Manejo clínico de los eventos adversos cutáneos en pacientes tratados con quimioterapia: consenso nacional de la Academia Española de Dermatología y Venereología y de la Sociedad Española de Oncología Médica / Clinical Management of Cutaneous Adverse Events in Patients on Chemotherapy: A National Consensus Statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology

A pesar del avance que ha supuesto en la supervivencia de los pacientes oncológicos, la aparición de nuevos agentes quimioterápicos y nuevas combinaciones, estos han traído consigo numerosos efectos adversos que pueden llegar a comprometer el tratamiento y, por consiguiente, el pronóstico de la enfermedad. Entre otros efectos secundarios los citostáticos pueden causar toxicidad dermatológica. El efecto adverso más conocido de la quimioterapia es la alopecia que, aunque no es grave, altera la apariencia externa de los pacientes con cáncer. Otros efectos adversos que pueden observarse son las reacciones de hipersensibilidad y fotosensibilidad, el síndrome mano-pie, la necrólisis epidérmica, las reacciones de reactivación, las reacciones esclerodermiformes, el fenómeno de Raynaud, la siringometaplasia escamosa ecrina, la hidradenitis neutrofílica ecrina, las alteraciones ungueales, las alteraciones en la pigmentación y las lesiones por extravasación. La aparición de estos efectos adversos produce en muchas ocasiones una reducción de dosis y/o retraso del tratamiento, lo que puede afectar a la supervivencia y a la calidad de vida del paciente. Por ello, es importante prevenir su aparición e instaurar un tratamiento temprano, para lo que se hace imprescindible la colaboración entre oncólogos médicos y dermatólogos. En este artículo se revisa la toxicidad dermatológica asociada con la quimioterapia, así como su diagnóstico y abordaje terapéutico

Although the arrival of new chemotherapy drugs and combinations has brought progress in terms of cancer patient survival, they entail many adverse effects that can compromise treatment, and hence prognosis, of the disease. Cytostatic agents can cause dermatological toxicity, among other side effects. The most familiar adverse effect of chemotherapy is alopecia. Although not serious, this changes the outward appearance of cancer patients. Other adverse effects include hypersensitivity and photosensitivity reactions, hand-foot syndrome, epidermal necrolysis, recall reactions, scleroderma-like reactions, Raynaud's phenomenon, eccrine squamous syringometaplasia, neutrophilic eccrine hidradenitis, nail abnormalities, pigmentation changes and extravasation injuries. Onset of these adverse effects often causes dose reduction and/or delayed treatment, which can affect patient survival and quality of life. It is therefore important to prevent their occurrence and treat them promptly, which requires cooperation between medical oncologists and dermatologists. This article reviews chemotherapy-associated dermatological toxicity, along with its diagnosis and therapeutic management

Clinical Management of Cutaneous Adverse Events in Patients on Chemotherapy: A National Consensus Statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology. / Manejo clínico de los eventos adversos cutáneos en pacientes tratados con quimioterapia: consenso nacional de la Academia Española de Dermatología y Venereología y de la Sociedad Española de Oncología Médica.

Although the arrival of new chemotherapy drugs and combinations has brought progress in terms of cancer patient survival, they entail many adverse effects that can compromise treatment, and hence prognosis, of the disease. Cytostatic agents can cause dermatological toxicity, among other side effects. The most familiar adverse effect of chemotherapy is alopecia. Although not serious, this changes the outward appearance of cancer patients. Other adverse effects include hypersensitivity and photosensitivity reactions, hand-foot syndrome, epidermal necrolysis, recall reactions, scleroderma-like reactions, Raynaud's phenomenon, eccrine squamous syringometaplasia, neutrophilic eccrine hidradenitis, nail abnormalities, pigmentation changes and extravasation injuries. Onset of these adverse effects often causes dose reduction and/or delayed treatment, which can affect patient survival and quality of life. It is therefore important to prevent their occurrence and treat them promptly, which requires cooperation between medical oncologists and dermatologists. This article reviews chemotherapy-associated dermatological toxicity, along with its diagnosis and therapeutic management.

Clinical management of cutaneous adverse events in patients on targeted anticancer therapies and immunotherapies: a national consensus statement by the Spanish Academy of Dermatology and Venereology and the Spanish Society of Medical Oncology.

Progress in the understanding of many tumors has enabled the development of new therapies, such as those targeted at specific molecules involved in cell growth (targeted therapies) or intended to modulate the immune system (immunotherapy). However, along with the clinical benefit provided by these new treatments, new adverse effects have also appeared. Dermatological toxicities such as papulopustular eruptions, xerosis, and pruritus are common with EGFR inhibitors. Other adverse effects have also been described with PDGFR, BCR-ABL, and MAPK tyrosine kinase inhibitors, antiangiogenic drugs, and inhibitors at immune checkpoints such as CTLA-4 and PD-1/PD-L1. Onset of these adverse effects often causes dose reductions and/or delays in administering the prescribed therapy, which can affect patient survival and quality of life. It is, therefore, important to prevent the occurrence of these adverse effects, or to treat unavoidable ones as soon as possible. This requires cooperation between medical oncologists and dermatologists. This article reviews the various dermatological toxicities associated with targeted therapies and immunotherapies, along with their diagnosis and therapeutic management.

Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients.

Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRß sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-ß and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1ß concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti-PD-1 treatment in melanoma and non-small-cell lung cancer patients.

BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P =  0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P =  0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P =  0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P =  0.001) and NSCLC (P =  0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.

SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2016)

Chemotherapy-induced nausea and vomiting is one of the most worrisome adverse effects of chemotherapy for cancer patients. It can cause severe discomfort and affect the quality of life. In recent years, the incorporation of new drugs has increased the efficacy of antiemetic treatments in the control of emesis associated with chemotherapy. This guideline, in which we give some treatment recommendations with level of evidence and grade of recommendation, provides an update of the previously published guideline of the Spanish Society of Medical Oncology and represents our continued commitment to improving supportive care in cancer patients (AU)

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SEOM Clinical Guideline update for the prevention of chemotherapy-induced nausea and vomiting (2016).

Chemotherapy-induced nausea and vomiting is one of the most worrisome adverse effects of chemotherapy for cancer patients. It can cause severe discomfort and affect the quality of life. In recent years, the incorporation of new drugs has increased the efficacy of antiemetic treatments in the control of emesis associated with chemotherapy. This guideline, in which we give some treatment recommendations with level of evidence and grade of recommendation, provides an update of the previously published guideline of the Spanish Society of Medical Oncology and represents our continued commitment to improving supportive care in cancer patients.

Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value.

Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %. Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median. Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations.

Tratamiento del cáncer de próstata en función de la esperanza de vida, la comorbilidad y las guías de práctica clínica / Treatment of prostate cancer according to life expectancy, comorbidity and clinical practice guidelines

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Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study.

INTRODUCTION: The haemostatic system plays an important role in the process of cancer development and spread. Anticoagulants, mainly low molecular weight heparins, could prolong survival in cancer patients, particularly in patients with lung cancer, beyond prevention of thromboembolic events. METHODS: In a multicenter, investigator-initiated, open-label, randomized, sequential study, 38 patients with newly-diagnosed, limited-stage small-cell lung cancer were randomized to receive standard chemoradiotherapy or the same therapy plus 3,500 IU daily of bemiparin for a maximum of 26 weeks. The primary outcome was progression-free survival. RESULTS: The study was terminated early due to slow recruitment. Median progression-free survival was 272 days with chemoradiotherapy alone and 410 days in the bemiparin group; hazard ratio, 2.58 (95% confidence interval [CI], 1.15-5.80); p=0.022. Median overall survival was 345 days with chemoradiotherapy alone and 1133 days in the bemiparin group; hazard ratio, 2.96 (95% CI, 1.22-7.21); p=0.017. The rate of tumor response was similar in both study arms. There was no significant between-group difference in the rates of major bleeding. Toxicity related with the experimental treatment was minimal. CONCLUSION: The addition of bemiparin to first line therapy with chemoradiotherapy significantly increases survival in patients with newly-diagnosed, limited-stage small-cell lung cancer. (Funded by the Instituto Científico y Tecnológico, University of Navarra. ClinicalTrials.gov identifier: NCT00324558).

The multimodal management of locally advanced N2-non-small cell lung cancer: is there a role for surgical resection? A single institution's experience

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 (AU)

Alteraciones de funciones cognitivas y ejecutivas en pacientes dependientes de cocaína: estudio de casos y controles / Cognitive and executive dysfunctions in cocaine dependence: a case-control study

Introducción. Diferentes estudios previos han puesto en relación el consumo crónico de cocaína con diversos daños neuropsicológicos.No obstante, la mayor parte de estos estudios ofrecen resultados parciales a través de baterías poco ecológicas.Objetivo. Evaluar el daño neuropsicológico (en especial de las funciones ejecutivas) asociado al consumo crónico y grave de cocaína, medido de una manera global a través de pruebas más ecológicas, considerando factores de confusión como edad, años de escolarización, sexo, raza, dependencia de opiáceos y consumo de alcohol. Sujetos y métodos. Para ello se realiza un análisis observacional, comparando los resultados del grupo de consumidores crónicos de cocaína (n = 24) y de un grupo control no consumidor (n = 27). Resultados. Los principales resultados señalan diferencias significativas en la prueba de dígitos directa (p = 0,008) e inversa (p < 0,001) y en el test de las cartas (p < 0,001), así como en el test del mapa del zoo (p = 0,001) y en algunas medidas del test de Wisconsin (número de aciertos y número de errores), pero no en todas. Conclusiones. Estos resultados confirman que el consumo crónico de cocaína per se provoca un daño neuropsicológico en diferentes funciones cognitivas y ejecutivas. Dicho daño va a condicionar la funcionalidad del paciente y su perspectiva de evolución, así como la respuesta terapéutica (AU)

Introduction. In the past, various studies have related chronic cocaine use to diverse types of neuropsychological impairment.However, the majority of these studies offer partial results using batteries of tests of little ecological weight.Aim. To investigate neuropsychological impairment (and of executive functions in particular) amongst severe chroniccocaine users, measured by means of more ecological tests and in a more global manner, taking confounding factors into account, such as age, years of schooling, gender, race, opioid dependence and alcohol consumption. Subjects and methods. We performed an observational study, comparing the cocaine dependence group (n = 24) with a non-cocaine use control group (n = 27). Results. The principal results revealed significant differences in the direct and reverse digit span tests (p = 0.008 andp < 0.001 respectively), and in the Cards Test (p < 0.001). They also showed a significance result in the Zoo Map Test (p = 0.001), and in different measurements but not in all forming part of the Wisconsin test (number of correct responses andnumber of errors). Conclusions. These results confirm that the chronic use of cocaine per se causes neuropsychological impairment that is manifested in classical and ecologically-valid tests. This impairment may influence patients’ functionality and prognosis,and also therapeutic failure (AU)

Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation.

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene. We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib. EGFR mutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according to EGFR mutational status. 69 NSCLC patients with brain metastases were identified, 17 of whom harboured EGFR mutations. Objective response rate in patients with EGFR mutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouring EGFR mutations was 11.7 (7.9-15.5) months, compared to 5.8 (5.2-6.4) months for control patients whose EGFR mutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2-19.7) months and 3.1 (2.5-3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed. Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of the EGFR gene.

Trastorno por déficit de atención e hiperactividad (TDAH) y consumo de sustancias: datos preliminares de seguimiento en una población de sujetos jóvenes / Attention deficit and hyperactivity disorder (ADHD) and substance use: preliminary outcomes of a follow-up in a young population

Introducción: La relación entre el consumo de sustancias y el trastorno por déficit de atención e hiperactividad (TDAH) se considera cada vez más importante entre adolescentes y jóvenes. Objetivo: Valorar los TDAH que presentan los adolescentes y jóvenes atendidos en el Programa para Adolescentes y Familias de Proyecto Hombre Madrid. Material y métodos: Se han incluido en el estudio los 223 adolescentes y jóvenes (75 % varones) atendidos en el Programa para Adolescentes y Familias de Proyecto Hombre Madrid, desde agosto de 2006 hasta abril de 2009. Para ello se realizó la valoración psiquiátrica de los adolescentes con antecedentes psiquiátricos, en tratamiento con psicofármacos o con sintomatología sugestiva de patología psiquiátrica. Resultados: Del total de la muestra, 15 adolescentes (todos varones) fueron diagnosticados de trastorno comórbido con TDAH (6,72 % del total de adolescentes atendidos). Estos adolescentes consumían principalmente cannabis, y en menor medida, alcohol y/o cocaína. El diagnóstico de TDAH se realizó de forma previa al consumo de sustancias en 13 de ellos, y aunque 11 habían recibido en algún momento tratamiento farmacológico específico, sólo tres lo tomaban en el momento de la evaluación (cuatro lo habían abandonado voluntariamente, y a cuatro les había sido retirado). Durante el tratamiento, 14 de ellos realizaron tratamiento farmacológico específico para el TDAH. Conclusiones: Se considera que el TDAH con consumo de sustancias presenta mayor gravedad, más alteraciones conductuales y mayor dificultad de tratamiento. Estos resultados apoyan la necesidad de extremar los cuidados y desplegar herramientas que favorezcan la adherencia terapéutica, sobre todo en los primeros meses del programa, así como prestar especial atención al consumo continuado, junto con el adecuado abordaje del TDAH (AU)

Introduction: The relationship between substance use and attention deficit and hyperactivity disorder (ADHD) is considered increasingly important among adolescents and youth. Objetives: The aim of this study is to assess ADHD in adolescent and young people treated in the Program for Adolescents and Families by "Proyecto Hombre" organization (Madrid, Spain). Material and methods: We have included 223 adolescent and young people (75 % male) treated in the Program for Adolescents and Families from 2006 to April 2009. The psychiatric evaluation is conducted of adolescents with psychiatric history, treatment with psychotropic drugs or psychiatric symptoms suggesting. Results: Of the total sample, 15 adolescents (all boys) were diagnosed with ADHD comorbid disorder (6.72 % of all the sample). These adolescents consumed mainly cannabis, and less alcohol and/or cocaine. The diagnosis of ADHD was held prior to substance use in 13 of them; 11 had received any specific drug treatment (only three at the time of evaluation; four had left voluntarily, and in four cases the treatment had been retired). During therapeutic programme, 14 of them receive specific drug treatment for ADHD. Conclusions: Patients with ADHD and substance misuse are more serious, with more important behavioural alterations, and with special difficulties in the treatment. This way, it is important to take special care and to improve the adherence, especially during the first months in the therapeutic program. In addition it's necessary to treat adequately the ADHD (AU)

Selection of extreme phenotypes: the role of clinical observation in translational research

Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology (AU)

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Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array.

BACKGROUND: Several drugs are available to treat metastatic renal-cell carcinoma (MRCC), and predictive markers to identify the most adequate treatment for each patient are needed. Our objective was to identify potential predictive markers of sunitinib activity in MRCC. METHODS: We collected sequential serum samples from 31 patients treated with sunitinib. Sera of six patients with extreme phenotypes of either marked responses or clear progressions were analysed with a Human Cytokine Array which evaluates 174 cytokines before and after treatment. Variations in cytokine signal intensity were compared between both groups and the most relevant cytokines were assessed by ELISA in all the patients. RESULTS: Twenty-seven of the 174 cytokines varied significantly between both groups. Five of them (TNF-alpha, MMP-9, ICAM-1, BDNF and SDF-1) were assessed by ELISA in 21 evaluable patients. TNF-alpha and MMP-9 baseline levels were significantly increased in non-responders and significantly associated with reduced overall survival and time-to-progression, respectively. The area under the ROC curves for TNF-alpha and MMP-9 as predictive markers of sunitinib activity were 0.83 and 0.77. CONCLUSION: Baseline levels of TNF-alpha and MMP-9 warrant further study as predictive markers of sunitinib activity in MRCC. Selection of patients with extreme phenotypes seems a valid method to identify potential predictive factors of response.

Role of surgery in a multidisciplinary approach to superior sulcus tumors (SST): morbidity and prognostic factors for long-term success after resection.

BACKGROUND: Optimal management of SST is still controversial several years after the proposal of a multidisciplinary approach including neoadjuvant chemotherapy and external radiation. Our objective is to report our experience of this multidisciplinary approach from the surgical point of view. PATIENTS AND METHODS: From January 1997 to January 2008, 24 patients were treated surgically (18 with induction chemotherapy and 15 with radiotherapy). The surgical approach was thoracic (14 cases, 1 with a spinal approach) or cervical (10 patients, 2 thoracotomies). Pulmonary surgery performed consisted of 11 wedge resections, 10 lobectomies, 1 pneumonectomy and 2 cases without lung resection (1 exploratory thoracotomy and 1 local progression after a previously resected tumor). Intraoperative radiotherapy (IORT) was given in 7 cases. Partial vertebral body resection was performed in 5 cases. A pathologically complete response (pT0) was found in 7 cases (29 %). RESULTS: Surgery-related morbidity was mainly due to respiratory distress (5 patients). Two patients died in the first month after surgery (mortality: 8 %). The surgical approach (cervical vs. thoracic) did not influence postoperative morbidity ( p = NS). Overall 5-year survival was 56.6 % according to the Kaplan-Meier method. No influence on survival was observed with regard to the approach (cervical vs. thoracic), the use of IORT, or the performance of spinal surgery. Patients with a complete pathological response had a better 5-year survival, but this did not reach statistical significance. CONCLUSION: Surgery has a role in the multidisciplinary approach, especially when we consider long-term survival. A multidisciplinary approach using neoadjuvant chemo and radiotherapy has a high rate of complete pathological response. It is also associated with a high incidence of postoperative distress syndrome. The 5-year survival is acceptable.

Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes.

Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.

Diferencias de género en el tratamiento de la dependencia de opiáceos con naltrexona / Gender differences in the treatment of the opiate dependence with naltrexone

Introducción. Se quiere conocer la influencia del factor género en las características de consumo, apoyo social y evolución en el tratamiento con naltrexona de un grupo de dependientes de opiáceos. Material y métodos. Mil cuatrocientos treinta y dos pacientes (83,1% hombres y 16,9% mujeres) que sucesivamente y durante 12 años inician tratamiento con naltrexona en la unidad de toxicomanías. Estudio observacional retrospectivo con diseño de grupo de tratamiento sin grupo control. Evaluamos el papel del género en la retención con la prueba de Mantel-Cox. Con tablas de contingencia se analizan las diferencias en función del género. Resultados. La retención al año de iniciarse el tratamiento para el total es del 29,75%, siendo del 30,92% para hombres y del 23,97% para mujeres. Esta diferencia al año es significativa según la prueba de Mantel-Cox (estadístico: 8,38; gl: 1; significación: 0,0038). Las mujeres presentan menor frecuencia de consumo (p=0,011) y uso de la vía intravenosa para cocaína (p=0,048), menor frecuencia de consumo de alcohol (p=0,000) y de cannabis (p=0,002), menor tiempo de consumo de heroína (p=0,016) y mayor proporción consumen sólo heroína (p=0,015). Tienen menor independencia económica (p=0,001), cuentan con mayor frecuencia con pareja consumidora (p=0,000), contando con menor apoyo para el tratamiento de una pareja no consumidora (p=0,000).Conclusiones. Existen diferencias relevantes respecto a las características del consumo, apoyo social y evolución del tratamiento según el género (sea hombre o mujer). Los hombres tienen mejor pronóstico que las mujeres en la población estudiada. Dichas diferencias parecen deberse al contenido sociocultural del concepto género (AU)

Introduction. We want to know the influence of gender factor in the consumption characteristics, social support and evolution in treatment with naltrexone in an opiate addict group. Material and methods. 1.432 patients (83.1% males and 16.9% females) recruited over a 12 year period who successively initiated treatment period years with naltrexone. Retrospective observance study, with design of treatment group without control group. We evaluated the role of gender in retention with the Mantel-Cox test. The differences were analyzed according to the gender with contingency tables. Results. One year retention for all of them was 29.75%, this being 30.92% for men and 23.97% for women. This difference is significant at one year according to the Mantel-Cox test (statistics: 8.38%; gl: 1; signification: 0.0038). Women show less frequency of cocaine use (p=0.011) and less use of intravenous cocaine (p=0.048), lower frequency of consumption of alcohol (p=0.000)and cannabis (p=0.002), a shorter period of heroine abuse(p=0.016) and a higher proportion of them only use heroine (p=0.015). They have less economic independence (p=0.001), their partner is more frequently an addict (p=0.000), they have less help for the treatment from anon-consuming partner (p=0.000).Conclusions. There are outstanding differences with regard to consume characteristics, social support and evolution of the treatment according to the gender (either male or female). Men have better prognosis than women in the population studied. These differences seem to be due to the socio cultural contents of the gender concept (AU)