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1.
Ann Oncol ; 34(12): 1187-1193, 2023 12.
Article En | MEDLINE | ID: mdl-37805131

BACKGROUND: Detection of circulating tumor DNA (ctDNA) is a minimally invasive and convenient blood-based screening strategy that may increase effectiveness of colorectal cancer (CRC) screening. PATIENTS AND METHODS: A novel multimodal ctDNA-based blood assay that integrates genomics, epigenomics and fragmentomics, as well as proteomics in a refined version, was tested in blood samples from two cohorts: (i) consecutive fecal immunochemical test (FIT)-positive individuals from the CRC Barcelona stool-based screening program; (ii) patients diagnosed with CRC. Primary endpoint was the performance of the test to detect CRC at different tumor-node-metastasis (TNM) stages. Secondary endpoint was the ability of the test to detect advanced precancerous lesions (advanced adenoma or advanced serrated lesion). RESULTS: A total of 623 blood samples were analyzed in the primary analysis. Sensitivity and specificity of the assay to detect CRC was 93% and 90%, respectively. The sensitivity of CRC detection according to TNM stages was 84% for stage I, 94% for stage II and 96% for stage III (70/73) (P< 0.024). Sensitivity to detect advanced precancerous lesions was 23% with a refined version of the test (including protein and updating bioinformatic thresholding). CONCLUSION: A blood-based multimodal ctDNA assay detected CRC with high accuracy. This minimally invasive, accessible and convenient assay may help to increase the effectiveness of CRC screening.


Colorectal Neoplasms , Precancerous Conditions , Humans , Sensitivity and Specificity , Mass Screening , Proteins , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Early Detection of Cancer
2.
Ann Oncol ; 33(8): 750-768, 2022 08.
Article En | MEDLINE | ID: mdl-35809752

Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made.


Circulating Tumor DNA , Biomarkers, Tumor/genetics , Circulating Tumor DNA/genetics , Humans , Mutation , Neoplasm Recurrence, Local , Precision Medicine/methods
3.
ESMO Open ; 7(1): 100352, 2022 02.
Article En | MEDLINE | ID: mdl-34920292
5.
Ann Oncol ; 30(3): 439-446, 2019 03 01.
Article En | MEDLINE | ID: mdl-30689692

BACKGROUND: Extended RAS analysis is mandatory in metastatic colorectal cancer (mCRC) patients. The optimal threshold of RAS mutated subclones to identify patients most likely to benefit from antiepidermal growth factor receptor (EGFR) therapy is controversial. Our aim was to assess the clinical impact of detecting mutations in RAS, BRAF, PIK3CA and EGFRS492R in basal tissue tumour samples by using a highly sensitive next-generation sequencing (NGS) technology in mCRC patients treated with chemotherapy plus anti-EGFR or anti-vascular endothelial growth factor. PATIENTS AND METHODS: Five hundred and eighty-one tumour samples from untreated mCRC patients from 7 clinical studies were collected. Mutational analysis was carried out by standard-of-care (therascreen pyro) with a sensitivity detection of 5% mutant allele fraction (MAF), and compared with NGS technology using 454GS Junior platform (Roche Applied Science, Germany) with a sensitivity of 1%. Molecular results were correlated with clinical outcomes. RESULTS: After quality assessment, 380 samples were evaluable for molecular analysis. Standard-of-care mutational analysis detected RAS, BRAFV600E or PIK3CA mutations in 56.05% of samples compared with 69.21% by NGS (P = 0.00018). NGS identified coexistence of multiple low-frequency mutant alleles in 96 of the 263 mutated cases (36.5%; range 2-7). Response rate (RR), progression-free survival (PFS) and overall survival (OS) were increasingly improved in patients with RAS wild-type, RAS/BRAF wild-type or quadruple (KRAS/NRAS/BRAF/PIK3CA) wild-type tumours treated with anti-EGFR, assessed by standard-of-care. No additional benefit in RR, PFS or OS was observed by increasing the detection threshold to 1% by NGS. An inverse correlation between the MAF of the most prevalent mutation detected by NGS and anti-EGFR response was observed (P = 0.039). EGFRS492Rmutation was not detected in untreated samples. CONCLUSIONS: No improvement in the selection of patients for anti-EGFR therapy was obtained by adjusting the mutation detection threshold in tissue samples from 5% to 1% MAF. Response to anti-EGFR was significantly better in patients with quadruple wild-type tumours.


Colorectal Neoplasms/drug therapy , GTP Phosphohydrolases/genetics , Membrane Proteins/genetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cetuximab/administration & dosage , Class I Phosphatidylinositol 3-Kinases/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Female , Germany , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation/genetics , Neoplasm Metastasis , Protein Kinase Inhibitors/administration & dosage , Treatment Outcome
8.
Ann Oncol ; 29(2): 439-444, 2018 02 01.
Article En | MEDLINE | ID: mdl-29145602

Background: There has been little progress toward personalized therapy for patients with metastatic colorectal cancer (mCRC). TYMS-3' untranslated region (UTR) 6 bp ins/del and ERCC1-118C/T polymorphisms were previously reported to facilitate selecting patients for fluoropyrimidine-based treatment in combination with oxaliplatin as first-line therapy. We assessed the utility of these markers in selecting therapy for patients with mCRC. Patients and methods: This randomized, open-label phase II trial compared bevacizumab plus XELOX (control) versus treatment tailored according to TYMS-3'UTR 6 bp ins/del and ERCC1-118C/T polymorphisms. Patients randomized to the experimental treatment received bevacizumab plus FUOX, FUIRI, XELIRI, or XELOX depending on their combination of favorable polymorphisms for FUOX treatment (TYMS-3'UTR ins/del or del/del; ERCC1-118T/T). Progression-free survival (PFS) was the primary end point. Results: Overall, 195 patients were randomized (control n = 65; experimental n = 130). The primary objective was not met: median PFS was 9.4 months in the control group and 10.1 months in the experimental group (P = 0.745). Median overall survival was similar in both groups (16.5 versus 19.1 months, respectively; P = 0.797). Patients in the experimental group had a significantly higher overall response rate (ORR; 65% versus 47% in the control group; P = 0.042) and R0 resection rate (86% versus 44%, respectively; P = 0.018). Neuropathy, hand-foot syndrome, thrombocytopenia, and dysesthesia were significantly less common in the experimental group. Conclusions: This study did not show survival benefits after treatment personalization based on polymorphisms in mCRC. However, the improved ORR and R0 resection rate and fewer disabling toxicities suggest that tailoring therapy by TYMS-3'UTR and ERCC1-118 polymorphisms warrants further investigation in patients with mCRC. ClinicalTrials.gov: NCT01071655.


Colorectal Neoplasms/drug therapy , DNA-Binding Proteins/genetics , Endonucleases/genetics , Pharmacogenomic Testing/methods , Pharmacogenomic Variants/genetics , Thymidylate Synthase/genetics , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Female , Genotype , Humans , Male , Middle Aged , Patient Selection , Precision Medicine/methods , Progression-Free Survival , Treatment Outcome
9.
Clin. transl. oncol. (Print) ; 19(6): 761-768, jun. 2017. tab, graf
Article En | IBECS | ID: ibc-162834

Background. The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. Methods. Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. Results. Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. Conclusion. Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases (AU)


No disponible


Humans , Male , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Melanoma/drug therapy , Neoplasm Metastasis/drug therapy , Health Promotion/standards , Neoplasm Staging/methods , Retrospective Studies , Prognosis , Surveys and Questionnaires , Multivariate Analysis , Melanoma/classification , Skin Neoplasms/drug therapy , Uveal Neoplasms/drug therapy
10.
Ann Oncol ; 28(6): 1294-1301, 2017 Jun 01.
Article En | MEDLINE | ID: mdl-28368441

BACKGROUND: Circulating tumor DNA (ctDNA) is a potential source for tumor genome analysis. We explored the concordance between the mutational status of RAS in tumor tissue and ctDNA in metastatic colorectal cancer (mCRC) patients to establish eligibility for anti-epidermal growth factor receptor (EGFR) therapy. PATIENTS AND METHODS: A prospective-retrospective cohort study was carried out. Tumor tissue from 146 mCRC patients was tested for RAS status with standard of care (SoC) PCR techniques, and Digital PCR (BEAMing) was used both in plasma and tumor tissue. RESULTS: ctDNA BEAMing RAS testing showed 89.7% agreement with SoC (Kappa index 0.80; 95% CI 0.71 - 0.90) and BEAMing in tissue showed 90.9% agreement with SoC (Kappa index 0.83; 95% CI 0.74 - 0.92). Fifteen cases (10.3%) showed discordant tissue-plasma results. ctDNA analysis identified nine cases of low frequency RAS mutations that were not detected in tissue, possibly due to technical sensitivity or heterogeneity. In six cases, RAS mutations were not detected in plasma, potentially explained by low tumor burden or ctDNA shedding. Prediction of treatment benefit in patients receiving anti-EGFR plus irinotecan in second- or third-line was equivalent if tested with SoC PCR and ctDNA. Forty-eight percent of the patients showed mutant allele fractions in plasma below 1%. CONCLUSIONS: Plasma RAS determination showed high overall agreement and captured a mCRC population responsive to anti-EGFR therapy with the same predictive level as SoC tissue testing. The feasibility and practicality of ctDNA analysis may translate into an alternative tool for anti-EGFR treatment selection.


Colorectal Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Genes, ras , Mutation , Colorectal Neoplasms/blood , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Humans , Neoplasm Metastasis
11.
Ann Oncol ; 28(2): 344-353, 2017 02 01.
Article En | MEDLINE | ID: mdl-28426108

Background: Primary chemotherapy has been tested as a possible approach for patients with high risk features but predicted clear mesorectal margins on preoperative MRI assessment. This study investigates the prognostic relevance of baseline and post-treatment MRI and pathology staging in rectal cancer patients undergoing primary chemotherapy. Patients and methods: Forty-six patients with T3 tumour > =2 mm from the mesorectal fascia were prospectively treated with Neoadjuvant Capecitabine, Oxaliplatin and Bevacizumab prior to surgery between 2009 and 2011. The baseline and post-treatment MRI: T, Nodal and Extra-mural venous invasion (EMVI) status were recorded as well as post-treatment MRI Tumour regression grade (TRG) and modified-RECIST assessment of tumour length. The post-treatment pathology (yp) assessments of T3 substage, N, EMVI and TRG status were also recorded. Three-year disease-free survival (DFS) and cumulative incidence of recurrence were estimated by using the Kaplan-Meier product-limit method, and Cox proportional hazards models were used to determine associations between staging and response on MRI and pathology with survival outcomes. Results: About 46 patients underwent neoadjuvant chemotherapy alone for high risk margin safe primary rectal cancer. The median follow-up was 41 months, 5 patients died and 11 patients experienced relapse (2 local, 8 distant and 1 both). In total 23/46 patients were identified with MRI features of EMVI at baseline. mrEMVI positive status carried independent prognostic significance for DFS (P = 0.0097) with a hazard ratio of 31.33 (95% CI: 2.3-425.4). The histopathologic factor that was of independent prognostic importance was a final ypT downstage of ypT3a or less, hazard ratio: 14.0 (95% CI: 1.5-132.5). Conclusions: mrEMVI is an independent prognostic factor at baseline for poor outcomes in rectal cancer treated with neoadjuvant chemotherapy while ≤ypT3a is associated with an improvement in DFS. Future preoperative therapy evaluation in rectal cancer patients will need to stratify treatment according to baseline EMVI status as a crucial risk factor for recurrence in patients with predicted CRM clear rectal cancer.


Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Rectal Neoplasms/therapy , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/mortality , Aged , Bevacizumab/administration & dosage , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Male , Middle Aged , Multivariate Analysis , Neoadjuvant Therapy , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Proportional Hazards Models , Prospective Studies , Rectal Neoplasms/diagnostic imaging , Rectal Neoplasms/mortality , Treatment Outcome
12.
Ann Oncol ; 28(6): 1325-1332, 2017 Jun 01.
Article En | MEDLINE | ID: mdl-28419195

BACKGROUND: RAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice. PATIENTS AND METHODS: RAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients. RESULTS: Analysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment. CONCLUSION: The high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.


Colorectal Neoplasms/diagnosis , DNA Mutational Analysis/methods , DNA, Neoplasm/blood , Genes, ras , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/blood , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , Humans , Monitoring, Physiologic/methods , Neoplasm Metastasis , Prospective Studies , Retrospective Studies
13.
Clin Transl Oncol ; 19(6): 761-768, 2017 Jun.
Article En | MEDLINE | ID: mdl-28054320

BACKGROUND: The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. METHODS: Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. RESULTS: Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. CONCLUSION: Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases.


Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Melanoma/mortality , Middle Aged , Proportional Hazards Models , Retrospective Studies , Salvage Therapy/methods , Spain , Treatment Outcome
14.
Br J Cancer ; 115(10): 1223-1233, 2016 Nov 08.
Article En | MEDLINE | ID: mdl-27685445

BACKGROUND: Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response. METHODS: We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. RESULTS: We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS. CONCLUSIONS: We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.


Cell Death/drug effects , Cell Proliferation/drug effects , Cetuximab/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/metabolism , Forkhead Box Protein O3/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Caco-2 Cells , Cell Line, Tumor , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Mice , Mice, Nude , Signal Transduction/drug effects , Up-Regulation/drug effects , ras Proteins/metabolism
15.
Ann Oncol ; 26(8): 1722-8, 2015 Aug.
Article En | MEDLINE | ID: mdl-25957330

BACKGROUND: The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. PATIENTS AND METHODS: Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A-preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). RESULTS: A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. CONCLUSION: Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.


Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemoradiotherapy/methods , Chemotherapy, Adjuvant/methods , Induction Chemotherapy/methods , Neoplasm Recurrence, Local , Rectal Neoplasms/therapy , Rectum/surgery , Adult , Aged , Capecitabine/administration & dosage , Disease-Free Survival , Female , Humans , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Oxaliplatin
17.
Invest New Drugs ; 31(2): 390-8, 2013 Apr.
Article En | MEDLINE | ID: mdl-22615059

Background This phase I, open-label, dose-escalation study examined the safety, maximum tolerated dose (MTD), and pharmacokinetics of sunitinib plus chemotherapy in patients with advanced gastric cancer. Patients and methods Sunitinib (25 or 37.5 mg/day, Schedule 2/1: 2 weeks on treatment/1 week off) plus chemotherapy (fixed starting doses of cisplatin 80 mg/m(2) and 5-fluorouracil [5-FU] 4,000 mg/m(2)) was administered to patients with advanced gastric cancer who had not received prior therapy for metastatic disease. Results Thirty-four patients were enrolled and received sunitinib 25 mg/day (n = 24) or 37.5 mg/day (n = 10) plus chemotherapy. No dose-limiting toxicity (DLT) was reported in the sunitinib 37.5 mg cohort. However, repeated patterns of myelosuppression beyond the first cycle led to investigation of sunitinib 25 mg/day. This was the MTD, and one DLT (grade 3 mucosal inflammation) was reported. The combination had an acceptable adverse event profile; generally of grade 1/2. There was no evidence of a pharmacokinetic drug-drug interaction between sunitinib and 5-FU. Six patients (26 %) receiving the MTD had a partial response and eight patients experienced stable disease ≥3 months. Conclusions Sunitinib plus cisplatin 80 mg/m(2) and 5-FU 4,000 mg/m(2) were combinable and adverse events were manageable. The MTD of sunitinib was established as 25 mg/day on Schedule 2/1.


Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Stomach Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Cisplatin/administration & dosage , Cohort Studies , Dose-Response Relationship, Drug , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Indoles/administration & dosage , Infusions, Intravenous , Male , Maximum Tolerated Dose , Middle Aged , Prognosis , Pyrroles/administration & dosage , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Sunitinib , Survival Rate , Tissue Distribution
18.
Ann Oncol ; 23(3): 664-670, 2012 Mar.
Article En | MEDLINE | ID: mdl-21652581

BACKGROUND: Based on a phase I study showing the feasibility of combining of oxaliplatin, cisplatin, and 5-fluorouracil (5-FU) (OCF) with radiation therapy (RT) in esophageal cancer, the efficacy of this regimen in esophageal, gastroesophageal (GE), and gastric (G) cancer was assessed in this phase II multicenter study. PATIENTS AND METHODS: Patients with resectable tumors were eligible. Treatment included two cycles of oxaliplatin 85 mg/m(2), cisplatin 55 mg/m(2), and continuously infused 5-FU 3 g/m(2) in 96 h and concurrent RT (45 Gy), followed by surgery after 6-8 weeks. Primary end point was complete pathologic response (pCR). RESULTS: Forty-one patients were enrolled. Tumor location was esophagus 39% (squamous 10/adenocarcinoma 6), GE junction 32%, and stomach 29%. G3-G4 adverse events included asthenia (27%) and neutropenia (14%). One toxic death occurred. Thirty-one patients (75.6%) underwent surgery (R0 in 94%). Pathologic response was achieved in 58% of patients, with pCR in 50% and 16% of esophageal and GE/G cancer, respectively. pCR was achieved in 67% of squamous cell carcinoma. Survival: median follow-up, 50.4 months; median progression-free survival and overall survival were 23.2 and 28.4 months, respectively. CONCLUSION: Preoperative OCF plus RT showed an acceptable toxicity and promising activity especially in squamous cell esophageal cancer.


Adenocarcinoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy , Esophageal Neoplasms/therapy , Neoadjuvant Therapy/methods , Stomach Neoplasms/therapy , Adenocarcinoma/pathology , Adult , Aged , Carcinoma, Squamous Cell/pathology , Chemoradiotherapy/methods , Cisplatin/administration & dosage , Cisplatin/adverse effects , Disease-Free Survival , Esophageal Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin , Stomach Neoplasms/pathology
19.
Nutr Hosp ; 26(2): 337-44, 2011.
Article Es | MEDLINE | ID: mdl-21666972

OBJECTIVE: To identify dietary patterns and nutritional status of the population between 18-44 years visited at a health center (HC) and explore the associated factors. METHODS: Cross-sectional study conducted in an urban HC in a random sample of 201 people. Were analyzed socio-demographic data, anthropometric measurements, 24 hours latest reminder intake, weekly food frequency questionnaire. RESULTS: The mean age of participants was 32.81 years (standard deviation 6.72). 63.68% (128) were women and 62.69% (126) immigrants. 45.27% (91) expressed no exercise. About 60% of participants related a deficit in consumption milk, fruits, meat and farinaceous and 80% vegetables, 58% related excessive fat. 44.4% (56) of immigrants was 20.3% with respect to obese (15) of native (P = 0.001). The proportion of people with "waist-risk" was higher among immigrants as compared to the native (19.0% vs 6.8%, P = 0.017) and among those who did not exercise with respect to each other (17.6% vs 8.1%, P = 0.049). Immigrants perform less physical activity related to the native (42.1% vs 62.7%, P = 0.013). Being an immigrant was the variable explaining of distribution acceptable daily macronutrient intake (Odds Ratio 4.7, Confidence Interval 95% 2.02-11.03). DISCUSSION: The participants related excessive consumption of fats and deficient in the rest of food groups. Obesity and the "risk waist" were more common among immigrants and sedentary population. Immigrants talked of a better distribution of nutrients in your daily diet.


Feeding Behavior , Nutritional Status , Primary Health Care/statistics & numerical data , Adolescent , Adult , Anthropometry , Cross-Sectional Studies , Emigrants and Immigrants , Female , Humans , Male , Malnutrition/epidemiology , Motor Activity , Obesity/epidemiology , Risk , Socioeconomic Factors , Spain/epidemiology , Surveys and Questionnaires , Urban Population , Waist Circumference , Young Adult
20.
Nutr. hosp ; 26(2): 337-344, mar.-abr. 2011. tab
Article Es | IBECS | ID: ibc-94581

Introducción: Identificar los hábitos alimentarios y el estado nutricional de la población entre 18-44 años atendida en un centro de salud (CS) y estudiar los factores asociados. Métodos: Estudio transversal realizado en un CS urbano en el que se seleccionó una muestra aleatoria de 201 personas. Se analizaron datos socio-demográficos, medidas antropométricas, recordatorio ingesta últimas 24 horas, cuestionario de frecuencia alimentaria semanal. Resultados: La edad media de los participantes fue de 32,81 años (Desviación Estándar 6,72). El 63,68%(128) eran mujeres y 62,69%(126) inmigrantes. El 45,27%(91) manifestaba no realizar ejercicio. Alrededor del 60% de los participantes refería un consumo deficitario de lácteos, frutas, cárnicos y farináceos y el 80% de verduras; el 58% lo refería excesivo de lípidos. El 44,4%(56) de inmigrantes era obeso respecto al 20,3%(15) de autóctonos (P= 0,001). La proporción de personas con «cintura de riesgo» era superior entre los inmigrantes respecto a los autóctonos (19,0% vs 6,8%; P= 0,017) y entre los que no hacían ejercicio respecto a los que sí (17,6% vs 8,1%; P= 0,049). Los inmigrantes referían realizar menos ejercicio físico que los autóctonos (42,1% vs 62,7%; P= 0,013). Ser inmigrante era la variable más explicativa de la distribución aceptable de macronutrientes en la ingesta diaria (Odds Ratio 4,7; Intervalo de Confianza del 95% 2,02-11,03). Discusión: Los participantes referían un consumo excesivo de lípidos y deficitario del resto de grupos alimentarios. La obesidad y la «cintura de riesgo» eran más frecuentes entre los inmigrantes y los participantes más sedentarios. Los inmigrantes referían una mejor distribución de macronutrientes en su alimentación diaria (AU)


Objective: To identify dietary patterns and nutritional status of the population between 18-44 years visited at a health center (HC) and explore the associated factors. Methods: Cross-sectional study conducted in an urban HC in a random sample of 201 people. Were analyzed socio-demographic data, anthropometric measurements, 24 hours latest reminder intake, weekly food frequency questionnaire. Results: The mean age of participants was 32.81 years (standard deviation 6.72). 63.68% (128) were women and 62.69% (126) immigrants. 45.27% (91) expressed no exercise. About 60% of participants related a deficit in consumption milk, fruits, meat and farinaceous and 80% vegetables, 58% related excessive fat. 44.4% (56) of immigrants was 20.3% with respect to obese (15) of native (P = 0.001). The proportion of people with «waist-risk» was higher among immigrants as compared to the native (19.0% vs 6.8%, P = 0.017) and among those who did not exercise with respect to each other (17.6% vs 8.1%, P = 0.049). Immigrants perform less physical activity related to the native (42.1% vs 62.7%, P = 0.013). Being an immigrant was the variable explaining of distribution acceptable daily macronutrient intake (Odds Ratio 4.7, Confidence Interval 95% 2.02-11.03). Discussion: The participants related excessive consumption of fats and deficient in the rest of food groups. Obesity and the «risk waist» were more common among immigrants and sedentary population. Immigrants talked of a better distribution of nutrients in your daily diet (AU)


Humans , Male , Female , Adult , Nutrition Assessment , Feeding Behavior , Nutrition Disorders/epidemiology , Primary Health Care/methods , Body Weights and Measures/statistics & numerical data , Human Migration
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