Implantable LENUS pro pump for treprostinil infusion in three pediatric patients.

BACKGROUND: Prostanoid treatment in patients with severe pulmonary arterial hypertension (PAH) has been proven safe and effective. Subcutaneous administration of treprostinil has side effects, which limits their use and acceptance. An implantable pump for continuous intravenous treprostinil infusion has been recently approved. We describe our experience with the implantable pump in three pediatric patients. DESCRIPTION OF CASES: The LENUS pro pump was implanted in three adolescents with severe PAH, who were treated with tadalafil, ambrisentan, and subcutaneous treprostinil. The indication of the Lenus pro pump implantation was the local side effects of subcutaneous treprostinil (pain, inflammation, and local infection) that were not well tolerated and that severely decreased their quality of life. The pump was surgically implanted under general anesthesia.One patient, in functional class IV, suffered postoperative hemodynamic instability and small pneumothorax, requiring an increase in treprostinil dose up to 85 ng/kg/min and a decrease 9 days after the pump implantation. The second patient who was discharged 4 days after surgery with treprostinil at 60 ng/kg/min reported improvement in his quality of life, but the dose requirement increased up to 92 ng/kg/min. After a 21-month follow-up, this patient received a lung transplant. The third patient presented a hematoma at the pump site with no other complications and had a follow-up of 9 months with an improvement in her quality of life. COMMENTS: Implantable pumps for continuous parenteral prostanoid infusion in pediatric patients are an alternative to external pumps, especially when familiar psychological or psychomotor issues hinder the use of external pumps.

Anti-VEGF Treatment and Response in Age-related Macular Degeneration: Disease's Susceptibility, Pharmacogenetics and Pharmacokinetics.

The current review is focussing different factors that contribute and directly correlate to the onset and progression of Age-related Macular Degeneration (AMD). In particular, the susceptibility to AMD due to genetic and non-genetic factors and the establishment of risk scores, based on the analysis of different genes to measure the risk of developing the disease. A correlation with the actual therapeutic landscape to treat AMD patients from the point of view of pharmacokinetics and pharmacogenetics is also exposed. Treatments commonly used, as well as different regimes of administration, will be especially important in trying to classify individuals as "responders" and "non-responders". Analysis of different genes correlated with drug response and also the emerging field of microRNAs (miRNAs) as possible biomarkers for early AMD detection and response will be also reviewed. This article aims to provide the reader a review of different publications correlated with AMD from the molecular and kinetic point of view as well as its commonly used treatments, major pitfalls and future directions that, to our knowledge, could be interesting to assess and follow in order to develop a personalized medicine model for AMD.

An Observational Study of the Efficacy and Safety of Voriconazole in a Real-Life Clinical Setting.

An observational retrospective study in patients treated with voriconazole was made to evaluate outcomes, safety, drug interactions and characteristics of the treatment. A total of 96 patients were included. In 78.12%, at least one inducer or enzyme inhibitor was detected. The most frequently observed potential interaction was the simultaneous administration of omeprazole. A large number of patients were concurrently treated with corticosteroids. The simultaneous administration of drugs acting as CYP450 enzyme inhibitors was associated with a higher risk of toxicity while concomitant administration of corticosteroids seemed a protective factor. Our study is one of the few ones, which evaluate the use of voriconazole in a real life clinical setting. We demonstrate the wide variety of strategies in the voriconazole using and the large number of dugs that are susceptible to pharmacokinetic interactions. This study reinforces the need to implement voriconazole pharmacokinetic monitoring in order to optimize antifungal treatment.

A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12.

BACKGROUND: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. RESULTS: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values <10-5. We therefore evaluated the 24 loci in another Spanish replication cohort (1481 cases and 1850 controls). Two of these SNPs, rs12080929 at 1p33 (Preplication=0.042; Ppooled=5.523x10-03; OR (CI95%)=0.866(0.782-0.959)) and rs11987193 at 8p12 (Preplication=0.039; Ppooled=6.985x10-5; OR (CI95%)=0.786(0.705-0.878)) were replicated in the second Phase, although they did not reach genome-wide statistical significance. CONCLUSIONS: We have performed the first CRC GWAS in a Southern European population and by these means we were able to identify two new susceptibility variants at 1p33 and 8p12 loci. These two SNPs are located near the SLC5A9 and DUSP4 loci, respectively, which could be good functional candidates for the association signals. We therefore believe that these two markers constitute good candidates for CRC susceptibility loci and should be further evaluated in other larger datasets. Moreover, we highlight that were these two SNPs true susceptibility variants, they would constitute a decrease in the CRC missing heritability fraction.

X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients.

PURPOSE: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. METHODS AND MATERIALS: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). RESULTS: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression. CONCLUSIONS: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.

Anti-EGFR therapy in first-line colorectal cancer.

This Phase II clinical trial investigates the activity and safety of FOLFOX-cetuximab in the first-line treatment of colorectal cancer. This turns out to be an active regimen which allows a high rate of conversion and radical metastectomy. Overall response rate is concordant with those previously reported. The toxicity profile is also similar, and cutaneous toxicity severity seems to be a marker of activity. Retrospectively, the authors analyze the status of KRAS and BRAF in a subgroup of patients, only in 50%. KRAS appears mutated in 37%, and BRAF does not present as mutated in any of the remaining wild-type KRAS patients. KRAS mutation correlates with shorter overall survival and possibly time to progression. The sample is too small to find mutations in BRAF, or to convincingly establish the role of both biomarkers. These data demonstrate an active regimen that is first in line to be confirmed in larger Phase III trials.

Use of a comprehensive panel of biomarkers to predict response to a fluorouracil-oxaliplatin regimen in patients with metastatic colorectal cancer.

AIM: Polymorphisms in the metabolism, detoxification or DNA repair pathways have been proposed as potential predictors of response to 5-fluorouracil and oxaliplatin. We have studied the predictive value of a set of germline genetic polymorphisms in metastatic colorectal cancer patients treated with mFolfox-6. MATERIALS & METHODS: A total of 72 patients, comprising 50 men (69.4%) and 22 women (30.6%), were included after the signing of an informed consent form. Median age was 65.5 years (range: 32-80). All participants received mFolfox-6. DNA was extracted from peripheral blood samples and genotyped by direct sequencing, SnapShot(®) and multiplex PCR techniques. Eight polymorphisms within six genes were investigated: TS 5´-UTR (variable number tandem repeat + G/C), TS 3´-UTR (TS1494del6); MTHFR C677T and A1298C; GSTP1 I105V; ERCC1 C118T; XPD Lys751Gln and XRCC1 Arg399Gln. Association was evaluated by univariate analysis, and Cox regression and Kaplan-Meier assessed survival. The local ethics committee approved the pharmacogenetic study protocol and all subjects signed an informed consent before participating in the study. RESULTS: The sample was in Hardy-Weinberg equilibrium. Only XPD Lys751Gln was found to be significantly associated with a favorable progression-free survival (PFS). Median PFS for XPD Lys751Gln patients (n = 33) was 16 months (95% CI: 9.2-22.7), 10 months (95% CI: 6.1-13.9) for Gln/Gln (n = 11) and 8 months (95% CI: 5.8-10.2) for Lys/Lys (n = 28), p = 0.019. The increased risk of progression was: 1.93 (95% CI: 1.13-13.30; p = 0.017) for Lys/Lys and 2.1 (95% CI: 1.01-4.22; p = 0.047) for Gln/Gln. Patients with one or two Val alleles of GSTP1 tended to a lower risk of progression compared with Ile/Ile homozygotes, p = 0.067. When XPD Lys751Gln and GSTP1 were analyzed jointly, patients who carried one or two favorable genotypes, XPD Lys751Gln and Val, had a longer median PFS: 11 months (95% CI: 7.4-14.6) compared with six (95% CI: 4.6-7.4) with unfavorable genotypes, p < 0.001. CONCLUSION: In metastatic colorectal cancer patients treated with mFolfox-6, the combination of haplotype XPD Lys751Gln-GSTP1 105Val seems to predict the risk of progression.

[A patient with cardiac angiosarcoma who survived for four years. Case report and literature review]. / Angiosarcoma cardíaco. Cuatro años de supervivencia. Revisión a propósito de un caso.

We describe a 57-year-old woman with a diagnosis of primary cardiac angiosarcoma. She underwent emergency surgery with a preoperative diagnosis of atrial myxoma, and pathological analysis confirmed the diagnosis of cardiac angiosarcoma. Two years later she was readmitted to the hospital with recurrence of the tumor in the left atrium and involvement of the mitral valve. Another operation was carried out for mitral valve and left atrial wall reconstruction with a bovine pericardial patch. Two years later a new recurrence of the tumor was discovered, and she died of multiorgan failure. The mortality associated with primary cardiac neoplasm is very high, although aggressive treatment together with appropriate chemotherapy may significantly prolong patient's lifespan.

Angiosarcoma cardíaco. Cuatro años de supervivencia. Revisión a propósito de un caso / A patient with cardiac angiosarcoma who survived for four years. Case report and literature review

Presentamos el caso de una mujer de 57 años intervenida de urgencias con el diagnóstico de mixoma auricular; tras el estudio anatomopatológico se confirmó el diagnóstico de angiosarcoma primario cardíaco. A los 2años, la paciente presentó recidiva del tumor en aurícula izquierda con infiltración de la válvula mitral. Fue reintervenida realizándose una reconstrucción valvular y dela aurícula izquierda con pericardio bovino. Dos años después presentó una nueva recidiva del tumor, falleció en fracaso multiorgánico. Los tumores cardíacos primarios presentan una elevada mortalidad, aunque un tratamiento quirúrgico agresivo combinado con una quimioterapia adecuada puede prolongar la supervivencia

We describe a 57-year-old woman with a diagnosis ofprimary cardiac angiosarcoma. She underwent emergency surgery with a preoperative diagnosis of atrial myxoma, and pathological analysis confirmed the diagnosis of cardiac angiosarcoma. Two years later she was readmitted to the hospital with recurrence of the tumor in the left atrium and involvement of the mitral valve. Another operation was carried out for mitral valve and left atrial wall reconstruction with a bovine pericardial patch. Two years later a new recurrence of the tumor was discovered, and she died of multiorgan failure. The mortality associated with primary cardiac neoplasm is very high, although aggressive treatment together with appropriate chemotherapy may significantly prolong patient’s lifespan