Delphi consensus on the diagnosis and treatment of patients with short stature in Spain: GROW-SENS study.

PURPOSE: To identify consensus aspects related to the diagnosis, monitoring, and treatment of short stature in children to promote excellence in clinical practice. METHODS: Delphi consensus organised in three rounds completed by 36 paediatric endocrinologists. The questionnaire consisted of 26 topics grouped into: (1) diagnosis; (2) monitoring of the small-for-gestational-age (SGA) patient; (3) growth hormone treatment; and (4) treatment adherence. For each topic, different questions or statements were proposed. RESULTS: After three rounds, consensus was reached on 16 of the 26 topics. The main agreements were: (1) diagnosis tests considered as a priority in Primary Care were complete blood count, biochemistry, thyroid profile, and coeliac disease screening. The genetic test with the greatest diagnostic value was karyotyping. The main criterion for initiating a diagnostic study was prediction of adult stature 2 standard deviations below the target height; (2) the main criterion for initiating treatment in SGA patients was the previous growth pattern and mean parental stature; (3) the main criterion for response to treatment was a significant increase in growth velocity and the most important parameter to monitor adverse events was carbohydrate metabolism; (4) the main attitude towards non-responding patients is to check their treatment adherence with recording devices. The most important criterion for choosing the delivery device was its technical characteristics. CONCLUSIONS: This study shows the different degrees of consensus among paediatric endocrinologists in Spain concerning the diagnosis and treatment of short stature, which enables the identification of research areas to optimise the management of such patients.

Oral versus transdermal oestrogen delivery for endometrial preparation before embryo transfer: a prospective, comparative, randomized clinical trial.

RESEARCH QUESTION: To determine whether the transdermal route is equal or superior to the oral route, when preparing the endometrium with oestrogens for embryo transfer. DESIGN: Prospective, randomized controlled trial; 140 patients randomized; the pills group followed a protocol with oestradiol valerate pills and the patches group followed a protocol with oestradiol hemihydrate patches. The primary variable was endometrial thickness on day 10 ± 1 of treatment. Secondary variables were endometrial thickness on day 15 ± 1 of treatment, patient satisfaction, plasma levels of oestradiol, rates of pregnancy, miscarriage and delivery. Endometrial thickness was measured on day 10 ± 1 of the cycle, if the lining was 7 mm or less in thickness, another measurement was made on day 15 ± 1. Blood oestradiol levels were analysed on the day the endometrial lining was greater than 7 mm (day 10 ± 1 or day 15 ± 1). Patients completed a survey to evaluate comfort and side-effects. RESULTS: The patches group achieved significantly thicker endometrium by the first check-up on day 10 ± 1 (7.6 mm versus 7.0 mm; P = 0.026), with lower blood levels of oestradiol (159.2 pg/ml versus 237.1 pg/ml; P < 0.001) when the endometrial thickness was over 7mm. The pills group considered the treatment more comfortable, with less side-effects. No significant differences in the rates of pregnancy, miscarriage or live birth were found. CONCLUSIONS: Transdermal oestrogen treatment allows patients to reach a higher endometrial thickness after 10 days of treatment, with lower plasma levels of oestradiol, although it is not tolerated as well.

Study of the efficacy of a Streptococcus uberis mastitis vaccine against an experimental intramammary infection with a heterologous strain in dairy cows.

Streptococcus uberis is a worldwide pathogen that causes intramammary infections in dairy cattle. Nevertheless, commercial vaccines are currently not available and measures to control S. uberis mastitis are limited to the implementation of good management practices. The aim of the present study was to evaluate the efficacy of an S. uberis subunit vaccine against bovine mastitis (Laboratorios Hipra S.A., Amer, Spain) administered precalving against an experimental intramammary challenge with a heterologous S. uberis strain in dairy cows postcalving. With this objective, 25 gestating Holstein-Friesian heifers were randomly assigned to 1 of 2 groups: group 1 (n = 13), vaccinated by intramuscular route with the vaccine, and group 2 (n = 12), vaccinated by intramuscular route with phosphate-buffered saline as a control group. Both groups were immunized 60 and 21 d before the expected parturition date (75 and 36 d before challenge). Fourteen days after calving all cows were challenged by intramammary infusion of 100 colony-forming units of a heterologous S. uberis strain in 2 quarters per cow. Then, challenged quarters were monitored for clinical signs of mastitis, bacterial count, and somatic cell count for the following 21 d. Rectal temperature and daily milk yield per cow were also assessed. Results showed that all challenged quarters developed clinical mastitis. Nevertheless, vaccination significantly reduced the clinical signs of mastitis, bacterial count, rectal temperature, and daily milk yield losses after the intramammary infection and significantly increased the number of quarters with no bacterial isolation and somatic cell count <200,000 cells/mL at the end of the study (d 19, 20, and 21 after challenge). To confirm the efficacy of this vaccine, further studies under field conditions are needed.

A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).

BACKGROUND: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. PATIENTS AND METHODS: This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. RESULTS: Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms. CONCLUSION: This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously. TRIAL NUMBER: NCT01830231.

Incidence and prognostic impact of U2AF1 mutations and other gene alterations in myelodysplastic neoplasms with isolated 20q deletion.

BACKGROUND: In myelodysplastic neoplasms (MDS), the 20q deletion [del(20q)] is a recurrent chromosomal abnormality that it has a high co-occurrence with U2AF1 mutations. Nevertheless, the prognostic impact of U2AF1 in these MDS patients is uncertain and the possible clinical and/or prognostic differences between the mutation type and the mutational burden are also unknown. METHODS: Our study analyzes different molecular variables in 100 MDS patients with isolated del(20q). RESULTS & CONCLUSIONS: We describe the high incidence and negative prognostic impact of U2AF1 mutations and other alterations such as in ASXL1 gene to identify prognostic markers that would benefit patients to receive earlier treatment.

Response to azacitidine in patients with chronic myelomonocytic leukemia according to overlap myelodysplastic/myeloproliferative neoplasms criteria.

BACKGROUND: Azacitidine (AZA) is approved for the treatment of high-risk chronic myelomonocytic leukemia (CMML) of myelodysplastic (MD) subtype. Data of response rates using the specific response criteria for this disease are scarce. The aim of this study was to evaluate the response to AZA in patients diagnosed with CMML from the Spanish Registry of Myelodysplastic Syndromes (MDS) applying the overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) response criteria. METHODS: We retrospectively studied 91 patients with CMML treated with at least one cycle of AZA from the Spanish Registry of MDS. As it was a real-world study, the response rate was evaluated between cycle 4 and 6, applying the MDS/MPN response criteria FINDINGS: The overall response rate at cycle 4-6 was 58%. Almost half of the patients achieved transfusion independence and one quarter showed clinical benefit, regardless of the CMML French-American-British (FAB) and World Health Organization (WHO) subtypes and CMML Specific Prognosis Scoring (CPSS) risk groups. Toxicity was higher in the MD-CMML subtype. INTERPRETATION: In our series, most CMML patients achieved an overall response rate with AZA according to the overlap-MDS/MPN response criteria regardless of the CMML FAB and WHO subtypes and CPSS risk groups. Thus, AZA may also be a treatment option for patients with the myeloproliferative CMML subtype and those with a lower-risk CPSS, but symptomatic.

Ecchymosis and/or haematoma formation after prophylactic administration of subcutaneous enoxaparin in the abdomen or arm of the critically ill patient. / Formación de equimosis y/o hematoma tras la administración profiláctica de enoxaparina subcutánea en abdomen o brazo en pacientes críticos.

INTRODUCTION: Ecchymosis and/or haematoma are the most common adverse events after subcutaneous administration of low molecular weight heparin. There is no strong recommendation as to the puncture site. OBJECTIVE: To evaluate the adverse events, ecchymosis and/or haematoma after the administration of prophylactic subcutaneous enoxaparin in the abdomen vs the arm in the critically ill patient. METHODOLOGY: A randomised, two-arm clinical trial (injection in the abdomen vs the arm), performed between July 2014 and January 2017, in an 18-bed, polyvalent intensive care unit. Patients receiving prophylactic enoxaparin, admitted >72h, with no liver or haematological disorders, a body mass index (BMI) >18.5, not pregnant, of legal age and with no skin lesions which would impede assessment were included. We excluded patients who died or who were transferred to another hospital before completing the evaluation. We gathered demographic and clinical variables, and the onset of ecchymosis and/or haematomas at the injection site after 12, 24, 48 and 72hours. A descriptive analysis was undertaken, with group comparison and logistic regression. The study was approved by the ethics committee with the signed consent of patients/families. RESULTS: 301 cases (11 excluded): 149 were injected in the abdomen vs 141 in the arm. There were no significant differences in demographic and clinical variables, BMI, enoxaparin dose or antiplatelet administration [ecchymosis, abdomen vs arm, n(%): 66(44) vs 72(51), P=.25] [haematoma abdomen vs arm, n(%): 9(6) vs 14(10), P=.2]. Statistical significance was found in the size of the haematomas after 72h: [area of haematoma (mm2) abdomen vs arm, median (IQR): 2(1-5.25) vs 20(5.25-156), P=.027]. CONCLUSIONS: In our patient cohort, prophylactic subcutaneous enoxaparin administered in the abdomen causes fewer haematomas after 72hours, than when administered in the arm. The incidence rate of ecchymosis and haematoma was lower than the published incidence in critically ill patients, although patients receiving anti-platelet agents present a higher risk of injury. No relationship was observed in relation to BMI.

Effect of a training programme on blood culture contamination rate in critical care. / Efecto de una acción formativa en cuidados intensivos sobre la tasa de contaminación de hemocultivos.

Blood culture contamination can occur from extraction to processing; its rate should not exceed 3%. OBJECTIVE: To evaluate the impact of a training programme on the rate of contaminated blood cultures after the implementation of sample extraction recommendations based on the best evidence. METHOD: Prospective before-after study in a polyvalent intensive care unit with 18 beds. Two phases were established (January-June 2012, October 2012-October 2015) with a training period between them. Main recommendations: sterile technique, surgical mask, double skin disinfection (70° alcohol and 2% alcoholic chlorhexidine), 70° alcohol disinfection of culture flasks and injection of samples without changing needles. Including all blood cultures of patients with extraction request. VARIABLES: demographic, severity, pathology, reason for admission, stay and results of blood cultures (negative, positive and contaminated). Basic descriptive statistics: mean (standard deviation), median (interquartile range) and percentage (95% confidence interval). Calculated contamination rates per 100 blood cultures extracted. Bivariate analysis between periods. RESULTS: Four hundred and eight patients were included. Eight hundred and forty-one blood cultures were taken, 33 of which were contaminated. In the demographic variables, severity, diagnosis and stay of patients with contaminated samples, no differences were observed from those with uncontaminated samples. Pre-training vs post-training contamination rates: 14 vs 5.6 per 100 blood cultures extracted (P=.00003). CONCLUSION: An evidence-based training programme reduced the contamination of samples. It is necessary to continue working on the planning of activities and care to improve the detection of pollutants and prevent contamination of samples.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

Classification and scoring systems in myelodysplastic syndromes: a retrospective analysis of 311 patients.

The main objective of this study was to evaluate the role of the recent World Health Organization (WHO) classification for assessing prognosis in patients with myelodysplastic syndromes (MDS). To this effect, we analyzed the prognostic impact of the WHO and French-American-British (FAB) morphologic classifications and of four different scoring systems in a series of 311 patients with primary MDS diagnosed between October 1990 and June 2001. Both the FAB and WHO classifications identified groups with different prognoses (p<0.0001), those presenting refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS) showing the best prognosis. The WHO classification subdivided RA into RA with only red cell dysplasia, and refractory cytopenia with multilineage dysplasia (RCMD), and RARS into RARS plus refractory cytopenia with multilineage dysplasia and ringed sideroblast (RCMD-RS). In our population, we have shown that the two subtypes characterized by dysplasia affecting exclusively the erythroid population (RA and RARS) have a better prognosis, with a median survival of 122.2 and 81.9 months, respectively, than those with multilineage dysplasia (RCMD and RCMD-RS) with a median survival of 32.3 and 43.2 months, respectively. There were no significant differences in median survival comparing RA with RAS (p<0.95), or comparing RCMD with RSCMD (p<0.97). Besides, the four scoring systems discriminated our MDS patients in terms of survival, and an increase in prognostic capacity was achieved on adding the score to the morphological classifications. Risk scoring had a greater prognostic impact than the FAB and WHO classifications. Prognostic scoring systems may be an important tool for risk stratification in hematological practice, and add significance to morphological classification. Combined application of the WHO classification and score system is useful for improving the identification of patients with a poorer prognosis. The WHO classification establishes more homogeneous subcategories than the FAB classification and is also able to identify groups with different prognoses.

Chromosome 11 abnormalities in myelodysplastic syndromes.

Cytogenetic studies were performed in 140 patients with myelodysplastic syndrome (MDS) at diagnosis. Chromosome 11 anomalies were found in 7 cases (5%); 2 of these patients had refractory anemia (RA), 2 had refractory anemia with excess of blasts (RAEB), 1 had RAEB in transformation (RAEB-t), and 2 had chronic myelomonocytic leukemia (CMMoL) according to the French-American-British (FAB) Cooperative Group criteria. The chromosome 11 abnormalities comprised trisomy 11 (2 patients), monosomy 11 (1 patient), del(11)(q23) (2 patients), add(11)(p15) (1 patient), and der(11) t(3;11)(p21;q23) (1 patient). Abnormalities involving band q23 of chromosome 11 occurred in 3 cases and were the most common alteration. However, specific chromosomal alterations were not associated with any FAB classification group. These findings and their implications in the biology of MDS are discussed.

Effectiveness of different vaccine formulations against vibriosis caused by Vibrio vulnificus serovar E (biotype 2) in European eels Anguilla anguilla.

Vibriosis due to Vibrio vulnificus serovar E (biotype 2) is one of the main causes of mortality in European eels cultured in Europe. The main objective of this study was to develop a vaccine and a vaccination procedure against this pathogen. With this aim, we tested several vaccine formulations (inactivated whole-cells with and without toxoids--inactivated extracellular products--from capsulated and uncapsulated strains, attenuated live vaccines and purified lipopolysaccharide [LPS]) on eels maintained under controlled laboratory conditions using different delivery routes (injection and immersion). To study the immune response we estimated antibody titers and bactericidal/bacteriostatic activity in mucus and serum. To evaluate protection, we calculated the relative percent survival (RPS) after intraperitoneal (i.p.) injection and bath challenge of the pathogen. The overall results indicate that: (1) capsular antigens seem to be essential for protective immunization; (2) vaccines confer the highest protection when administered by i.p. injection; (3) booster is needed to achieve good protection by immersion; (4) enriching the vaccine with toxoids enhances protection to optimal levels (RPS values around 70 to 100%, depending on the delivery route); and (5) the protective effect in serum and mucus depends on the route of administration and seems to be related to the production of specific antibodies.

Rhabdomyoma of the heart: surgical treatment.

Rhabdomyoma of the heart may cause severe hemodynamic obstruction specially in infants. Medical treatment carries a 100% mortality, but there are no clear surgical indications for these patients. Accordingly we reviewed the world literature (30 operated patients) adding our own experience (1 successfully operated patient) Based on our data and that of other we conclude: (1) Severely ill patients with rhabdomyoma should be operated upon. Age or associated tuberous sclerosis are not surgical contraindications. (2) Removal of the hemodynamic obstruction should be the main surgical goal. Radical resection of the tumor is not necessary and may be dangerous. (3) Surgical mortality is acceptable and it is becoming lower with time. (4) Long-term outcome for successfully operated patients is unknown.

[Divided left atrium: operative results and follow-up in the cor triatriatum]. / Aurícula izquierda dividida: resultados quirúrgicos y seguimiento en el cor triatriatum.

INTRODUCTION AND OBJECTIVES: A divided left atrium because of cor triatriatum is a relatively rare cardiac anomaly requiring corrective surgery. We describe here our clinical and surgical experience with this congenital heart defect as well as the different medium and long term diagnostic, surgical and evolution aspects. PATIENTS AND METHODS: From 1981 to 1999, 15 children with cor triatriatum without complex associated cardiovascular defects underwent surgery at a mean age of 13 months (excision of the obstructive membrane). The surgical reports were reviewed and the clinical and echocardiographic data were analyzed before and after the intervention; six of these patients (40%) were referred to operating room only with the 2-D echo Doppler technique and color flow mapping information. The follow-up period ranged from 8 months to 19.3 years. RESULTS: Diagnosis was confirmed during the surgical procedure. One 9 month old patient died 60 days after a successful corrective surgery because of sepsis (7%). No late deaths or reoperations were found in the follow-up period. All 14 patients who survived the operation have a functional class I (NYHA), and they are asymptomatic in the follow-up. The overall survival rate was 93% (70% CI: 87-90). CONCLUSIONS: Corrective surgery with excision of the obstructive membrane dividing the left atrium restores normal anatomic, hemodynamic and clinical status in children with cor triatriatum without complex associated defects.

[Feminization: a paradoxical effect of stimulation with hCG/hMG in the infertile male]. / Feminización: un efecto paradójico de la estimulación con hCG/hMG en el varón infertil.

Male feminization is an uncommon and complex phenomenon which occurs as a consequence of an imbalance in the effective oestrogen/androgen relationship. One of the many approaches used in the treatment of idiopathic male infertility is hCG/hMG stimulation. This paper reports one case of an infertile male treated with hCG/hMG after surgical correction of a varicocele, which resulted in a feminization effect evidenced by gynaecomastia and severe spermatogenesis blockade. When therapy was discontinued the feminization disappeared, a rebound phenomenon with normalization of most of the seminal parameters being seen. No other fully documented cases were found in the literature. Finally, the pathoetiological mechanisms involved in the feminization are analyzed and a revision is made of the causes that may cause it.

[Urocolpos: a cause of pseudo-incontinence in aged women]. / Urocolpos: una causa de falsa incontinencia en la mujer senil.

Presentation of our experience in three cases of urocolpos (acquired pudendal lip fusion), a series numerically equivalent to the total number of cases published until now. All patients in our series were older women and presented complete fusion of the small pudendal lips, with only a small pointed puncture in the lower part of the vulva. The main clinical signs and symptoms in our series were: urinary infection in 100%, false incontinence in 66% due to output of urine retained in the vagina, a symptom that has not been described earlier, and acute urine retention in 33%. All patients were successfully treated by means of surgical loosening of the fusioned lips and application of topical estrogens. An analysis is made of clinical and pathoanatomical features which differentiate this entity from the sclerotic and atrophic lichen. Finally, an etiopathogenic hypothesis is raised to explain the fusion acquired by the small pudendal lips in the urocolpos.

[Autoplastic closure of vesicovaginal fistulae with posterosuperior bladder flap (Gil-Vernet operation)]. / Cierre autoplástico de las fístulas vésico-vaginales con colgajo vesical posterosuperior (operación de Gil-Vernet).

OBJECTIVE: To describe our experience in the treatment of vesico-vaginal fistula with autoplastic closure using a postero-superior vesical flap. Also, to discuss the technical details of the procedure. MATERIAL AND METHOD: Between 1985 and 1996, 15 patients with vesico-vaginal fistulae secondary to gynaecological surgery were operated. The fistula was considered complex in 5 patients based on previous attempts for surgical closure, number of openings or because they were located in the posterior gradient of the vesical neck. In all cases, autoplastic closure of the fistula was done with a vesical flap through an extraperitoneal abdominal approach. RESULTS: In 100% cases closure of the fistula was achieved at the first surgical attempt. There was no need to interpose vascular tissue between the bladder and the vagina to secure closure of fistula. Post-operatively, 5 patients showed decreased vesical capacity which was recovered within six months; two patients had non-obstructive post-surgical vesical instability. No patient had changes in the mechanism of urinary continence.

[Open or closed drainage systems: their impact on urinary infections]. / Influencia en la infección urinaria. Sistemas de drenaje. Abierto o cerrado?

Starting on the premise that the risks of infection due to vesical catheterism lasting more than 48 hours fundamentally depends on the type of drainage system employed, the authors make a study to see if it is possible to achieve a decrease in the rate of urinary tract infections by utilizing closed systems. This study follows a quasi-experimental design having two groups of patients who require this form of catheterism and analyzes its results. This study lasted five months and concluded that "the utilization of a closed drainage system having an anti-backup flow valve significantly reduces the rate of urinary tract infections".

[Left ventricular mass, forced baseline spirometry and adipocytokine profiles in obese children with and without metabolic syndrome]. / Masa ventricular izquierda, espirometría basal forzada y perfil de adipocitocinas en niños obesos con y sin síndrome metabólico.

INTRODUCTION: Recent reports have shown an increase in changes in cardiac and pulmonary function among obese patients. Furthermore, it has also been demonstrated that obesity is a state of chronic inflammation. We hypothesized that obese children with metabolic syndrome exhibit a higher percentage of left ventricular hypertrophy and altered spirometry values due to higher levels of inflammation. PATIENTS AND METHODS: Left ventricular mass was studied using echocardiography, baseline forced spirometry by spirometer (FlowScreen) and adipocytokine profiles (adiponectin, IL-6, leptin, MCP-1, PCR-Hs, RBP-4, TNF-( and visfatin) were evaluated in peripubertal obese children with and without metabolic syndrome. RESULTS: Forty-one patients (20 girls and 21 boys) were included in the study, 20 of whom (10 boys and 10 girls) were subjects with metabolic syndrome. Of the adipocytokines studied, only leptin, hs-CRP, MCP-1, and the leptin/adiponectin ratio yielded values that were substantially greater in the group with metabolic syndrome (P<.01). An analysis of left ventricular mass index and baseline spirometry showed no differences between the groups studied. However, of the entire cohort, 9.5% had left ventricular hypertrophy. No significant relationship was found between anthropometric data and adipocytokines and the parameters used to study left ventricular mass and spirometry values on the other. CONCLUSION: At the time the study was performed, left ventricular mass and baseline forced spirometry did not appear to be influenced by inflammatory mechanisms.