Timing of Pulmonary Valve Replacement: How Much Can the Right Ventricle Dilate Before it Looses Its Remodeling Potential?

Congenital heart disease patients that develop secondary pulmonary regurgitation require a pulmonary valve replacement (PVR) in their follow-up. The indications for PVR in asymptomatic patients are debated. Most guidelines consider a RV end-diastolic volume (RVEDV) over 150 ml/m(2) as an indication for PVR. We analyzed clinical, echocardiographic and MRI variables of patients that underwent a surgical PVR between September 2006 and February 2013. The included patients were asymptomatic, without pulmonary stenosis and with both pre- and post-surgery MRI. Thirty-five patients (74.3 % males) were included. Mean age at PVR was 25.8 years (SD = 7.18), and weight was 64.5 Kg (SD = 12.03). The main diagnosis was tetralogy of Fallot (n = 28), pulmonary atresia (n = 2), primary pulmonary regurgitation (n = 2) and pulmonary regurgitation after percutaneous treatment (n = 2). The maximal RVEDV pre-PVR was 267 ml/m(2), and right ventricular end-systolic volume (RVESV) was 183 ml/m(2). RV size and function were established by MRI: Pre-PVR Post-PVR p RVEDV (ml/m(2)) 162 (SD = 39.1) 94 (SD = 23.6) <0.001 RVESV (ml/m(2)) 87 (SD = 28.9) 44 (SD = 15.7) <0.001 RVEF 44.8 % (SD = 8.17) 52 % (SD = 9.9) <0.001 Patients with a RVEDV under 170 ml/m(2) combined with a RVESV under 90 ml/m(2) had a favorable RV remodeling, defined as RVEDV under 110 ml/m(2) (sensitivity 87.5 %), RVESV under 55 ml/m(2) (sensitivity 100 %) and RVEF over 50 % (sensitivity 100 %). When deciding the optimal PVR timing in asymptomatic patients, both RVEDV and RVESV should be considered. Our results suggest that higher volumes than used in the clinical practice can achieve a good remodeling. Therefore, PVR could be performed later in the follow-up reducing the number of cardiac interventions.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale.

Infective endocarditis in congenital heart disease: a frequent community-acquired complication.

BACKGROUND: Infective endocarditis (IE) is a severe complication in patients with congenital heart disease (CHD). Epidemiology, etiology, and outcome in this group are different to those of patients with acquired heart disease. METHODS: We reviewed all cases of proven and probable IE (Duke's criteria) diagnosed in our center during the last two decades. RESULTS: We observed 45 cases of IE in patients with CHD (age range 8 months to 35 years); these represented 5.5 % of all the episodes of IE in our institution during the study period. The most frequent CHD were ventricular septal defect (31 %), tetralogy of Fallot (19 %), and atrioventricular septal defect (11 %). Twenty cases of IE (44 %) were recorded in patients with non-corrected native-valve CHD. Of the 24 patients with prosthetic-valve IE, post-operative acquisition during the first 6 months was confirmed in 11 patients (range 4-110 days). IE was community-acquired in 62 % of cases. Streptococcus spp. were the most frequent etiologic agents (33 %), followed by Staphylococcus spp. (32 %). Surgery was required to treat IE in 47 % of patients (52 % in prosthetic-valve IE and 41 % in native-valve IE, p = ns). In comparison to native-valve IE, prosthetic-valve IE was significantly more nosocomial-acquired (61 vs. 14 %, p = 0.002), presented a higher heart failure rate at diagnosis (39 vs. 9 %, p = 0.035), and developed more breakthrough bacteremia episodes (19 vs. 0 %, p = 0.048). Global mortality was 24 % (75 % in patients with prosthetic-valve IE who required surgery and 0 % in patients with native-valve IE who required surgery, p = 0.001). Multivariate analysis excluding breakthrough bacteremia (100 % mortality in this condition) confirmed that nosocomial IE [odds ratio (OR), 23.7; 95 % confidence interval (CI), 2.3-239.9] and the presence of heart failure at diagnosis of IE (OR, 25.9; 95 % CI, 2.5-269.6) were independent factors associated with mortality. CONCLUSION: Half of all cases of IE in patients with CHD occurred in patients with non-corrected native-valve CHD and two-thirds were community-acquired. Streptococcus spp. were the most frequent etiological agents. Patients with prosthetic-valve IE present a worse outcome, especially those requiring surgery. Breakthrough bacteremia, nosocomial IE, and heart failure are independent factors of mortality in patients with CHD presenting IE.

Treatment of chronic sternal fistulae following cardiac surgery with a bone substitute.

Chronic sternal infection is a relatively rare complication following cardiac surgery that can cause high morbidity and mortality and can require repeated surgical procedures, including sternal resection, to resolve. However, preserving sternal integrity is essential, particularly in children. A variety of conservative treatments for this complication of cardiac surgery have been reported. Here, we report three cases of children in whom a bone substitute containing tricalcium phosphate and hydroxyapatite was used to fill sternal defects. After extensive surgical debridement, this method yielded primary wound closure with good resolution, preventing the recurrence of sternal infection.

Paclitaxel and cisplatin in the treatment of metastatic non-small-cell lung cancer during pregnancy.

The concomitant occurrence of cancer during pregnancy is a rare event. The cancers most frequently detected during pregnancy are breast, cervical, melanoma, ovarian, leukaemia and lymphoma, however the diagnosis of lung cancer during pregnancy is particularly exceptional. In this case, we report on a pregnant woman who was diagnosed with non-small-cell lung cancer and received therapy with paclitaxel and cisplatin.

Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma.

INTRODUCTION: There are several second-line treatment options for patients with renal cell carcinoma after first-line failure of a tyrosine kinase inhibitor, especially with the recent approvals of cabozantinib, nivolumab, and the lenvatinib plus everolimus combination. A lack of reliable biomarkers and an overall lack of prospective head-to-head comparisons make it a challenge to choose a second-line treatment in the clinic. Areas covered: In this review/meta-opinion, we describe the safety profile of the lenvatinib plus everolimus combination in renal cell carcinoma. The combination of lenvatinib plus everolimus has achieved the highest rates of objective responses and the longest progression free and overall survival in cross-comparison trials. At the same time, the safety profile of this combination, including the rate of total and severe adverse events, the percentage of dose reductions required, and the rate of treatment discontinuation, was less favorable compared with available monotherapy options, suggesting that better management could help to maximize the activity of this combination while protecting patients from undue harm. Expert opinion: Herein, we aim to postulate multidisciplinary recommendations on the advice to offer to patients and caregivers before starting treatment and how to manage the combination from the perspective of daily clinical practice.

Ocular safety comparison of non-steroidal anti-inflammatory eye drops used in pseudophakic cystoid macular edema prevention.

Non-steroidal anti-inflammatory drug (NSAID) eye drops are widely used to treat ocular inflammatory conditions related to ophthalmic surgical procedures, such as pseudophakic cystoid macular edema, and they have been used for off-label treatments. The most commonly used NSAIDs are diclofenac and ketorolac and the new molecules bromfenac and nepafenac have also been used. We used primary human keratocytes in cell culture in combination with a novel technology that evaluates dynamic real-time cytotoxicity through impedance analysis. This study also included classic cell viability tests (WST-1(®) and AlamarBlue(®)), wound healing assay, Hen's Egg Test and an ex vivo histopathological assay. NSAIDs were shown to have important cytotoxicities and to retard the healing response. Furthermore, the new eye drops containing bromfenac and nepafenac were more cytotoxic than the more classical eye drops. Nevertheless, no immuno-histochemical changes or acute irritation processes were observed after the administration of any eye drops tested. Due to cytotoxicity and the total absence of discomfort and observable injuries after the administration of these drugs, significant corneal alterations, such as corneal melts, can develop without any previous warning signs of toxicity.

[Quality control of total parenteral nutrition in the 1991-1992 biennium]. / Control de calidad de la nutrición parenteral total en el bienio 1991-1992.

OBJECTIVE: To assess the degree of compliance with standards defined for Total Parenteral Nutrition (TPN) quality control in our hospital in the two-year period 1991-1992. MATERIAL AND METHODS: All available information was assessed concerning 52 patients (32 men and 17 women) for whom a TPN course was prescribed in relation with certain pre-set indications. These patients received a total of 1140 TPN units with the TPN lasting an average of 21.9 days (range, 1-73 days). Monitoring was done by the Nutrition and Diet Section. The degree of compliance was assessed with the standards model proposed by the Providence Medical Center, Portland (USA) (PMCP) with 24 parameters (PM): indications, initiation in the first 24 hours, nutritional assessment in the first 24 hours, period of the TPN, metabolic complications (14 PM), septic complications (3 PM), nutritional consequences (2 PM) and TPN losses. All parameters were appraised and admitted, except for urea, which was corrected to standard values of our Laboratory (< 44 mg/dl), with Transferrin evaluation instead of iron binding capacity (TIBC), taking as compliance standard a figure of > 190 mg/dl. All analytical calculations were carried out in our Central Laboratory Service. RESULTS: Of all the parameters, the following were discarded, not being calculated on a routine basis: total CO2, serous magnesium, urinary uric nitrogen, nitrogen balance, positive hemocultures, catheters and TPN losses. Levels of compliance varied between 31.9% and 100%, with 8 parameters within the standards (Initiation, 100%; evaluation in first 24 hours, 100%; extent, 100%; creatinine, 100%; total bilirubin, 92.2%; cholesterol, 99.5%; transferrin, 35.9%). Seven parameters fell short (Na, 88.1%; K, 92.9%; Cl, 89.3%; Urea, 54.4%; Glucose, 96.4%; P, 94.1%; Triglycerides, 71.9%). CONCLUSIONS: We infer from our study that there is a need to make use of a large part of the indicators described in the literature as indicators for quality guarantee of a TPN program, and the use of new parameters must be assessed in normal monitoring.

[Cost-effectiveness analysis of aflibercept in combination with FOLFIRI in the treatment of patients with metastatic colorectal cancer]. / Análisis coste-efectividad de aflibercept en combinación con FOLFIRI en el tratamiento de pacientes con cáncer colorrectal metastásico.

OBJECTIVES: To estimate the incremental cost per life-year gained (LYG) of aflibercept in combination with FOLFIRI as second-line treatment in metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. METHODS: Based on clinical trial VELOUR results, a three-state Markov model (stable disease, progression and death) with 2-week cycle duration was designed. Transition to health state «progression¼ implied the interruption of second-line treatment and administration of a third-line treatment (post-second line chemotherapy). Cost estimation included disease management cost (pharmaceutical, adverse event management, administration costs, etc.). Both cost and outcomes were discounted (3% annually). Sensitivity analyses (SA) were performed to test model robustness. RESULTS: Administration of aflibercept + FOLFIRI as second-line treatment provided 1.78 LYG (21 life-months gained). With FOLFIRI 1.43 LYG (17 months) were obtained. The cost of the clinical management of aflibercept + FOLFIRI implied an additional investment of Euros 13,564 compared with FOLFIRI for a lifetime horizon, being total costs for aflibercept + FOLFIRI of Euros 38,346, compared to Euros 24,782 with FOLFIRI. In the cost-effectiveness analysis Euros 38,931/LYG was obtained with aflibercept in combination with FOLFIRI versus FOLFIRI. CONCLUSION: Aflibercept in combination with FOLFIRI increased overall survival versus FOLFIRI, so it is an effective strategy in the treatment of patients with mCRC. Aflibercept in combination with FOLFIRI is an efficient strategy for second-line mCRC treatment from the National Health System perspective.

OBJETIVOS: Estimar el coste incremental por año de vida ganado (AVG) de la utilización de aflibercept en combinación con FOLFIRI como tratamiento de 2ª línea en pacientes con cáncer colorrectal metastásico (CCRm) previamente tratados con oxaliplatino. MATERIAL Y MÉTODOS: Basándose en los resultados del ensayo clínico VELOUR, se utilizó un modelo de Markov con 3 estados de salud (enfermedad estable, progresión y muerte) y ciclos de 2 semanas. La transición al estado de salud «progresión¼ implicaba interrumpir el tratamiento en 2ª línea y administrar una 3ª línea de tratamiento. La estimación de costes incluyó costes del manejo de la enfermedad (farmacológicos, acontecimientos adversos, administración, etc.). Costes y resultados en salud fueron descontados al 3% anualmente. Para probar la robustez del modelo se realizaron análisis de sensibilidad determinístico y probabilístico. RESULTADOS: La administración de aflibercept + FOLFIRI como 2ª línea de quimioterapia aporta 1,78 AVG (21 meses de vida ganados). Con FOLFIRI se consiguen 1,43 AVG (17 meses). El coste del manejo clínico de aflibercept + FOLFIRI supone una inversión adicional de 13.564 frente a FOLFIRI a lo largo de toda la vida del paciente, siendo el coste total de 38.346 para aflibercept + FOLFIRI y 24.782 para FOLFIRI. Se obtiene un RCEI (ratio coste efectividad incremental) de 38.931 /AVG con aflibercept + FOLFIRI frente a FOLFIRI. CONCLUSIÓN: Aflibercept en combinación con FOLFIRI incrementa la supervivencia global frente a FOLFIRI, lo que supone una estrategia efectiva en el tratamiento de pacientes con CCRm. La relación coste-efectividad incremental de aflibercept en combinación con FOLFIRI supone una estrategia eficiente, coste-efectiva, para el Sistema Nacional de Salud.

The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.

PURPOSE: We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions. METHODS: Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity. RESULTS: Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. CONCLUSION: The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.

A novel real-time genotyping assay for detection of the E6-350G HPV 16 variant.

It has been suggested that some E6 human papillomavirus (HPV) type 16 variants could be involved in viral persistence and progression of HPV infection. A novel one-step allelic discrimination real-time PCR was evaluated for E6-350G variant detection in 102 endocervical HPV 16 positive samples. This assay was also used to assess the distribution of this variant in Spanish women with cervical cancer related to HPV 16. The detection limit for the allelic discrimination assay was 50 copies per reaction, even where the E6-350G variant represents only 20% of the variants in the sample. Complete concordance was observed between DNA sequencing and the novel AD RT-PCR assay. Fourteen E6-350T reference strains and 18 E6-350G variants were detected out of 32 endocervical samples from women with cervical cancer. The average age of women who were infected by the E6-350G HPV 16 variant was 10 years lower in these samples than in women who were infected by the reference strain. This novel allelic discrimination assay is a fast, sensitive and specific method for detection of the E6-350G HPV 16 variant.

Paclitaxel and cisplatin in the treatment of metastatic non-small-cell lung cancer during pregnancy

The concomitant occurrence of cancer during pregnancy is a rare event. The cancers most frequently detected during pregnancy are breast, cervical, melanoma, ovarian, leukaemia and lymphoma, however the diagnosis of lung cancer during pregnancy is particularly exceptional. In this case, we report on a pregnant woman who was diagnosed with non-small-cell lung cancer and received therapy with paclitaxel and cisplatin (AU)

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Citología peritoneal en pacientes con carcinoma de endometrio según la realización previa de histeroscopia diagnóstica y biopsia dirigida frente a legrado fraccionado / Peritoneal cytology in patients with endometrial carcinoma following previous diagnostic hysteroscopy and biopsy versus fractionated curettage procedure

El estudio pretendía determinar el efecto que la histeroscopia ejerce en la frecuencia de citología peritoneal positiva recogida en el tratamiento quirúrgico del carcinoma de endometrio. Se realizó un estudio observacional retrospectivo de 119 pacientes diagnosticadas de carcinoma de endometrio entre 1993 y 2003. Se comparó la frecuencia de lavados peritoneales positivos en el grupo de pacientes a las que se practicó histeroscopia y en pacientes diagnosticadas con otro método diferente. No se encontró asociación entre la realización previa de histeroscopia y la positividad de la citología peritoneal en el momento del tratamiento. La histeroscopia es un método que puede utilizarse sin riesgos adicionales en el diagnóstico de carcinoma de endometrio (AU)