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1.  Switching to second-generation tyrosine kinase inhibitor improves the response and outcome of frontline imatinib-treated patients with chronic myeloid leukemia with more than 10% of BCR-ABL/ABL ratio at 3 months 
Cancer Medicine  2015;4(7):995-1002.
Chronic myeloid leukemia patients display heterogeneous responses to imatinib. Survival depends on baseline clinical characteristics (including prognostic scoring systems) and on early response (such as >10% BCR-ABL/ABL ratio at 3 months of therapy). The results of switching to second-generation tyrosine kinase inhibitors (2GTKIs) may contain a bias since, in the majority of these studies, patients who switch treatment due to intolerance or failure are censored or excluded. We analyzed the Spanish Registry data on switching in an intention-to-treat analysis of patients in standard clinical practice. Switching to 2GTKIs improves responses from 45% to 75% of complete cytogenetic response (CCyR) and from 15% to 45% of major molecular response (MMR) in the group without molecular response 1 (MR1) at 3 months and from 70% to 87% in CCyR and from 52% to 87% in MMR in the group with MR1. The final response rate is poorer in the group with no MR1 at 3 months. Nevertheless, the differences in the rates of response were not translated into differences in major events (transformations or deaths), and the final progression-free survival and overall survival were similar.
PMCID: PMC4529338  PMID: 25756742
BCR-ABL/ABL ratio; chronic myeloid leukemia; dasatinib; imatinib; nilotinib
2.  Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients 
BMC Gastroenterology  2012;12:114.
Portal vein thrombosis is a frequent complication in end-stage cirrhosis with a considerable peri-operative risk for liver transplant candidates. We aimed to characterize the pre-transplant portal vein thrombosis in a cohort of liver transplant recipients, and to identify independent risk factors for this complication.
380 consecutive primary orthotopic liver transplants were performed in the Digestive Surgery Department of “12 de Octubre” Hospital (Madrid, Spain), between January 2001 and December 2006. The main risk factors considered were smoking, obesity, metabolic disorders, previous immobility, surgery or trauma, nephrotic syndrome, associated tumor, inflammatory disease, neoplasm myeloprolipherative. Furthermore we have reported genetic thrombophilia results for 271 recipients.
Sixty-two (16.3%) patients developed pre-transplant portal vein thrombosis and its presence had no impact in the overall survival of liver recipients. Obesity was the only independent risk factor for pre-transplant portal vein thrombosis.
We recommend close control of cardiovascular factors in patients with liver cirrhosis in order to avoid associated thrombosis.
PMCID: PMC3502589  PMID: 22909075
Thrombophilia; Portal vein thrombosis; Liver transplant recipient
3.  Efficacy and safety of reduced-intensity induction therapy with a bortezomib-based regimen in elderly patients with multiple myeloma 
The therapeutic effects of bortezomib in untreated and refractory/relapsed multiple myeloma have been demonstrated in several clinical trials, displaying superiority to the conventional treatments. However, many treatment-related toxicities, such as bone marrow suppression, infections and peripheral neuropathy, are well known and lead to treatment discontinuation and dose modification, especially in elderly patients. The purpose of this review is to summarize the published literature concerning the efficacy and safety of reduced-intensity induction therapy with bortezomib-based regimens in elderly patients with multiple myeloma. We used the VISTA trial as a reference and compared it with the seven trials identified in a systematic search. The data suggest that low-dose bortezomib significantly reduces therapy-related toxicities, especially neuropathy, and decreases the rate of discontinuation compared with the twice-weekly regimen, without losing efficacy. In light of this review, we suggest that once-weekly infusion of bortezomib in addition to melphalan–prednisone may be considered as a new standard of care in frontline treatment of elderly patients with symptomatic multiple myeloma.
PMCID: PMC3573442  PMID: 23556121
bortezomib; elderly patients; multiple myeloma
4.  Recipient and donor thrombophilia and the risk of portal venous thrombosis and hepatic artery thrombosis in liver recipients 
BMC Gastroenterology  2011;11:130.
Vascular complications, such as HAT, are an important cause of graft loss and recipient mortality. We aimed to characterize post-transplant thrombotic events in a cohort of liver transplant recipients, and identify independent risk factors for these complications.
We conducted a thrombophilic study of 293 orthotopic liver transplants performed in the Digestive Surgery Department of the 12 de Octubre Hospital (Madrid, Spain) between January 2001 and December 2006.
The most frequent post-transplant thrombotic events were HAT (9%) and PVT (1.7%). The one variable associated with post-transplant thrombotic event was a high fibrinogen level in the global cohort of liver transplantation. But toxicity as event post-OLT has been associated with post-transplant thrombotic event in the retrospective group and high fibrinogen level and low protein C levels were associated post-transplant thrombotic event in the prospective group. Liver disease relapse (HR 6.609, p < 0.001), high levels of FVIII (HR 1.008, p = 0.019)) and low levels of antithrombin (HR 0.946, p < 0.001) were associated with poor overall survival (OS).
In conclusion, high fibrinogen and decreased protein C levels were associated with allograft thrombosis. Further studies are required in order to assess the clinical relevance of these parameters in prospective studies and to study the effect of anticoagulation prophylaxis in this group of risk.
PMCID: PMC3287260  PMID: 22123067
5.  Simplifying the detection of MUTYH mutations by high resolution melting analysis 
BMC Cancer  2010;10:408.
MUTYH-associated polyposis (MAP) is a disorder caused by bi-allelic germline MUTYH mutation, characterized by multiple colorectal adenomas. In order to identify mutations in MUTYH gene we applied High Resolution Melting (HRM) genotyping. HRM analysis is extensively employed as a scanning method for the detection of heterozygous mutations. Therefore, we applied HRM to show effectiveness in detecting homozygous mutations for these clinically important and frequent patients.
In this study, we analyzed phenotype and genotype data from 82 patients, with multiple (>= 10) synchronous (19/82) or metachronous (63/82) adenomas and negative APC study (except one case). Analysis was performed by HRM-PCR and direct sequencing, in order to identify mutations in MUTYH exons 7, 12 and 13, where the most prevalent mutations are located. In monoallelic mutation carriers, we evaluated entire MUTYH gene in search of another possible alteration. HRM-PCR was performed with strict conditions in several rounds: the first one to discriminate the heteroduplex patterns and homoduplex patterns and the next ones, in order to refine and confirm parameters. The genotypes obtained were correlated to phenotypic features (number of adenomas (synchronous or metachronous), colorectal cancer (CRC) and family history).
MUTYH germline mutations were found in 15.8% (13/82) of patients. The hot spots, Y179C (exon 7) and G396D (exon 13), were readily identified and other mutations were also detected. Each mutation had a reproducible melting profile by HRM, both heterozygous mutations and homozygous mutations. In our study of 82 patients, biallelic mutation is associated with being a carrier of ≥10 synchronous polyps (p = 0.05) and there is no association between biallelic mutation and CRC (p = 0.39) nor family history (p = 0.63). G338H non-pathogenic polymorphism (exon 12) was found in 23.1% (19/82) of patients. In all cases there was concordance between HRM (first and subsequent rounds) and sequencing data.
Here, we describe a screening method, HRM, for the detection of both heterozygous and homozygous mutations in the gene encoding MUTYH in selected samples of patients with phenotype of MAP. We refine the capabilities of HRM-PCR and apply it to a gene not yet analyzed by this tool. As clinical decisions will increasingly rely on molecular medicine, the power of identifying germline mutations must be continuously evaluated and improved.
PMCID: PMC2924853  PMID: 20687945

Results 1-5 (5)