Pilar Alfonso - Academia.edu (original) (raw)
Papers by Pilar Alfonso
Journal of Clinical Oncology, 2018
3536Background: FOLFOXIRI plus bevacizumab has demonstrated a survival benefit compared with FOLF... more 3536Background: FOLFOXIRI plus bevacizumab has demonstrated a survival benefit compared with FOLFIRI plus bevacizumab (TRIBE Lancet Oncol 2015) in first-line mCRC. This schedule is not routinely re...
BMC Cancer, 2019
Background: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. T... more Background: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. Methods: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. Main objective: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). Results: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirtynine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). Conclusions: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. Trial registration: This trial was prospectively registered at EudraCT (2013-000236-94). Date of trial registration: April 9th, 2013.
Clinical and Translational Oncology, 2014
Colorectal cancer is one of the most common tumors worldwide and at least 50 % of patients with t... more Colorectal cancer is one of the most common tumors worldwide and at least 50 % of patients with this disease develop metastases. In this setting, additional treatment options are needed for patients presenting disease progression after exhausting all standard therapies. Regorafenib is an orally administered multikinase inhibitor which has been shown to provide survival benefits to patients with metastatic colorectal cancer (mCRC). Although most adverse events (AEs) associated with regorafenib may resolve within the first 8 weeks of treatment, some of them may require dose reduction or treatment interruption. Overall, while remaining aware of the safety profile of regorafenib and how to manage the most common toxicities related to its use, this drug should be considered a new standard of care for patients with pretreated mCRC. This review addresses practical aspects of its use, such as dosing, patient monitoring, and management of the most common regorafenib-related AEs.
Journal of Clinical Oncology, 2017
3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. T... more 3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and...
British journal of cancer, Jan 9, 2010
Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treat... more Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treatment for metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the efficacy and safety of this regimen in combination with bevacizumab (BV), as first-line treatment for mCRC. A total of 46 consecutive patients received a combination of BV (5 mg kg⁻¹, day 1), irinotecan (175 mg m⁻², day 1) and capecitabine (1000 mg m⁻² twice daily on day 2-8), every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary objective was to determine the progression-free survival (PFS) and safety profile. The overall response rate (ORR) was 67.4%, with a disease control rate (ORR+stable disease) of 93.5%. Median PFS and overall survival (OS) were 12.3 months (95% confidence interval (CI): 6.5-18.1 months) and 23.7 months (95% CI: 16.7-30.6 months), respectively. The most frequent grade 3/4 treatment-related adverse events were asthenia (7%), diarrho...
British journal of cancer, Jan 6, 2009
Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim o... more Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim of this study was to determine the efficacy and safety of capecitabine+irinotecan (2-weekly schedule), as first-line therapy of MCRC. Patients received irinotecan 175 mg m(-2) on day 1 and oral capecitabine 1000 mg m(-2) twice daily on days 2-8 every 2 weeks. For patients aged > or =65 years, the starting doses of irinotecan and capecitabine were reduced to 140 and 750 mg m(-2), respectively. A total of 53 patients were enrolled: 29 (55%) were > or =65 years old. In an intention-to-treat analysis, complete response was achieved in three patients for an overall response rate (ORR) of 32%. The disease control rate (ORR + stable disease) was 66% and the median duration of response was 7.3 months. Median time to progression and overall survival were 9.0 and 19.2 months, respectively. Grade 4 neutropenia was reported in one patient: no other grade 4 toxicities were recorded. Grade 3 diar...
Journal of Clinical Oncology, 2017
663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. R... more 663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did ...
Clinical and Translational Oncology, 2009
Clinical Translational Oncology, 2012
This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and... more This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and the Spanish Society of Medical Oncology, makes diagnostic and treatment recommendations for the management of patients with hereditary, localised and advanced CRC based on the current scientific evidence on biomarker use. This consensus statement thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the currently available data on this subject, this expert group recommends testing for microsatellite instability (MSI) in patients with localised CRC, as this is a strong predictive factor for deciding on adjuvant treatment. However, although the ColoPrint(®) and Oncotype Dx(®) gene expression signatures have been shown to have prognostic value, no consensus yet exists concerning their use in clinical practice. For advanced CRC, it is essential to test for KRAS mutation status before administering an anti-EGFR treatment, such as cetuximab or panitumumab. However, testing for other biomarkers, such as BRAF, EGFR, PI3K and PTEN mutations, should not be done routinely, because this does not influence treatment planning at the present time. Other important issues addressed include organisational requirements and the quality controls needed for proper testing of these biomarkers as well as the legal implications to be borne in mind when testing some biomarkers.
Molecular cancer therapeutics, Sep 16, 2017
In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately qua... more In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR (n=255) or bevacizumab (n=328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas®, therascreen® and dPCR. We evaluated concordance between techniques using Cohen's kappa index. Response rate, progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen's kappa index around 0.75). We observed an inverse correlation between...
Molecular cancer therapeutics, Sep 16, 2017
In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately qua... more In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR (n=255) or bevacizumab (n=328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas®, therascreen® and dPCR. We evaluated concordance between techniques using Cohen's kappa index. Response rate, progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen's kappa index around 0.75). We observed an inverse correlation between...
![Research paper thumbnail of [Genetics of Gaucher's disease. Genotype-phenotype correlation]](https://attachments.academia-assets.com/42428363/thumbnails/1.jpg)
](Medicina Clínica
Gaucher's disease (GD) results from a deficiency of the lysosomal en... more Gaucher's disease (GD) results from a deficiency of the lysosomal enzyme glucocerebrosidase and, in very rare occasions, a deficiency of its activator, the saposin C. The complexity of identification and characterization of mutations in the gene of glucocerebrosidase (GBA1) is caused by a great amount of mutated alleles, the existence of a highly homologous pseudogene and its location in a very rich zone in genes, which promotes the presence of complex alleles. Although genotype-phenotype correlations in EG are not completely established, there are a series of generalities, as the mutation c.1226A>G (N370S) is often associated with a certain degree of neuroprotection and the homozygosity for the c.1448T>C (L444P) mutation presents with neurological symptoms.
International Journal of Clinical Pharmacy
Journal of Clinical Oncology
To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction... more To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction treatment of low-grade non-Hodgkin's lymphoma (NHL), and to assess the role of maintenance IFN. A multicenter, two-phase controlled trial with double randomization was conducted in 155 patients with low-grade NHL. In the first randomization, 78 patients received cyclophosphamide, vincristine, and prednisone (CVP) and IFN, 3 MU/m2 three times a week for 3 months, and 77 patients received CVP alone. Responding patients were randomized to receive IFN for 1 year versus observation. Of 144 assessable patients, 73 received CVP + IFN and 71 received CVP. Responses were similar: CVP + IFN 79% versus CVP 76% (P = .62). The number of patients who did not complete the treatment was higher in the CVP + IFN group than in the CVP group (18% v 4%; P = .009), although the received dose-intensity of chemotherapy was comparable. Duration of response and progression-free survival (PFS) were significan...
Medicina Clínica
Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indi... more Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indicate that GD relatives could develop neurological abnormalities more frequently than the general population. We aimed to know the presence of neurological symptoms (NS) in GD patients and their relatives. From January to December 2006 we performed a postal survey contacting 42 physicians and 92 families to evaluate NS and correlate them with genetic characteristics. Statistical analysis using descriptive parameters, ANOVA, t-test and a correlation study including Pearson coefficient were performed. Information from 72 families (78.3% responses) including 99 patients and 266 relatives was obtained. Thirty type 1 GD (32.6%) reported NS: tremor 8 (8.7%), uncoordinated movements 9 (9.8%), concentration defects 11 (11.9%), strabism 7 (7.6%), deafness 8 (8.7%), Parkinson disease (PD) 7 (7.6%) and peripheral neuropathy 10 (10.9%). Thirty-six (13.5%) first or second degrees relatives presented t...
Cancer Treatment Reviews, 2010
Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and ox... more Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and oxaliplatin, patients with metastatic colorectal cancer (mCRC) still have a poor prognosis. More effective and better-tolerated treatment strategies are needed to improve patient outcomes, particularly in subsequent lines of treatment following chemotherapy failure. The favourable efficacy and acceptable safety profiles of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have led to the approval of panitumumab and cetuximab monotherapy for the treatment of patients with EGFR-expressing mCRC whose tumours express non-mutated (wildtype) KRAS, after failure of standard chemotherapy. Cetuximab is also approved in combination with chemotherapy for the treatment of mCRC in this patient population. In phase III monotherapy studies, panitumumab and cetuximab demonstrated significant improvements in progression-free survival when administered with best supportive care (BSC) vs. BSC alone in chemotherapy-refractory mCRC patients. A planned retrospective analysis of the panitumumab monotherapy trial was the first large-scale clinical demonstration that efficacy was confined to patients with tumours expressing wild-type KRAS. It is now recognised that anti-EGFR mAb therapy should only be used in patients whose tumours express wild-type KRAS. While generally well tolerated, anti-EGFR mAb monotherapy is associated with skin toxicity, and severity of the skin rash has been proposed as an early marker of response to treatment. BRAF, PTEN, and PI3K are also emerging as future potential predictive markers of response; however, further clinical studies are warranted to define the role of these biomarkers.
Haematologica, 2001
Chitinases are enzymes that hydolyze chitin and have been found in a wide variety of nonvertebrat... more Chitinases are enzymes that hydolyze chitin and have been found in a wide variety of nonvertebrate species; recently an human analogue of chitinases, chitotriosidase (CT) has been identified. Extreme elevations of plasma CT activity are observed in patients with Gaucher disease (GD), being Gaucher cells the source of the CT. It has been reported a 24 bp duplication in CT gene that results an inactive protein. The carrier prevalence is high as 30 to 40% and the CT activity is half that in wild individuals. However no systematic evaluation of plasma CT activity has been carried in GD patients taken into account status of allele defective for CT and dose in patients on enzyme replacement therapy (ERT). We had previously study 210 subjects from 99 unrelated Spanish GD families; 121 were non-affected carriers and 89 were non-carriers to establish carrier prevalence of CT genotypes. Plasma CTactivity and CTgenotypes by PCR and gel electrophoresis have been measured in 109 GD patients befo...
Journal of Clinical Oncology, 2018
3536Background: FOLFOXIRI plus bevacizumab has demonstrated a survival benefit compared with FOLF... more 3536Background: FOLFOXIRI plus bevacizumab has demonstrated a survival benefit compared with FOLFIRI plus bevacizumab (TRIBE Lancet Oncol 2015) in first-line mCRC. This schedule is not routinely re...
BMC Cancer, 2019
Background: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. T... more Background: Treatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC. Methods: Frail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. Main objective: to assess progression-free survival (PFS) rate at 6 months. Treatment consisted of 28-day cycles of orally administered regorafenib 160 mg/day (3 weeks followed by 1 week rest). Results: Forty-seven patients were included in the study. Median age was 81 years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6 months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6 months (95%CI 2.7-8.4). Median overall survival (OS) was 16 months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirtynine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%). Conclusions: The study did not meet the pre-specified boundary of 55% PFS rate at 6 months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach. Trial registration: This trial was prospectively registered at EudraCT (2013-000236-94). Date of trial registration: April 9th, 2013.
Clinical and Translational Oncology, 2014
Colorectal cancer is one of the most common tumors worldwide and at least 50 % of patients with t... more Colorectal cancer is one of the most common tumors worldwide and at least 50 % of patients with this disease develop metastases. In this setting, additional treatment options are needed for patients presenting disease progression after exhausting all standard therapies. Regorafenib is an orally administered multikinase inhibitor which has been shown to provide survival benefits to patients with metastatic colorectal cancer (mCRC). Although most adverse events (AEs) associated with regorafenib may resolve within the first 8 weeks of treatment, some of them may require dose reduction or treatment interruption. Overall, while remaining aware of the safety profile of regorafenib and how to manage the most common toxicities related to its use, this drug should be considered a new standard of care for patients with pretreated mCRC. This review addresses practical aspects of its use, such as dosing, patient monitoring, and management of the most common regorafenib-related AEs.
Journal of Clinical Oncology, 2017
3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. T... more 3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and...
British journal of cancer, Jan 9, 2010
Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treat... more Combination of capecitabine and irinotecan (XELIRI regimen) is an active and well tolerated treatment for metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the efficacy and safety of this regimen in combination with bevacizumab (BV), as first-line treatment for mCRC. A total of 46 consecutive patients received a combination of BV (5 mg kg⁻¹, day 1), irinotecan (175 mg m⁻², day 1) and capecitabine (1000 mg m⁻² twice daily on day 2-8), every 2 weeks. Patients were treated until disease progression or unacceptable toxicity. The primary objective was to determine the progression-free survival (PFS) and safety profile. The overall response rate (ORR) was 67.4%, with a disease control rate (ORR+stable disease) of 93.5%. Median PFS and overall survival (OS) were 12.3 months (95% confidence interval (CI): 6.5-18.1 months) and 23.7 months (95% CI: 16.7-30.6 months), respectively. The most frequent grade 3/4 treatment-related adverse events were asthenia (7%), diarrho...
British journal of cancer, Jan 6, 2009
Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim o... more Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim of this study was to determine the efficacy and safety of capecitabine+irinotecan (2-weekly schedule), as first-line therapy of MCRC. Patients received irinotecan 175 mg m(-2) on day 1 and oral capecitabine 1000 mg m(-2) twice daily on days 2-8 every 2 weeks. For patients aged > or =65 years, the starting doses of irinotecan and capecitabine were reduced to 140 and 750 mg m(-2), respectively. A total of 53 patients were enrolled: 29 (55%) were > or =65 years old. In an intention-to-treat analysis, complete response was achieved in three patients for an overall response rate (ORR) of 32%. The disease control rate (ORR + stable disease) was 66% and the median duration of response was 7.3 months. Median time to progression and overall survival were 9.0 and 19.2 months, respectively. Grade 4 neutropenia was reported in one patient: no other grade 4 toxicities were recorded. Grade 3 diar...
Journal of Clinical Oncology, 2017
663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. R... more 663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did ...
Clinical and Translational Oncology, 2009
Clinical Translational Oncology, 2012
This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and... more This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and the Spanish Society of Medical Oncology, makes diagnostic and treatment recommendations for the management of patients with hereditary, localised and advanced CRC based on the current scientific evidence on biomarker use. This consensus statement thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the currently available data on this subject, this expert group recommends testing for microsatellite instability (MSI) in patients with localised CRC, as this is a strong predictive factor for deciding on adjuvant treatment. However, although the ColoPrint(®) and Oncotype Dx(®) gene expression signatures have been shown to have prognostic value, no consensus yet exists concerning their use in clinical practice. For advanced CRC, it is essential to test for KRAS mutation status before administering an anti-EGFR treatment, such as cetuximab or panitumumab. However, testing for other biomarkers, such as BRAF, EGFR, PI3K and PTEN mutations, should not be done routinely, because this does not influence treatment planning at the present time. Other important issues addressed include organisational requirements and the quality controls needed for proper testing of these biomarkers as well as the legal implications to be borne in mind when testing some biomarkers.
Molecular cancer therapeutics, Sep 16, 2017
In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately qua... more In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR (n=255) or bevacizumab (n=328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas®, therascreen® and dPCR. We evaluated concordance between techniques using Cohen's kappa index. Response rate, progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen's kappa index around 0.75). We observed an inverse correlation between...
Molecular cancer therapeutics, Sep 16, 2017
In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately qua... more In metastatic colorectal cancer (mCRC) recent studies have shown the importance to accurately quantify low-abundance mutations of RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR (n=255) or bevacizumab (n=328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas®, therascreen® and dPCR. We evaluated concordance between techniques using Cohen's kappa index. Response rate, progression-free survival (PFS) and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen's kappa index around 0.75). We observed an inverse correlation between...
Medicina Clínica
Gaucher's disease (GD) results from a deficiency of the lysosomal en... more Gaucher's disease (GD) results from a deficiency of the lysosomal enzyme glucocerebrosidase and, in very rare occasions, a deficiency of its activator, the saposin C. The complexity of identification and characterization of mutations in the gene of glucocerebrosidase (GBA1) is caused by a great amount of mutated alleles, the existence of a highly homologous pseudogene and its location in a very rich zone in genes, which promotes the presence of complex alleles. Although genotype-phenotype correlations in EG are not completely established, there are a series of generalities, as the mutation c.1226A>G (N370S) is often associated with a certain degree of neuroprotection and the homozygosity for the c.1448T>C (L444P) mutation presents with neurological symptoms.
International Journal of Clinical Pharmacy
Journal of Clinical Oncology
To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction... more To evaluate the effectiveness of adding interferon (IFN) alfa-2b to chemotherapy in the induction treatment of low-grade non-Hodgkin's lymphoma (NHL), and to assess the role of maintenance IFN. A multicenter, two-phase controlled trial with double randomization was conducted in 155 patients with low-grade NHL. In the first randomization, 78 patients received cyclophosphamide, vincristine, and prednisone (CVP) and IFN, 3 MU/m2 three times a week for 3 months, and 77 patients received CVP alone. Responding patients were randomized to receive IFN for 1 year versus observation. Of 144 assessable patients, 73 received CVP + IFN and 71 received CVP. Responses were similar: CVP + IFN 79% versus CVP 76% (P = .62). The number of patients who did not complete the treatment was higher in the CVP + IFN group than in the CVP group (18% v 4%; P = .009), although the received dose-intensity of chemotherapy was comparable. Duration of response and progression-free survival (PFS) were significan...
Medicina Clínica
Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indi... more Gaucher disease (GD) is characterized by a wide spectrum of manifestations. Previous reports indicate that GD relatives could develop neurological abnormalities more frequently than the general population. We aimed to know the presence of neurological symptoms (NS) in GD patients and their relatives. From January to December 2006 we performed a postal survey contacting 42 physicians and 92 families to evaluate NS and correlate them with genetic characteristics. Statistical analysis using descriptive parameters, ANOVA, t-test and a correlation study including Pearson coefficient were performed. Information from 72 families (78.3% responses) including 99 patients and 266 relatives was obtained. Thirty type 1 GD (32.6%) reported NS: tremor 8 (8.7%), uncoordinated movements 9 (9.8%), concentration defects 11 (11.9%), strabism 7 (7.6%), deafness 8 (8.7%), Parkinson disease (PD) 7 (7.6%) and peripheral neuropathy 10 (10.9%). Thirty-six (13.5%) first or second degrees relatives presented t...
Cancer Treatment Reviews, 2010
Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and ox... more Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and oxaliplatin, patients with metastatic colorectal cancer (mCRC) still have a poor prognosis. More effective and better-tolerated treatment strategies are needed to improve patient outcomes, particularly in subsequent lines of treatment following chemotherapy failure. The favourable efficacy and acceptable safety profiles of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have led to the approval of panitumumab and cetuximab monotherapy for the treatment of patients with EGFR-expressing mCRC whose tumours express non-mutated (wildtype) KRAS, after failure of standard chemotherapy. Cetuximab is also approved in combination with chemotherapy for the treatment of mCRC in this patient population. In phase III monotherapy studies, panitumumab and cetuximab demonstrated significant improvements in progression-free survival when administered with best supportive care (BSC) vs. BSC alone in chemotherapy-refractory mCRC patients. A planned retrospective analysis of the panitumumab monotherapy trial was the first large-scale clinical demonstration that efficacy was confined to patients with tumours expressing wild-type KRAS. It is now recognised that anti-EGFR mAb therapy should only be used in patients whose tumours express wild-type KRAS. While generally well tolerated, anti-EGFR mAb monotherapy is associated with skin toxicity, and severity of the skin rash has been proposed as an early marker of response to treatment. BRAF, PTEN, and PI3K are also emerging as future potential predictive markers of response; however, further clinical studies are warranted to define the role of these biomarkers.
Haematologica, 2001
Chitinases are enzymes that hydolyze chitin and have been found in a wide variety of nonvertebrat... more Chitinases are enzymes that hydolyze chitin and have been found in a wide variety of nonvertebrate species; recently an human analogue of chitinases, chitotriosidase (CT) has been identified. Extreme elevations of plasma CT activity are observed in patients with Gaucher disease (GD), being Gaucher cells the source of the CT. It has been reported a 24 bp duplication in CT gene that results an inactive protein. The carrier prevalence is high as 30 to 40% and the CT activity is half that in wild individuals. However no systematic evaluation of plasma CT activity has been carried in GD patients taken into account status of allele defective for CT and dose in patients on enzyme replacement therapy (ERT). We had previously study 210 subjects from 99 unrelated Spanish GD families; 121 were non-affected carriers and 89 were non-carriers to establish carrier prevalence of CT genotypes. Plasma CTactivity and CTgenotypes by PCR and gel electrophoresis have been measured in 109 GD patients befo...