Urinary Concentrations of Colistimethate and Formed Colistin after Intravenous Administration in Patients with Multidrug-Resistant Gram-Negative Bacterial Infections.

Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose (Cmin ss) and at the end of the CMS infusion (Cmax ss) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, <0.1 to 95.4 mg/liter; Cmin ss and Cmax ss of colistin in plasma, 0.9 (<0.2 to 1.4) and 0.9 (<0.2 to 1.4) mg/liter, respectively. In 6/12 (50%) patients, more than 40% of the CMS dose was recovered in the urine within the first 6 h after CMS administration. This study demonstrated rapid urinary excretion of CMS in patients within the first 6 h after intravenous administration. In all but one patient, the concentrations of formed colistin in urine were above the MIC for the most predominant isolate of P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

Drug-drug interactions of telaprevir and boceprevir in HCV-monoinfected and HIV/HCV-coinfected patients can modify the adherence.

BACKGROUND & AIMS: The first generation protease inhibitors, boceprevir (BOC) and telaprevir (TVR), are both CYP3A4 inhibitors, which predispose drug-drug interactions (DDIs). The aim of this study was to evaluate the prevalence of potential DDIs, the management of outpatient medication and its impact on adherence and efficacy to antiviral treatment in hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients receiving BOC and TVR. METHODS: The usual medication starting with BOC or TVR was screened by the pharmacist of the multidisciplinary support programme (MSP) for potential DDIs. Recommendations were made to avoid significant DDIs, and changes in the baseline medication were recorded. Adherence to antiviral treatment was considered as 80/80/95% of total doses. Sustained virological response was assessed at week 12 (SVR12). RESULTS: At least one potential DDI was found in 70 (64.8%) patients, 45 (54.2%) being HCV-monoinfected and 25 (100%) HIV/HCV-coinfected (P < 0.01). Baseline treatment modifications were required in 38 (35.2%) patients. Adherence and SVR12 were higher in patients without DDIs (86.8%) and (67.6%) compared to those with DDIs (62.8%) (P = 0.021) and (47.2%) (P = 0.097) respectively. CONCLUSIONS: More than half of the patients were at risk of presenting DDIs, leading to changes in the baseline medication in one-third of the patients. Drug interactions are frequent in patients with lower adherence.

An overview of randomized clinical trials in metastatic breast cancer: variables affecting regulatory drug approval.

The aim of this study was to analyse trial variables affecting drug approval in metastatic breast cancer (MBC). A literature search from 2000 to 2012 retrieved 66 phase III randomized controlled trials with reported primary endpoints in MBC and known outcomes in terms of approval. The influence of the primary endpoint, the line of therapy, crossover and the sample size was analysed. The primary endpoints used most frequently were progression-free survival (PFS) and time to progression or time to treatment failure (N=47; 71%). Overall survival (OS) was a primary endpoint in nine trials (14%). In 26 trials (39%), statistically significant results were found with respect to the primary endpoint, and in 13 trials (20%), this was found with respect to the secondary endpoint. Gains in OS were found in 12 trials (18%), whereas a benefit to PFS was found in 30 trials (46%). The average median OS was 23.1 months. Postprogression survival accounted for 64% of OS. Trials with crossover did not have OS as the primary endpoint. Trials that resulted in drug approval had a more pronounced gain in OS or PFS and had more patients than those without regulatory consequences. PFS was the main primary endpoint in randomized clinical trials in MBC and was significantly associated with drug approval. OS benefit was rarely achieved in trials where this was not the primary endpoint. The number of randomized patients, the primary endpoint and crossover are factors linked to regulatory requirements for approval, which should be considered in future trial designs.

Design of a score to identify hospitalized patients at risk of drug-related problems.

PURPOSE: The potential impact of drug-related problems (DRP) on morbidity and mortality is a serious concern in hospitalized patients. This study aimed to design a risk score to identify patients most at risk of a DRP. METHODS: Data from patients admitted to a tertiary university hospital between January and August 2009 were used to design the risk score (training set). DRP were detected through a pharmacy warning system integrated in the computerized medical history. The variables associated with developing a DRP were identified through a binary multivariate logistic regression analysis and were used to compute the DRP risk score, which was subsequently validated in patients admitted between September and December 2009 (validation set). RESULTS: Of the 8713 patients included in the training set, at least one DRP was detected in 2425 (27.8%). Prescription of a higher number of drugs, higher comorbidity, advanced age, certain groups of the Anatomical Therapeutic Chemical classification system, and some major diagnostic categories were associated with risk of DRP. These variables were used to compute the DRP risk score. The area under the receiver operator characteristic curve was 0.778 (95%CI [0.768, 0.789]). Of the 4058 admissions included in the validation set, at least one DRP was detected in 876 (21.6%). The area under the receiver operator characteristic curve was 0.776 (95%CI [0.759, 0.792]). CONCLUSIONS: Knowledge of the variables associated with DRP could aid their early detection in at-risk patients. The use of an application that can be continually updated in daily clinical practice helps to optimize resources.

Bisphosphonate-induced cutaneous adverse events: the difficulty of assessing imputability through patch testing.

BACKGROUND: Cutaneous adverse drug reactions (CADRs) due to bisphosphonates (BPs) have been scarcely described in the literature. OBJECTIVE: To discuss the diagnostic value and limitations of cutaneous provocation tests with BPs. METHODS: A descriptive case series study with a control group of CADRs due to BPs studied using patch testing from 2005 to 2010 is presented. RESULTS: Patient 1 showed a positive D4++ with alendronate at 1% in petrolatum and D4+++ with alendronate at 1 and 0.1% in water. Patient 2 showed a positive intradermal test D3++ with alendronate at 0.1% in water. Patient 3 showed a positive patch test D4+ with ibandronate at 1% in petrolatum and D4++ with ibandronate at 1% in water, and a positive intradermal test D3+++ with ibandronate at 0.1% in water. CONCLUSION: Establishing a correct interpretation of a patch test reaction is difficult based just on cutaneous test results. Too high concentrations of the drug can cause irritation and too low concentrations can be responsible of false-negative test reactions.

A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C.

BACKGROUND & AIMS: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC. METHODS: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003-2004, n=147), MSP group (2005-2006, n=131), and MSP-validation group (2007-2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model. RESULTS: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes. CONCLUSIONS: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.

[Shedding light on the use of colistin: still gaps to be filled]. / Luces y sombras en el uso de colistina: falta mucho por conocer.

Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

Impact of non-formulary drugs on pharmacological prescription in hospitalised patients.

OBJECTIVES: The growing number of drugs on the market makes it necessary to adapt hospital formularies in order to ensure consistent drug coverage. The aim of this study was to evaluate the impact of the prescription of non-formulary drugs (NFD) on the therapeutic management of admitted patients. METHODS: This retrospective observational study included NFD prescriptions in patients hospitalised in a tertiary university hospital during the period 2012-2015. NFD prescriptions are displayed on the computerised medical order as a pending alert to be reviewed by the clinical pharmacists, who make a notation to the clinical course that includes a recommendation for an available therapeutic alternative when available in the hospital formulary. The degree of acceptance of the recommendation by physicians is recorded. RESULTS: Approximately 0.5% of patients hospitalised during the study period were affected by an NFD prescription. A total of 52 (9.5%) NFD were of doubtful therapeutic efficacy, five (0.9%) were non-replaceable drugs and 490 (89.4%) were prescriptions for drugs with an alternative available in the hospital formulary. The acceptance rate for the recommended alternative was 34.9% in the evaluable NFD prescriptions. No correlation was observed between the number of NFD prescriptions or the number of NFD and the availability index (drugs included in the hospital formulary in relation to the total number of drugs marketed). CONCLUSIONS: The number of patients with a NFD prescription was very low. The lack of correlation between the number of NFD or NFD prescriptions and the availability index demonstrated that the hospital formulary covers practically all therapeutic needs.

[Analysis of drug-related problems in a tertiary university hospital in Barcelona (Spain)]. / Análisis de los problemas relacionados con los medicamentos en un hospital de tercer nivel de Barcelona.

OBJECTIVE: To describe drug-related problems identified in hospitalized patients and to assess physicians' acceptance rate of pharmacists' recommendations. METHODS: Retrospective observational study that included all drug-related problems detected in hospitalized patients during 2014-2015. Statistical analysis included a descriptive analysis of the data and a multivariate logistic regression to evaluate the association between pharmacists' recommendation acceptance rate and the variable of interest. RESULTS: During the study period 4587 drug-related problems were identified in 44,870 hospitalized patients. Main drug-related problems were prescription errors due to incorrect use of the computerized physician order entry (18.1%), inappropriate drug-drug combination (13.3%) and dose adjustment by renal and/or hepatic function (11.5%). Acceptance rate of pharmacist therapy advice in evaluable cases was 81.0%. Medical versus surgical admitting department, specific types of intervention (addition of a new drug, drug discontinuation and correction of a prescription error) and oral communication of the recommendation were associated with a higher acceptance rate. CONCLUSIONS: The results of this study allow areas to be identified on which to implement optimization strategies. These include training courses for physicians on the computerized physician order entry, on drugs that need dose adjustment with renal impairment, and on relevant drug interactions.

Design of a relative value unit-based tool for the measurement and reimbursement of pharmacy services for clinical trials.

OBJECTIVE: To develop a relative value unit (RVU)-based tool for the measurement and reimbursement of pharmacy services for clinical trials. METHODS: A portfolio of activities was agreed by consensus in four tertiary hospitals. Related activities were pooled into several categories or intermediate products. We recorded the duration of each activity by multiple determinations. We then calculated the average time of all determinations. The reference activity was assigned a value of 1. All other activities were compared to the reference activity to obtain the RVU. To establish which items should be invoiced to third parties for the activities performed, we defined the final products (different types of clinical trials according to their complexity). RESULTS: Ten intermediate products and five final products were differentiated. Six intermediate products could be repeated over the course of a clinical trial and seven were performed whether or not the clinical trial had included patients. Each final product consisted of different categories. The total number of RVUs produced for a clinical trial was the sum of each constant category value plus the repetitive category values multiplied by the number of repetitions. CONCLUSION: The application of RVU methodology in investigational drug services allows a more precise quantification of services performed. After a prospective validation to confirm the applicability of this tool, it may contribute to more appropriate invoicing to third parties for these services.

Community-acquired pneumonia caused by methicillin-resistant Staphylococcus aureus in critically-ill patients: systematic review.

INTRODUCTION: Community-acquired pneumonia (CAP) is associated with high morbidity and mortality rates. Despite methicillin-resistant Staphylococcus aureus (MRSA) having often been associated with nosocomial pneumonia, the condition of some MRSA CAP patients is severe enough to warrant their being admitted to ICU. OBJECTIVE: The purpose of this study is to conduct a systematic review of the literature on antibiotic treatment of MRSA CAP in critically-ill patients. MATERIAL AND METHODS: An online search was conducted for locating articles on MRSA CAP in critically ill patients. Relevant publications were identified in PUBMED, the BestPractice database, UpToDate database and the Cochrane Library for articles published in English within the December 2001 - April 2016 time frame. RESULTS: A total of 70 articles were found to have been published, 13 (18.8%) having been included and 57 (81.4%) excluded. Cohort studies were predominant, having totaled 16 in number (20.7%) as compared to one sole cross-sectional study (3.5%). CONCLUSIONS: The experience in the treatment of MRSA CAP in patients requiring admission to ICU is quite limited. Vancomycin or linezolid seem to be the treatments of choice for MRSA CAP, although there not be any specific recommendation in this regard. It may be useful to use alternative routes, such as administration via aerosolized antibiotics, continuous infusion or in association with other antibiotics.

Introducción: La neumonía adquirida en la comunidad (NAC) está relacionada con unas tasas elevadas de morbi-mortalidad. A pesar de que Staphylococcus aureus resistente a meticilina (SARM) se ha relacionado frecuentemente con la neumonía nosocomial, algunos pacientes con NAC por este microorganismo revisten la suficiente gravedad como para precisar su ingreso en la UCI.Objetivos: Efectuar una revisión sistemática de la literatura sobre el tratamiento antibiótico de la NAC por SARM en pacientes críticos.Material y métodos: Se realizó una búsqueda de artículos sobre NAC por SARM en el paciente crítico. Se identificaron las publicaciones pertinentes en PUBMED, BestPractice database, UpTo-Date database y Cochrane Plus Library para artículos publicados en inglés desde diciembre del 2001 hasta abril del 2016. Resultados: Se encontraron 70 publicaciones, incluyendo 13 (18,8%) y excluyendo 57 (81,4%). Predominaron los estudios de cohortes con un total de 6 (20,7%), frente a una única publicación en forma de estudio transversal (3,5%). Conclusiones: La experiencia en el tratamiento de la NAC por SARM en pacientes que precisen ingreso en la UCI es muy limitada. La vancomicina o el linezolid parecen ser las terapias en las que se dispone de una mayor experiencia, aunque no existe ninguna recomendación específica al respecto. Puede ser útil la utilización de vías alternativas como la nebulizada, administración en perfusión continua o en asociación con otros antibióticos.

Patient risk factors for developing a drug-related problem in a cardiology ward.

BACKGROUND: Because of the high incidence of drug-related problems (DRPs) among hospitalized patients with cardiovascular diseases and their potential impact on morbidity and mortality, it is important to identify the most susceptible patients, who therefore require closer monitoring of drug therapy. PURPOSE: To identify the profile of patients at higher risk of developing at least one DRP during hospitalization in a cardiology ward. METHOD: We consecutively included all patients hospitalized in the cardiology ward of a teaching hospital in 2009. DRPs were identified through a computerized warning system designed by the pharmacy department and integrated into the electronic medical record. RESULTS: A total of 964 admissions were included, and at least one DRP was detected in 29.8%. The variables associated with a higher risk of these events were polypharmacy (odds ratio [OR]=1.228; 95% confidence interval [CI]=1.153-1.308), female sex (OR=1.496; 95% CI=1.026-2.180), and first admission (OR=1.494; 95% CI=1.005-2.221). CONCLUSION: Monitoring patients through a computerized warning system allowed the detection of at least one DRP in one-third of the patients. Knowledge of the risk factors for developing these problems in patients admitted to hospital for cardiovascular problems helps in identifying the most susceptible patients.

Survey of oral chemotherapy safety and adherence practices of hospitals in Spain.

BACKGROUND: Oral chemotherapy is increasingly used for cancer therapy but, without proper practices, creates safety and adherence issues. However, little is known on safety and adherence practices in wide clinical settings. OBJECTIVE: To assess the implementation level of safety and adherence practices in oral chemotherapy in Spanish hospitals. SETTING: All Pharmacy services from prescription, dispensation, patient education and monitoring hospitals that prescribe oral chemotherapy of Spain. MAIN OUTCOME MEASURE: Level of safety practices regarding oral chemotherapy prescription, dispensation, patient education and adherence. METHOD: An 11 multiple-choice-item questionnaire made in consensus with GEDEFO (Spanish Group of Oncology Pharmacists) was sent to all pharmacy services from hospitals that prescribe oral chemotherapy. This questionnaire comprised prescription, dispensation, education and monitoring. We arbitrarily defined three levels of practices: no sufficient specific practices were reported (we termed this as 'level I'); performance of an initial visit with a pharmacist providing written patient educational materials and monitoring adherence (termed as 'level II'); and level II requirements plus electronic chemotherapy ordering system and extra safety practices (termed as 'level III'). RESULTS: Of the 169 targeted health-care settings, 86 (50.9 %) responded to the survey. The majority of responding hospitals were public, general, and teaching hospitals with more than 200 beds. Main discrepancies were in electronic prescription of oral chemotherapy and monitoring adherence. There were 32 hospitals (37.2 %) with level I of safety and adherence practices, 38 hospitals (44.2 %) accomplished level II, 16 (18.6 %) hospitals reached level III. No hospital variables were found to be correlated with each level of safety. CONCLUSIONS: The majority of responding hospitals have safety and adherences practices for oral chemotherapy. However, the level of these practices varies. There are significant opportunities for improvement, particularly with regard to electronic prescription of oral chemotherapy and monitoring adherence.

Potential role of tedizolid phosphate in the treatment of acute bacterial skin infections.

Tedizolid phosphate (TR-701), a prodrug of tedizolid (TR-700), is a next-generation oxazolidinone that has shown favorable results in the treatment of acute bacterial skin and skin-structure infections in its first Phase III clinical trial. Tedizolid has high bioavailability, penetration, and tissue distribution when administered orally or intravenously. The activity of tedizolid was greater than linezolid against strains of Staphylococcus spp., Streptococcus spp., and Enterococcus spp. in vitro studies, including strains resistant to linezolid and those not susceptible to vancomycin or daptomycin. Its pharmacokinetic characteristics allow for a once-daily administration that leads to a more predictable efficacy and safety profile than those of linezolid. No hematological adverse effects have been reported associated with tedizolid when used at the therapeutic dose of 200 mg in Phase I, II, or III clinical trials of up to 3 weeks of tedizolid administration. Given that the clinical and microbiological efficacy are similar for the 200, 300, and 400 mg doses, the lowest effective dose of 200 mg once daily for 6 days was selected for Phase III studies in acute bacterial skin and skin-structure infections, providing a safe dosing regimen with low potential for development of myelosuppression. Unlike linezolid, tedizolid does not inhibit monoamine oxidase in vivo, therefore interactions with adrenergic, dopaminergic, and serotonergic drugs are not to be expected. In conclusion, tedizolid is a novel antibiotic with potent activity against Gram-positive microorganisms responsible for skin and soft tissue infections, including strains resistant to vancomycin, linezolid, and daptomycin, thus answers a growing therapeutic need.

[Influence of ethnicity on the pharmacokinetics of amikacin]. / Influencia de la etnia en el comportamiento farmacocinético de amikacina.

OBJECTIVE: Despite the increasing ethnic diversity, there are few studies of its influence on the pharmacokinetics of amikacin. The objective of this study was to compare the pharmacokinetics of amikacin in different populations: Asian, Hispanic, North Africans and Caucasian. METHODS: A retrospective observational study was performed in a tertiary teaching hospital during eight years. It was included all patients with intravenous amikacin treatment in extended interval dosing regimen with therapeutic drug monitoring of amikacin. Pharmacokinetic parameters were analysed. A bivariate and multiple linear regression statistical analysis were carried out. RESULTS: 164 patients were included: 7 asians, 135 Caucasians, 11 Hispanics and 11 from North Africa. It was shown a lower plasma concentrations of amikacin in North Africa population due to its greater clearance. CONCLUSIONS: Amikacin plasma concentrations monitoring is advisable in patients from North Africa in order to avoid subtherapeutic concentrations.

Pharmacoeconomic evaluation of linezolid versus teicoplanin in bacteremia by Gram-positive microorganisms.

OBJECTIVE: The objective of this study was to compare the efficiency of linezolid versus teicoplanin in the treatment of bacteremia produced by Gram-positive microorganisms through a pharmacoeconomic analysis based on clinical results obtained from a previous clinical trial. METHODS: We applied an analysis of cost-effectiveness elaborated through a pharmacoeconomic model. We defined each unit of effectiveness as 'each successfully cured of infections with bacteremia.' We used the program Pharma-Decision (version Hospital 1.1) that allows to build interactive pharmacoeconomic models. Effectiveness data of both antibiotics were obtained from a published clinical trial, while resources consumed were obtained from the same source and from a consensus provided by a local expert panel. Only direct costs were included in the analysis without taking into consideration indirect costs. The perspective chosen was hospital assistance and the time horizon was set to 28 days. All costs are expressed in Euros. RESULTS: Linezolid demonstrated a better clinical outcome with less associated costs compared to teicoplanin (88.5 versus 56.7% of cured patients and 5,557.04 versus 6,327.43 per treated patient, respectively), thus resulting in a lower cost-effectiveness ratio for linezolid versus teicoplanin (6,279.1 versus 11,159.5 per cured patient with a 95% CI of 5,960.2-6,510.4 and 10,865.2-12,647.3, respectively) which results in a the dominant position for linezolid. The sensitivity analysis showed that linezolid was always the most efficient option even when modifying the value of variables with higher uncertainty. CONCLUSIONS: Linezolid is a more efficient option than teicoplanin because it presents higher rate of effectiveness with lower consumption of resources, thus being a dominant alternative in the treatment of Gram-positive infection with bacteremia.

Cáncer del colon en la infancia: presentación de dos casos / Cancer of the colon in childhood: report of 2 cases

Se presentan los hallazgos clínico-patológicos de dos casos de adenocarcinoma de tipo mucinoso, en dos niños. En uno de los casos la evolución ha sido satisfactoria, encontrándose aparentemente libre de la enfermedad, luego de 18 meses de haber sido intervenido. En el otro caso no se tienen datos de su evolución actual. Se revisa la literatura tomando en cuenta las diferentes series de casos registrados en las tres primeras décadas de la vida y se coincide en la baja incidencia de esta neoplasia en niños y adolescentes. Se hacen algunas consideraciones respecto a la clínica, factores epidemiológicos, anatomía-patológica, pronóstico y tratamiento

Tumores malignos de células germinales: estudio clínico patológico de cinco casos / Malignant germ cell tumors: clinical and pathological study of 5 cases

Se presenta una serie de cinco casos de tumores malignos de células germinales diagnosticados en el Servicio de Anatomía Patológica del Hospital "Miguel Pérez Carreño", IVSS, Caracas, Venezuela, entre enero de 1992 y junio de 1993, con los principales hallazgos clínicos-patológicos. Tres de estos casos fueron tumores mixtos: dos con predominio de saco vitelino, uno de ellos asociado a un carcinoma embrionaro del testiculo y el segundo a un teratoma ovarico; el tercer caso constituido por un disgerminoma mas un teratoma. Se presentan además un caso de disgerminoma puro y un teratoma quistico benigno de ovario con transformación maligna. Se revisa la literatura al respecto