José María López-Picazo

Clínica Universidad de Navarra, Madrid, Madrid, Spain

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Publications (60)218.04 Total impact

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    ABSTRACT: CD137 (4-1BB) is a surface marker discovered on activated T lymphocytes. However, its expression pattern is broader and has also been described on activated NK cells, B-cells and myeloid cells including mature dendritic cells. In this study, we have immunostained for CD137 on paraffin-embedded lymphoid tissues including tonsils, lymph nodes, ectopic tertiary lymphoid tissue in Hashimoto thyroiditis and cancer. Surprisingly, immunostaining mainly decorates intrafollicular lymphocytes in the tissues analyzed, with only scattered staining in interfollicular areas. Moreover, pathologic lymphoid follicles in follicular lymphoma and tertiary lymphoid tissue associated to non-small cell lung cancer showed a similar pattern of immunostaining. Multicolor flow cytometry demonstrated that CD137 expression was restricted to CD4+ CXCR5+ follicular T helper lymphocytes in tonsils and lymph nodes. Short term culture of lymph node cell suspensions in the presence of an agonist anti-CD137 mAb or CD137-ligand results in the functional upregulation of TFH cells, including CD40L surface expression and cytokine production, in three out of six cases. As a consequence, immunostimulatory monoclonal antibodies, anti-CD137 mAb such as urelumab and PF-05082566 should be expected to primarily act on this lymphocyte subset, thus modifying ongoing humoral immune responses.
    OncoImmunology 05/2015; DOI:10.1080/2162402X.2015.1054597 · 6.28 Impact Factor
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  • Cancer Research 10/2014; 74(19 Supplement):1996-1996. DOI:10.1158/1538-7445.AM2014-1996 · 9.28 Impact Factor
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    ABSTRACT: Aim We analyzed the genome of individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco induced NSCLC to identify SNPs associated with these phenotypes. For this purpose, we used one of the most powerful GWAS platforms available. We hypothesized that SNPs may modulate individual susceptibility to carcinogens and that selection of extreme phenotypes would enrich the frequencies of alleles that contribute to the trait, thus increasing the power to identify them. Methods From an identification cohort (n=3631) we selected caucasian heavy smokers that either developed NSCLC at an early age (cancer-cohort) or that did not present NSCLC at an advanced age (cancer-free cohort). We analyzed their genomic DNA using the array Illumina HumanOmni 2.5 Quad that includes over 2 million powerful markers selected from the 1000 Genomes Project, targeting genetic variation down to 1% minor allele frequency. Statistical significance of SNPs was calculated using logistic regression and Fisher´s test. Results 96 patients (48 per cohort) were selected. Mean age for the cancer and cancer-free cohorts was 49 years (range 38-55) and 76 years (72-84). Mean tobacco consumption was 41 pack-years (range 18-99) and 68 pack-years (40-120). GWAS identified 8 SNPs differentially expressed by logistic regression and 54 SNP by Fisher´s test (p<10-5). Odds-ratio ranged between 0.08-0.29 for protective SNPs and 3.4-11.2 for SNPs that increased NSCLC risk. Candidate SNPs were located within or in adjacent regions of genes that have been previously related with cancer and that constitute potentially relevant targets (table 1): Function, Gene and Position - Oncogenes: MSX2 rs17064225 SOX11 rs6727285 - Tumor supressors: CSMD1 rs13253703 FOXF1 rs8055638 - Tobacco induced NSCLC: ABCB5 rs10281505, rs78057207, rs2390348 - Regulators of transcription: DROSHA rs17405280 HDAC9 rs13232564, rs2240419, rs10246722 KIAA0947 rs2913366 - Regulators of inflammation: PellinoE3 rs1189107, rs1300661 TRIM9 rs4375571 - Related with cancer ABHD6 rs7640259 GRIK1 rs465835 RAB40B rs2306911 SCN1A rs1020852 SLC24A2 rs4977304, rs4391516 SLC25A26 rs28544143 ZFYVE26 rs2235967 Conclusions We identified candidate SNPs associated with the risk of developing tobacco-induced NSCLC in individuals with extreme phenotypes. Several identified SNPs were located within or near genes that constitute potentially relevant targets for modulation of cancer risk. Validation of the most significant SNPs in an independent set of individuals with similar phenotypes, selected from the EPIC-Spain project (www.epic-spain.com, n=40,000) is ongoing.
    ESMO 2014 Congress, Abstract 1576P (poster presentation) http://www.poster-submission.com/search/sresult, Madrid; 09/2014
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    ABSTRACT: Aim We analyzed the genome of individuals presenting extreme phenotypes of sensitivity and resistance to develop tobacco induced NSCLC to identify SNPs associated with these phenotypes. For this purpose, we used one of the most powerful GWAS platforms available. We hypothesized that SNPs may modulate individual susceptibility to carcinogens and that selection of extreme phenotypes would enrich the frequencies of alleles that contribute to the trait, thus increasing the power to identify them. Methods From an identification cohort (n=3631) we selected caucasian heavy smokers that either developed NSCLC at an early age (cancer-cohort) or that did not present NSCLC at an advanced age (cancer-free cohort). We analyzed their genomic DNA using the array Illumina HumanOmni 2.5 Quad that includes over 2 million powerful markers selected from the 1000 Genomes Project, targeting genetic variation down to 1% minor allele frequency. Statistical significance of SNPs was calculated using logistic regression and Fisher´s test. Results 96 patients (48 per cohort) were selected. Mean age for the cancer and cancer-free cohorts was 49 years (range 38-55) and 76 years (72-84). Mean tobacco consumption was 41 pack-years (range 18-99) and 68 pack-years (40-120). GWAS identified 8 SNPs differentially expressed by logistic regression and 54 SNP by Fisher´s test (p<10-5). Odds-ratio ranged between 0.08-0.29 for protective SNPs and 3.4-11.2 for SNPs that increased NSCLC risk. Candidate SNPs were located within or in adjacent regions of genes that have been previously related with cancer and that constitute potentially relevant targets (table 1): Function Gene Position Oncogenes MSX2 rs17064225 SOX11 rs6727285 Tumor supressors CSMD1 rs13253703 FOXF1 rs8055638 Tobacco induced NSCLC ABCB5 rs10281505, rs78057207, rs2390348 Regulators of transcription DROSHA rs17405280 HDAC9 rs13232564, rs2240419, rs10246722 KIAA0947 rs2913366 Regulators of inflammation PellinoE3 rs1189107, rs1300661 TRIM9 rs4375571 Related with cancer ABHD6 rs7640259 GRIK1 rs465835 RAB40B rs2306911 SCN1A rs1020852 SLC24A2 rs4977304, rs4391516 SLC25A26 rs28544143 ZFYVE26 rs2235967 Conclusions We identified candidate SNPs associated with the risk of developing tobacco-induced NSCLC in individuals with extreme phenotypes. Several identified SNPs were located within or near genes that constitute potentially relevant targets for modulation of cancer risk. Validation of the most significant SNPs in an independent set of individuals with similar phenotypes, selected from the EPIC-Spain project (www.epic-spain.com, n=40,000) is ongoing.
    ESMO 2014 Congress, Abstract 1576P (poster presentation), Madrid; 09/2014
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    ABSTRACT: Background: IL-8 is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping pro-tumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL-8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden. Methods: IL-8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum and in samples from 126 cancer patients. We correlated IL-8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis. Results: IL-8 concentrations correlated with the number of IL-8 producing tumor cells in culture. In xenografted neoplasms, IL-8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n=16), renal cell carcinoma (n=23), non small cell lung cancer (n=21) or hepatocellular carcinoma (n=30), serum IL-8 concentrations correlated with tumor burden and stage, survival (melanoma, n=16; renal cell carcinoma, n=23; hepatocellular carcinoma, n=33) and objective responses to therapy, including those to BRAF inhibitors (melanoma, n=16) and immunomodulatory monoclonal-antibodies (melanoma, n=8). IL-8 concentrations in urine (n=18) were mainly elevated in tumors with direct contact with the urinary tract. Conclusions: IL-8 levels correlate with tumor burden in preclinical models and in cancer patients. IL-8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
    Clinical Cancer Research 09/2014; DOI:10.1158/1078-0432.CCR-13-3203 · 8.19 Impact Factor
  • 39th ESMO Congress (ESMO); 09/2014
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    ABSTRACT: Purpose The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [F-18]FDG PET might help predict KRAS and EFGR mutation status in NSCLC. Methods Between January 2005 and October 2011, 340 NSCLC patients were tested for KRAS and EGFR mutation status. We identified patients with stage III and IV disease who had undergone [F-18]FDG PET/CT scanning for initial staging. SUVpeak, SUVmax and SUVmean of the single hottest tumour lesions were calculated, and their association with KRAS and EGFR mutation status was assessed. A receiver operator characteristic (ROC) curve analysis and a multivariate analysis (including SUVmean, gender, age and AJCC stage) were performed to identify the potential value of [F-18]FDG PET/CT for predicting KRAS mutation. Results From 102 patients staged using [F-18]FDG PET/CT, 28 (27 %) had KRAS mutation (KRAS+), 22 (22 %) had EGFR mutation (EGFR+) and 52 (51 %) had wild-type KRAS and EGFR profiles (WT). KRAS+ patients showed significantly higher [F-18]FDG uptake than EGFR+ and WT patients (SUVmean 9.5, 5.7 and 6.6, respectively; p < 0.001). No significant differences were observed in [F-18]FDG uptake between EGFR+ patients and WT patients. ROC curve analysis for KRAS mutation status discrimination yielded an area under the curve of 0.740 for SUVmean (p < 0.001). The multivariate analysis showed a sensitivity and specificity of 78.6 % and 62.2 %, respectively, and the AUC was 0.773. Conclusion NSCLC patients with tumours harbouring KRAS mutations showed significantly higher [F-18]FDG uptake than WT patients, as assessed in terms of SUVpeak, SUVmax and SUVmean. A multivariate model based on age, gender, AJCC stage and SUVmean might be used as a predictive marker of KRAS mutation status in patients with stage III or IV NSCLC.
    European journal of nuclear medicine and molecular imaging 07/2014; 41(11). DOI:10.1007/s00259-014-2833-4 · 5.22 Impact Factor
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    ABSTRACT: Objective: To contribute ideas to answer advanced cancer patients asking about the use of medicinal cannabis as a symptomatic treatment. Method: Based on a real example, we present a summary of the pharmacology of natural and synthetic cannabinoids, the evidence on its effectiveness as a symptomatic treatment in advanced cancer, and the patient's attitude and expectations raised by the medicinal use of cannabis. Result: There are more than 60 different cannabinoids (the most relevant: delta-9-tetrahydrocannabinol) and other substances in cannabis. In our setting, patients who ask about the use of cannabis as a symptomatic treatment do not look for synthetic cannabinoids approved in other countries, but rather prefer herbal cannabis or its derivatives. They usually consume smoked cannabis (favoring the earlier onset of plasma levels) or, rarely, in infusion. Use of medicinal cannabis causes a wide variation in plasma concentrations of delta-9-tetrahydrocannabinol. There is evidence supporting a certain effect of synthetic cannabinoids in pain relief (also as an adjuvant), and as antiemetic for chemotherapy-induced nausea and vomiting in cancer patients. This evidence is based primarily on results of studies with limited methodological quality. There is insufficient evidence to assert its effectiveness in the treatment of anorexia. Side effects of moderate doses of synthetic cannabinoids or medicinal cannabis are mostly mild, as well as their psycho-neurological profile. The attitude and expectations of the patient, and the way to consume of medical cannabis may favor that part of its benefit may be due to a placebo effect. Conclusions: Medicinal cannabis does not seem as active as patients expect, or as toxic as many professionals suspect. To respond to the advanced cancer patient asking about their use as symptomatic treatment is advisable to avoid prejudice, to respect and to act with caution seeking the patient's symptomatic benefit.
    Medicina Paliativa 04/2014; 21(2):79-88. DOI:10.1016/j.medipa.2013.01.004 · 0.16 Impact Factor
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    ABSTRACT: Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy. ClinicalTrials.gov NCT01046240.
    PLoS ONE 02/2014; 9(2):e89747. DOI:10.1371/journal.pone.0089747 · 3.53 Impact Factor
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    ABSTRACT: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
    PLoS ONE 01/2014; 9(1):e86263. DOI:10.1371/journal.pone.0086263 · 3.53 Impact Factor
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    Dataset: EMCTO 2011
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    ABSTRACT: Abstract Within an oncology setting, certain chemotherapy drugs, such as cisplatin, may lead to magnesium loss causing nephropathy. Neurological and cardiovascular symptoms caused by hypomagnesaemia are well known. The relationship between serious hypomagnesemia and severe pain is not well documented but nevertheless, when faced with unexplained episodes of pain which do not respond to powerful analgesics, it is important to review blood magnesium levels. We present two cases of opioid-refractory pain attacks. Patients received drugs which have been linked to hypomagnesemia. In both cases, endovenous magnesium replacement led to a drastic improvement in pain management.
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    Reports of Practical Oncology and Radiotherapy 06/2013; 18:S254. DOI:10.1016/j.rpor.2013.03.286
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    ABSTRACT: PURPOSE: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. METHODS: Patients received cetuximab 250mg/m(2) (loading dose: 400mg/m(2))days 1, 8 and 15; pemetrexed 500mg/m(2)+cisplatin 75mg/m(2) on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. RESULTS: Sixty-six patients received ⩾1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. CONCLUSIONS: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected.
    European journal of cancer (Oxford, England: 1990) 05/2013; DOI:10.1016/j.ejca.2013.05.002 · 4.82 Impact Factor
  • Lung Cancer 05/2013; 80:S33. DOI:10.1016/S0169-5002(13)70292-7 · 3.74 Impact Factor
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    ABSTRACT: Background Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). Methods We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. Results Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) were also observed. Conclusions A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.
    Journal of Translational Medicine 01/2013; 11(1):13. DOI:10.1186/1479-5876-11-13 · 3.99 Impact Factor
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    ABSTRACT: Within an oncology setting, certain chemotherapy drugs, such as cisplatin, may lead to magnesium loss causing nephropathy. Neurological and cardiovascular symptoms caused by hypomagnesaemia are well known. The relationship between serious hypomagnesemia and severe pain is not well documented but nevertheless, when faced with unexplained episodes of pain which do not respond to powerful analgesics, it is important to review blood magnesium levels. We present two cases of opioid-refractory pain attacks. Patients received drugs which have been linked to hypomagnesemia. In both cases, endovenous magnesium replacement led to a drastic improvement in pain management.
    Supportive Care in Cancer 12/2012; 21(2). DOI:10.1007/s00520-012-1669-3 · 2.50 Impact Factor
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    ABSTRACT: Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.
    The Journal of Immunology 08/2012; 189(7):3299-310. DOI:10.4049/jimmunol.1102495 · 5.36 Impact Factor
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    ABSTRACT: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group. The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.
    Clinical and Translational Oncology 07/2012; 14(11):835-41. DOI:10.1007/s12094-012-0874-3 · 1.60 Impact Factor