mainly from breakage events. Additionally, a weak aneugenic effect was found at the higher concentrations in whole blood cultures as well as in isolated lymphocyte cultures. Cytotoxic effects of ASE were observed under both cell culture conditions with a linear dose-dependent relationship according to CBPI evaluation and were more pronounced in isolated lymphocyte cultures.

Hearing loss in Sjögren's syndrome patients. A comparative study.

OBJECTIVE: In an attempt to investigate the presence of hearing loss in primary Sjögren's syndrome (SS) patients and to determine the factors that might be involved in its pathogenesis, we prospectively evaluated 45 female SS patients with a mean age of 56.8 +/- 9.23 years and a mean disease duration of 8.32 +/- 5.39 years. METHODS: Forty patients underwent a complete ear-nose-throat physical examination and audiological evaluation with: (a) pure tone audiometry thresholds at octave frequencies of 250 to 8000 Hz; (b) impedance audiometry (tympanogram, static compliance, acoustic reflexes, reflex decay; and (c) speech audiometry and auditory brainstem response where indicated. In addition, glandular and extraglandular manifestations of the disease and drug therapy were recorded. Finally, all patients were tested for the presence of autoantibodies, including: rheumatoid factor, antinuclear antibodies, antibodies to Ro(SSA), La(SSB) nuclear antigens, anticardiolipin antibodies and antineutrophil cytoplasmatic antibodies. The results were compared with those of 40 healthy, age-matched women. RESULTS: We found sensorineural hearing loss (SNHL) in 9 patients (22.5%): 4 patients bilaterally, 4 patients in the left ear only and one in the right ear only. In all cases the site of the ear damage was cochlear. A correlation between SNHL and the duration of the disease was found, while there was no correlation with age, systemic manifestations of the disease or the presence of autoantibodies. In addition, no correlation was found between SNHL and drug therapy. CONCLUSION: Approximately one-fourth of our SS patients presented SNHL of cochlear origin affecting mainly the high frequencies. This prevalence was lower than that reported by other investigators. SNHL was associated only with disease duration. Further investigation is needed to attain a better understanding of the mechanism of inner ear involvement in SS patients.

Polymorphic MAO-A and 5-HT-transporter genes: analysis of interactions in panic disorder.

Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo- or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.

Skin biopsy of Mediterranean cetaceans for the investigation of interspecies susceptibility to xenobiotic contaminants.

Various studies on Mediterranean cetaceans have revealed bioaccumulation of contaminants such as organochlorines (OCs) and heavy metals. The susceptibility of these animals to organic pollutants and the relationship between bioaccumulation and population decline (as in the case of Delphinus delphis) are unexplored fields. In this study, we used a non-destructive approach (skin biopsy) to explore OC bioaccumulation processes and mixed-function oxidase activity (BPMO) in four species of cetaceans: striped dolphin (Stenella coeruleoalba), bottlenose dolphin (Tursiops truncatus), common dolphin (D. delphis) and fin whale (Balaenoptera physalus). Significant differences in BPMO induction and OC levels were found between odontocetes and mysticetes, the former having mixed-function oxidase activities four times higher than the latter, binding with levels of OCs one order of magnitude higher in odontocetes. A significant correlation (P < 0.05) between BPMO activities and OC levels was found in B. physalus. In an ongoing project, fibroblast cultures have been used as an alternative in vitro method of evaluating interspecies susceptibility to contaminants such as OCs and polycyclic aromatic hydrocarbons (PAHs). These results suggest that cetacean skin biopsies are a powerful non-invasive tool for assessing ecotoxicological risk to Mediterranean marine mammals species.

Artificial neural networks: a study in clinical psychopharmacology

Controlled trials in clinical psychopharmacology may fail to provide reliable information about the benefit of treatment when the patient is viewed in a real-life setting rather than as part of a well-defined sampling procedure. A viewpoint, rooted in systems theory, is proposed based on the identification of complex relationships among such dimensions as clinician's reasoning, drug properties, and patient's condition. Artificial Neural Network (ANN) technology provides efficient tools for data analysis within a systems-oriented approach. This study proposes a way to predict the outcome of psychopharmacological treatment. Analysis was conducted on retrospective data from clinical records of psychiatric patients treated with moclobemide. Twelve pharmacological, diagnostic, and topological variables were identified as the decisional items considered by six clinicians: age at onset, sex, previous treatment, duration and dose of moclobemide treatment, other drugs, psychiatric diagnosis and other clinical features. Data were binarily coded and transformed into observed frequencies in the sampling space; treatment outcome was binarily scored as the model's target. A Back-Propagation ANN based on the Delta rule with logistic transfer function was used. ANN correctly classified all cases of successful treatment (n = 51, 100%) but only half of the unsuccessful cases (n = 14, 52%). Patterns of response and areas of uncertainty were analyzed in a topological approach.