Robust segmentation of retinal layers in optical coherence tomography images based on a multistage active contour model.

Optical Coherence Tomography (OCT) constitutes an imaging technique that is increasing its popularity in the ophthalmology field, since it offers a more complete set of information about the main retinal structures. Hence, it offers detailed information about the eye fundus morphology, allowing the identification of many intraretinal pathological signs. For that reason, over the recent years, Computer-Aided Diagnosis (CAD) systems have spread to work with this image modality and analyze its information. A crucial step for the analysis of the retinal tissues implies the identification and delimitation of the different retinal layers. In this context, we present in this work a fully automatic method for the identification of the main retinal layers that delimits the retinal region. Thus, an active contour-based model was completely adapted and optimized to segment these main retinal boundaries. This fully automatic method uses the information of the horizontal placement of these retinal layers and their relative location over the analyzed images to restrict the search space, considering the presence of shadows that are normally generated by pathological or non-pathological artifacts. The validation process was done using the groundtruth of an expert ophthalmologist analyzing healthy as well as unhealthy patients with different degrees of diabetic retinopathy (without macular edema, with macular edema and with lesions in the photoreceptor layers). Quantitative results are in line with the state of the art of this domain, providing accurate segmentations of the retinal layers even when significative pathological alterations are present in the eye fundus. Therefore, the proposed method is robust enough to be used in complex environments, making it feasible for the ophthalmologists in their routine clinical practice.

Geochemical signature of NORM waste in Brazilian oil and gas industry.

The Brazilian Nuclear Energy Agency (CNEN) is responsible for any radioactive waste storage and disposal in the country. The storage of radioactive waste is carried out in the facilities under CNEN regulation and its disposal is operated, managed and controlled by the CNEN. Oil NORM (Naturally Occurring Radioactive Materials) in this article refers to waste coming from oil exploitation. Oil NORM has called much attention during the last decades, mostly because it is not possible to determine its primary source due to the actual absence of a regulatory control mechanism. There is no efficient regulatory tool which allows determining the origin of such NORM wastes even among those facilities under regulatory control. This fact may encourage non-authorized radioactive material transportation, smuggling and terrorism. The aim of this project is to provide a geochemical signature for oil NORM waste using its naturally occurring isotopic composition to identify its origin. The here proposed method is the modeling of radioisotopes normally present in oil pipe contamination such as 228Ac, 214Bi and 214Pb analyzed by gamma spectrometry. The specific activities of elements from different decay series are plotted in a scatter diagram. This method was successfully tested with gamma spectrometry analyses of oil sludge NORM samples from four different sources obtained from Petrobras reports for the Campos Basin/Brazil.

A comprehensive survey of Aeromonas sp. and Vibrio sp. in seabirds from southeastern Brazil: outcomes for public health.

AIMS: To perform a microbiological survey regarding the presence, prevalence and characterization of Aeromonas sp. and Vibrio sp. in debilitated wrecked marine birds recovered from the centre-north coast of the state of Rio de Janeiro, Brazil. METHODS AND RESULTS: Swabs obtained from 116 alive and debilitated wrecked marine birds, comprising 19 species, from the study area were evaluated by biochemical methods. Antimicrobial susceptibility tests and pathogenicity gene screening were performed for bacterial strains of public health importance. Vibrio sp. and Aeromonas sp. were identified, as well as certain pathogenic genes and resistance to selected antimicrobials. CONCLUSIONS: This study demonstrates that the identified bacteria, mainly Vibrio sp., are fairly prevalent and widespread among several species of seabirds and highlights the importance of migratory birds in bacterial dispersion. In addition, it demonstrates the importance of the bacterial strains regarding their pathogenic potential. Therefore, seabirds can act as bacterial reservoirs, and their monitoring is of the utmost importance in a public health context. SIGNIFICANCE AND IMPACT OF THE STUDY: The study comprehensively evaluates the importance of seabirds as bacteria of public health importance reservoirs, since birds comprising several pathogenic bacterial species were evaluated.

Incidence of marine debris in seabirds feeding at different water depths.

Marine debris such as plastic fragments and fishing gears are accumulating in the ocean at alarming rates. This study assesses the incidence of debris in the gastrointestinal tracts of seabirds feeding at different depths and found stranded along the Brazilian coast in the period 2010-2013. More than half (55%) of the species analysed, corresponding to 16% of the total number of individuals, presented plastic particles in their gastrointestinal tracts. The incidence of debris was higher in birds feeding predominantly at intermediate (3-6m) and deep (20-100m) waters than those feeding at surface (<2m). These results suggest that studying the presence of debris in organisms mainly feeding at the ocean surface provides a limited view about the risks that this form of pollution has on marine life and highlight the ubiquitous and three-dimensional distribution of plastic in the oceans.

Methicillin-Resistant Staphylococcus aureus from Brazilian Dairy Farms and Identification of Novel Sequence Types.

The aim of this study was to investigate the phenotypic and genotypic diversity and anti-microbial resistance among staphylococci of dairy herds that originated from Paraiba State, north-eastern Brazil, a region where such studies are rare. Milk samples (n = 552) were collected from 15 dairy farms. Isolates were evaluated for anti-microbial susceptibility by Kirby-Bauer disc diffusion method. Confirmation of methicillin-resistant Staphylococcus aureus (MRSA) was performed using multiplex PCR targeting mecA and nuc genes in addition to phenotypic assay based on PBP-2a latex agglutination. Clonal relatedness of isolates was determined by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) genotyping. Staphylococci were detected in 269 (49%) of the samples. Among these, 65 (24%) were S. aureus. The remaining 204 isolates were either coagulase-negative staphylococci (n = 188; 70%) or coagulase positive other than S. aureus (n = 16; 6%). Staphylococci were cultured in seven (35%) of the 20 hand swab samples, from which five isolates were S. aureus. The isolates were most commonly resistant against penicillin (43%), ampicillin (38%) and oxacillin (27%). The gene mecA was detected in 21 S. aureus from milk and in one isolate from a milker's hand. None of the isolates were resistant to vancomycin. PFGE findings showed high clonal diversity among the isolates. Based on MLST, we identified a total of 11 different sequence types (STs 1, 5, 6, 83, 97, 126, 1583, 1622, 1623, 1624 and 1625) with four novel STs (ST1622-ST1625). The findings show that MRSA is prevalent in milk from semi-extensive dairy cows in north-eastern Brazil, and further investigation on its extent in various types of milk production systems and the farm-to-table continuum is warranted.

Biochemical and immunological characteristics of Peruvian Loxosceles laeta spider venom: neutralization of its toxic effects by anti-loxoscelic antivenoms.

This manuscript describes the general biochemical properties and immunological characteristics of Peruvian spider Loxosceles laeta venom (PLlv), which is responsible for the largest number of accidents involving venomous animals in Peru. In this work, we observed that the venom of this spider is more lethal to mice when compared with L. laeta venom from Brazil (BLlv). The LD50 of PLlv was 1.213 mg/kg when the venom was intradermally injected. The venom displayed sphingomyelinase activity and produced dermonecrotic, hemorrhagic and edema effects in rabbits. 2-D SDS-PAGE separation of the soluble venoms resulted in a protein profile ranging from 20 to 205 kDa. Anti-PLlv and anti-BLlv sera produced in rabbits and assayed by ELISA showed that rabbit antibodies cross-reacted with PLlv and BLlv and also with other Brazilian Loxosceles venoms. Western blotting analysis showed that bands corresponding to 25-35 kDa are the proteins best recognized in every Loxosceles spp venoms analyzed. The immunized rabbits displayed protective effect after challenge with PLlv and BLlv. In vitro assays with horse anti-loxoscelic antivenoms produced in Brazil and Peru demonstrated that these commercial antivenoms were efficient to inhibit the sphingomyelinase activity of PLlv and BLlv.

Physiological, morphological, and immunochemical parameters used for the characterization of clinical and environmental isolates of Acanthamoeba.

The factors that characterize Acanthamoeba strains as harmless or potentially pathogenic have not been elucidated. Analysing the in vitro and in vivo parameters of Acanthamoeba samples, including heat tolerance at temperatures close to that of the human body, cytopathic effects, and their ability to cause infections in animals, has been proposed to identify their pathogenic potential. Another promising criterion for differentiating strains is the analysis of their biochemical and immunochemical properties. In this study, a comparative evaluation between clinical and environmental Acanthamoeba isolates was performed on the basis of physiological, morphological, and immunochemical criteria. Crude antigens were used to characterize the protein profiles by electrophoresis and immunize mice to produce polyclonal and monoclonal antibodies. The antibodies were characterized using ELISA, Western blotting, and immunofluorescence techniques. The results obtained with polyclonal antibodies suggest the presence of specific proteins for each studied isolate and co-reactive immunochemical profiles among conserved components. Ten monoclonal antibody clones were obtained; mAb3 recognized 3 out of 4 samples studied. The results of this study may help standardize criteria for identifying and characterizing Acanthamoeba strains. Taken together, our results support the view that a set of features may help differentiate Acanthamoeba species and isolates.

[CD4+, CD8+ AND CD19+ cells in individuals with dyslipidemia]. / Populações Celulares Periféricas (CD4+, CD8+ e CD19+) em Indivíduos Dislipidémicos.

INTRODUCTION: The past decade has witnessed an increasing recognition that inflammatory mechanisms play a central role in the pathogenesis of atherosclerosis and its complications. Recently, attention was focused on the potential role of plasma markers of inflammation as risk predictors among those at risk for cardiovascular events. Of these potential markers, C-reactive protein (CRP), IL6, metalloproteinases, ICAM, VCAM and other molecules, have been extensively studied. On the other hand, to our knowledge, there are only a few studies on the role of inflammatory cells, like T and B lymphocytes in the atherosclerosis. MATERIAL AND METHODS: By flow cytometry analysis we have determined on dyslipidemic people and on a control group, the percentage of some peripheral inflammatory cells, like CD3+, CD4+, CD8+, CD19+, CD56+, CD56CD8+, DN, CD25+, CD26+, CD25CD3+, CD26CD3+, CD25CD26CD3+, CCR5+, CCR5CD3+, CCR5CD4+, HLADR+, HLADRCD4+, HLADRCD8h+, HLADRCD8low+, HLADRCD8+, CD95+, CD95CD95L+, CD3CD95+, CD3CD95L+, CD62L+, CD3CD62L+, CD69+, CD69CD3+ e CD69CD4+. RESULTS: In the present study we have particularly studied the percentage of CD4+, CD8+ and CD19+ cells. The CD4+ cells have been significantly reduced in the people with dyslipidemia. DISCUSSION: We do not know the peripheral numbers of the subtype Th1 and Th2, neither the percentage of CD4+CD25+ cells (regulatory T cells). We have not find any differences on the percentage from the CD8+ and CD19+ cells. CONCLUSIONS: In spite of the identified limitations resulting from the small-sized samples, it was possible to show a reduction of some molecules after application of acetylsalicylic acid.

Introdução: Os mecanismos imunológicos e inflamatórios têm um papel crucial no desenvolvimento da aterosclerose e na sua tradução clínica. São inúmeros os estudos que procuraram relacionar os mais diversos marcadores inflamatórios ­ leucócitos, proteína C reactiva, interleucinas, quimiocinas, moléculas de adesão, metaloproteinases, etc ­ com os factores de risco clássicos da aterosclerose, a formação da placa e os fenómenos clínicos. Não são tantos, que tenhamos conhecimento, os trabalhos que analisaram o comportamento das diversas células mononucleares na fisiopatologia da aterosclerose. Sendo os monócitos/macrófagos e os linfócitos células fundamentais no desencadear e posterior evolução desta doença vascular, procurámos determinar as percentagens das diversas populações celulares periféricas em indivíduos dislipidémicos e em normolipidémicos.Material e Métodos: Por citometria de fluxo, determinámos em indivíduos com dislipidemia e num grupo controlo, as concentrações no sangue periférico dos CD3+, CD4+, CD8+, CD19+, CD56+, CD56CD8+, DN, CD25+, CD26+, CD25CD3+, CD26CD3+, CD25CD26CD3+, CCR5+, CCR5CD3+, CCR5CD4+, HLADR+, HLADRCD4+, HLADRCD8h+, HLADRCD8low+, HLADRCD8+, CD95+, CD95CD95L+, CD3CD95+, CD3CD95L+, CD62L+, CD3CD62L+, CD69+, CD69CD3+ e CD69CD4+. Resultados: Embora na sua grande maioria não tenham sido encontradas diferenças significativas entre os dois grupos de participantes, verificaram-se em algumas populações celulares, resultados que nos mereceram alguns comentários. Neste artigo debruçámo-nos apenas sobre as populações positivas para os CD4, CD8 e CD19.Discussão: A menor concentração das células CD4+ na nossa população de dislipidémicos foi aparentemente inesperada devido ao relacionamento existente entre este tipo celular, os factores de risco e a aterosclerose. Não foram determinados os subtipos Th1 e Th2, nem a população de células reguladoras CD4+CD25+, que poderiam explicar a menor percentagem de células CD4+ nos nossos dislipidémicos. Relativamente às células CD8+ e CD19+, apresentaram percentagens sobreponíveis nos dois grupos de participantes.Conclusões: Apesar das limitações evidenciadas em resultado da reduzida dimensão das populações, foi possível demonstrar uma redução em algumas moléculas após aplicação de ácido acetilsalicílico.

Protection against the toxic effects of Loxosceles intermedia spider venom elicited by mimotope peptides.

The venom of Loxosceles intermedia (Li) spiders is responsible for cutaneous lesions and other clinical manifestations. We previously reported that the monoclonal antibody LimAb7 can neutralize the dermonecrotic activity of crude Li venom. In this study, we observed that this antibody recognizes several proteins from the venom dermonecrotic fraction (DNF), including LiD1. Identifying the epitope of such a neutralizing antibody could help designing immunogens for producing therapeutic sera or vaccination approaches. To this aim, two sets of 25- and 15-mer overlapping peptides that cover the complete amino acid sequence of LiD1 were synthesized using the SPOT technique. None of them was recognized by LimAb7, suggesting that the epitope is discontinuous. Then, the screening of four peptide phage-display libraries yielded four possible epitope mimics that, however, did not show any obvious similarity with the LiD1 sequence. These mimotopes, together with a 3D model of LiD1, were used to predict with the MIMOP bioinformatic tool the putative epitope region (residues C197, Y224, W225, T226, D228, K229, R230, T232 and Y248 of LiD1) recognized by LimAb7. This analysis and the results of alanine-scanning experiments highlighted a few residues (such as W225 and D228) that are found in the active site of different SMases D and that may be important for LiD1 enzymatic activity. Finally, the only mimotope NCNKNDHLFACW that interacts with LimAb7 by SPOT and its analog NSNKNDHLFASW were used as immunogens in rabbits. The resulting antibodies could neutralize some of the biological effects induced by crude Li venom, demonstrating a mimotope-induced protection against L. intermedia venom.

[Digital ulcers in systemic sclerosis: use of endotheline antagonists]. / Úlceras digitais na esclerodermia: papel dos antagonistas dos receptores da endotelina na terap êutica.

INTRODUCTION: Systemic sclerosis (SSc) is a systemic disease, characterized by fibrosis and vasculopathy, with variable internal organ involvement. Skin is very often involved, namely digital ulcers (DU), seldom treatment resistant, responsible for important functional limitation. The DU can evolve from sclerodactily with superficial ulcers, isquemic lesions, deep necrosis, gangrene, loss of tissue, and consequently, to finger amputation. METHODS: The authors describe the case of a 36 year old female patient, with SSc diagnosed 6 years previously, with skin, lung and gut manifestations. The patient showed uncontrolled Raynaud's phenomenon (RF), despite the adequate treatment using nifedidpine and general local warming measures, with progressively worsening DU and isquemia, especially in cold seasons. Bosentan, 62.5 mg twice daily was started, and a significant improvement in the peripheral isquemic lesions was achieved. The ulcers' healing was fast, the patient totally recovered function and regained quality of life, and no further lesions developed. CONCLUSION: The authors review the RF and DU in SSc, as well as the use of bosentan, an endotheline receptor antagonist, and its indications. Although it is not formally approved, the use of bosentan in SS has shown benefits in reducing the incidence of DU, and despite no influence in the healing process, this drug prevents the development of new lesions.

[An exceptional case of renal angiomyolipoma extended to the inferior vena cava. Successfull surgical management]. / Um caso excepcional de angiomiolipoma renal com extensão à veia cava inferior. Tratamento cirúrgico com êxito.

The clinical case of a 39 years old female is reported, with the diagnosis of tumor of the right kidney extending into the infra-hepatic vena cava, assuming the shape of a floating thrombus. The patient underwent right radical nephrectomy, followed by resection of the intra caval tumor. Both the procedure and post operative course were uneventfull. Histopathological evaluation of the specimens, associated to specific imunohistochemistry studies, confirmed the diagnosis of angiomyolipoma of the kidney. A review of the literature concluded that this is the 27th case published of a kidney angiomyolipoma extending into the inferior vena cava, thus justifying its presentation and divulgation.

The Loxtox protein family in Loxosceles intermedia (Mello-Leitão) venom.

We isolated cDNA sequences coding for dermonecrotic/sphingomyelinases factor proteins from the brown spider Loxosceles intermedia, here named Loxtox proteins. The amino acid sequences based on cloned cDNA of several Loxtox proteins revealed at least six distinct groups of proteins expressed in the venom gland. The level of similarity among the toxins varied from 99% to 55%. The finding of several isoforms of Loxtox in the venom of this spider may reflect an evolutionary adaptation for different prey types and reinforces the idea of an efficient mutational mechanism in the venom gland of spiders.

The diseases we cause: Iatrogenic illness in a department of internal medicine.

BACKGROUND: The aim of this study was to estimate the incidence, main causes, and risk factors of iatrogenic disease occurring in a department of internal medicine. METHODS: Over a 1-year period, physicians systematically filled out a 2-page questionnaire for all patients admitted to the ward. A database was created and the data were statistically analyzed. Patients undergoing immunosuppressive, chemo-, or radiation therapy were excluded. Missing data were completed by reviewing the patients' charts. The patients were then divided into two groups: those with and those without iatrogenic disease. The groups were compared using several parameters including gender, age, social features, days of hospitalization, associated illness, functional status, medical impression, prognosis, associated renal or liver function impairment, drugs taken daily, and outcome. In the group with iatrogenic disease, the type, severity, and predictability were also analyzed. RESULTS: Of the 879 patients admitted to the ward, 445 completed questionnaires and were included in the study. A total of 102 patients (22.9%) developed 121 iatrogenic events. Forty-four patients (43.1%) were admitted for iatrogenic illness, 10 (9.8%) developed life-threatening events, and in 3 (6.8%) it was the cause of death. Fifty-eight patients (56.8%) registered 77 episodes of iatrogenic disease during their hospital stay, 20 (19.6%) developed life-threatening events, and 9 (11.7%) died, 4 (5.2%) of an iatrogenic cause (nosocomial infections). Significant differences were found in 20 out of 26 parameters studied (p<0.005 for all cases; 95% confidence interval). Eighteen percent of all iatrogenic disease was severe, 61.9% predictable, 54.5% avoidable, and 59% drug-related, 80% of which was due to side effects or adverse reactions. Infection and metabolic and electrolyte disorders were the most frequent effects. CONCLUSIONS: It is possible to identify risk factors for iatrogenic events. Chronically ill elderly inpatients are the main target of iatrogenic events.

Metabolic syndrome in dyslipidemia consultations.

AIMS: To evaluate the prevalence of the metabolic syndrome (MS) in dyslipidemia consultations, according to the criteria established by the National Cholesterol Education Program Adult Treatment Panel III (ATP III); to classify patients with MS according to ATP III risk categories and prevention type (primary versus secondary); and to evaluate evolution to type 2 diabetes in these patients. METHODS: A retrospective study was conducted based on analysis of the clinical records of 470 patients followed in dyslipidemia consultations at Internal Medicine II of Coimbra University Hospitals. MS was defined as the presence of three or more of the following abnormalities: waist circumference > 102/88 cm (male/female), triglyceride levels > or =150 mg/dl, HDL-cholesterol level < 40/50 mg/dl (male/female), blood pressure > or = 130/85 mmHg and fasting glucose > or = 110 mg/dl. The patients were classified into three risk categories according to the major risk factors defined by ATP III, regardless of LDL-cholesterol level. RESULTS: MS was diagnosed in 31.3% of the patients; 53.7% were male and mean age was 52.7+/-11.9 years. The most prevalent anomaly was hypertriglyceridemia (95.9%), followed by waist circumference (76.1%), HDL cholesterol (73.5%), blood pressure (69.4%) and fasting glycemia (36.7%). Based on the risk categories identified by ATP III, 30.6% of the patients had no or only one risk factor, 66.7% had multiple (2 or more) risk factors and 2.7% had coronary disease or an equivalent risk profile. 97.3% of the patients with MS were in primary prevention. 18.4% developed diabetes, the majority within 1-3 years of the first consultation. CONCLUSIONS: Our study identified a high MS prevalence in patients followed in dyslipidemia consultations, particularly in older age-groups. More than half of the MS patients had an intermediate risk profile and most of them were in primary prevention. We also found that a fifth of non-diabetic patients developed diabetes during follow-up.

Characterization of the venom from the Brazilian Brown Spider Loxosceles similis Moenkhaus, 1898 (Araneae, Sicariidae).

Accidents caused by brown spiders (Loxosceles genus) are frequent in Brazil and are associated with dermonecrotic lesions and, eventually, systemic reactions that may be lethal. The major species implicated with human envenoming have been: L. intermedia, L. gaucho and L. laeta. In this study we characterized the venom from Loxosceles similis, a species of spider normally found inside caves. L. similis venom was characterized by two-dimensional gel electrophoresis and enzymatic activity (dermonecrosis and haemolysis). The lethal dose to mice and the capacity of commercial anti-serum to neutralize this venom were also analysed. The cross-reactivity with anti-venoms against L. intermedia, L. laeta and L. gaucho were studied. Our results showed that this venom was able to induce severe dermonecrotic lesions and showed the presence of the bacteria Clostridium septicum in association with the fangs. In addition, we have cloned the DNA coding for a dermonecrotic protein (LsD1), using the genomic DNA of L. similis. The deduced amino acid sequence showed a toxin of approximately 31.2 kDa with an estimated pI of 7.37 and sequence similar to LiD1, a protein from the dermonecrotic family of Loxosceles intermedia spider venom, a synanthropic species of medical importance.

The methylenetetrahydrofolate reductase (MTHFR) 677C-->T mutation and cardiovascular risk--A case of ischemic stroke and acute myocardial infarction.

The authors report the case of a 39-year-old male patient who had an ischemic stroke (complete infarction of right anterior cerebral circulation) and an acute myocardial infarction during the same year. Molecular study revealed he was homozygous for the 677C-->T mutation in the gene coding for methylenetetrahydrofolate reductase, a key enzyme of folate metabolism; deficiency of this enzyme is associated with increased cardiovascular risk and neurological lesions. Some considerations are put forward about hyperhomocysteinemia and the MTHFR 677C-->T mutation as cardiovascular risk factors.

[Grawitz tumor with invasion of the inferior vena cava and right atrium: surgical management with a multidisciplinary team]. / Tumor de grawitz com invasão da veia cava inferioraté à auricula direita: tratamento cirúrgico com equipa multidisciplinar.

In this paper, the clinical condition of a 56 year old male patient is reported, with the diagnosis of renal cell carcinoma, complicated by a tumoral thrombus, extended from the renal vein into the vena cava and right atrium, who underwent surgical treatment. The operation consisted in the radical nephrectomy associated to the vena caval thrombectomy, under extracorporeal circulation, utilizing a multidisciplinary team composed by urologists, vascular and cardio-thoracic surgeons. The main features related to the diagnosis and surgical management of this case are described and discussed, according to data taken from the most recent publications of the literature on the subject.

[Urinary infection in the adult]. / Infecção urinária do adulto.

Infections of the urinary tract are common--only respiratory infections occur more often. Urinary tract infections (UTI) are a serious health problem producing significant morbidity in a vast number of people each year and mostly affecting the quality of life of young women. Accurate diagnosis and treatment results in successful resolution of most urinary tract infections. To achieve that objective, we present clinical guidelines focussing on specific categories of adult urinary tract infection based on host factors and clinical findings. Categorization of urinary tract infections allows more efficient use of laboratory testing in the workup of UTI and the most appropriate selection of treatment for UTI. Shorter course therapy and prophylactic antimicrobials have reduced the morbidity and cost associated to recurrent cystitis in women. New antimicrobial agents that achieve high urinary levels, administered orally and that are not nephrotoxic, have improved the ability to treat severe infections, reducing the need for hospitalization. Early identification of patients with complicated infections for urological referral remains compulsory.

Maximal androgen blockade: final analysis of EORTC phase III trial 30853. EORTC Genito-Urinary Tract Cancer Cooperative Group and the EORTC Data Center.

OBJECTIVES: This prospective, randomized phase III study was initiated to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist depot formulation, goserelin acetate (3.6 mg s.c. once every 4 weeks) and flutamide (250 mg 3 x daily) in patients with metastatic prostate cancer. METHODS: Relative treatment efficacy was assessed by comparing the two treatment groups with respect to response, time to first progression, progression-free survival, duration of survival and time to death due to malignant disease. RESULTS: There was a difference in response only with respect to a more frequent decrease to normal of the serum prostate acid phosphatase in patients assigned to maximal androgen blockade treatment. Additionally, maximal androgen blockade treatment showed significantly better results for duration of survival (p = 0.04), time to death due to malignant disease (p = 0.008), time to first progression (p = 0.009) and progression-free survival (p = 0.02). The most frequent side effects for both treatments included hot flushes and gynaecomastia. CONCLUSIONS: Increased time to progression and duration of survival is achieved by the combination of flutamide and goserelin when compared to bilateral orchiectomy.