Safety in radiation oncology: transposition of directive 2013/59/EURATOM in the Spanish Radiation Oncology Departments-recommendations for its adequate and effective application.

INTRODUCTION: The Official Journal of the European Union published on January 17, 2014 the Council Directive 2013/59/EURATOM of December 5, 2013, which establishes basic safety standards for the protection against the dangers derived from the exposure to ionizing radiation, and should have been transposed to the regulations of the member countries of the European Union. METHODS: We carried out and exhaustive review of the Directive, to highlight its aspects referred to radiotherapy, in order to issue recommendations for its adequate and effective application in Spain. RECOMMENDATIONS FOR ITS TRANSPOSITION: A series of recommendations are issued, from highest to lowest organizational level: Legislative, Scientific Societies, Healthcare Centers, Radiation Oncology Departments, Radiation Oncologists and Patients. CONCLUSIONS: The implementation of what the transposition of the Directive to our legal order implies, besides the implication of the professionals, Centers and Administration, a need and a consumption of resources. If not enough are allocated, there is a risk that the innovation and improvement that the transposition would imply in order to raise the level of patient safety and the quality of Radiation Oncology in Spain will remain a paper tiger and, as the Romans said, "Non progredi est regredi", that is, when it does not go forward, it goes backwards.

Patient safety in radiation oncology in Spain: a need to change.

PURPOSE: The Working Group on Patient Safety and Quality of the Spanish Society of Radiation Oncology, revised the most relevant national and international recommendations, selecting a series of important aspects for patient safety, evaluating whether they are included in Spanish legislation MATERIALS AND METHODS: We have considered a concept as relevant to the patient safety in radiotherapy if so defined in at least 8 of the 16 documents reviewed. RESULTS: 12 subjects were selected: training and qualification, human resources, protocols, safety culture, communication, peer review, accreditation: audits, checklists, areas without interruptions, maps of processes and risks, prospective risk analysis, notification, registration and incident learning, and quality control of the equipment. CONCLUSIONS: At the legislative level, as well as the professional organizations and the health center directorates, the implementation of safety culture must continue to be fostered. Only in this environment will the tools and measures to increase patient safety be effective. The current Spanish legislation must be revised and updated, in accordance with directive 2013/59/EURATOM and the Patient Safety Strategy 2015-2020 of the Spanish National Health System, introducing the obligation to perform risk analysis and incidents management. Audits and accreditations must be carried out, thus raising the general level of practice of the specialty. In this process, the Spanish Society of Radiation Oncology must continue playing its fundamental role, collaborating with the institutions and the rest of the scientific societies involved in the radiotherapy process, issuing recommendations on patient safety and disseminating the safety culture in our specialty.

Prevalence and characterization of breakthrough pain in cancer patients with proctalgia treated with 3D pelvic radiotherapy.

PURPOSE: Radiotherapy-induced dysfunction of the gastrointestinal tract is common in cancer patients and has a significant impact on their quality of life. In this study, we investigated the prevalence of breakthrough cancer pain (BTcP) in patients undergoing 3D pelvic radiotherapy and who had proctalgia. METHODS: This observational, multicenter, cross-sectional epidemiological study was performed in 13 Spanish hospitals. Data were obtained on the presence and characteristics of BTcP, demographics, common comorbidities, and treatments prescribed to the patients. RESULTS: The prevalence of BTcP in patients undergoing pelvic 3D external radiotherapy with proctalgia (N = 105) was 48.6% (95% CI 39.0-58.1%). BTcP was further characterized in 59 patients. The mean (± SD) intensity of the BTcP episodes was 7.45 ± 1.47 in a visual analog scale. We found several statistically significant associations between the descriptive variables of BTcP with demographic and clinical variables associated with the tumor or the patient, such as an increased number of BTcP episodes per day depending on the presence or absence of diabetes (p = 0.001, Chi-square) or time to the onset of pain relief depending on the location of the tumor (p = 0.019, Chi-square). Fentanyl was the drug of choice in BTcP episodes for 95% of the patients. CONCLUSIONS: This study demonstrated a high prevalence of BTcP prevalence in cancer patients undergoing pelvic 3D radiotherapy and with proctalgia. Although the variables determining the onset of BTcP are still unclear, our results could help in the design of future clinical studies addressing the treatment of BTcP in these patients.

Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential.

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation. Impairment of this signaling system and altered NO-cGMP homeostasis have been implicated in cardiovascular, pulmonary, renal, gastrointestinal, central nervous system, and hepatic pathologies. sGC stimulators, small molecule drugs that synergistically increase sGC enzyme activity with NO, have shown great potential to treat a variety of diseases via modulation of NO-sGC-cGMP signaling. Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models.

Merkel cell carcinoma: what do we know about it and what should we do?

Merkel cell carcinoma (MCC) is a rare primary cutaneous carcinoma of the skin that is highly aggressive, and has a high risk of locoregional and distant spread, a mortality rate considerably higher than that of cutaneous melanoma and poor survival. Its incidence has increased during the past twenty years. The studies published since 2008 have introduced changes in the understanding of its epidemiology and pathogenesis, and consequently the therapeutic approach. Despite this, there is still controversy surrounding its optimal management, which requires clarification. This is the purpose of this review (AU)

Eficacia y seguridad del tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomeruloesclerosis segmentaria y focal ciclosporina-resistente / Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis

Introducción: La asociación de ciclosporina A (CsA) y micofenolato mofetil (MMF) tiene un efecto inmunosupresor sinérgico y, en consecuencia, podría inducir una remisión del síndrome nefrótico en enfermos con glomeruloesclerosis segmentaria y focal resistente a esteroides y a CsA. Objetivo: Analizar la eficacia y el perfil de seguridad de la asociación CsA y MMF en enfermos con GSF resistente a ciclosporina A. Pacientes y método: 27 enfermos con GSF resistente a CsA recibieron tratamiento con CsA (4 mg/kg/día) asociada a MMF (2 g/día) durante 12 meses. El seguimiento total fue de 5 años. Como medida de resultado, se consideró la proporción de enfermos con remisión de la proteinuria y la evolución de la función renal a los 5 años. Resultados: Al finalizar el período de tratamiento, ningún paciente presentó remisión completa; 4 pacientes (14,8%) presentaron reducción de proteinuria a valores <3,5 g/día. Estos enfermos presentaban proteinuria basal (5,62 ± 2,19 frente a 8,1 ± 2,96 g/día, p = 0,042) y pendientes de FG (-0,08 ± 0,12 frente a -0,69 ± 0,38; p = 0,003) significativamente inferiores y mayor función renal basal (99,6 ± 12,9 frente a 85,05 ± 15,5 ml/min; p = 0,003). Dieciséis de los 27 enfermos (59,2%) presentaron una enfermedad renal progresiva o estadio V al final del período de seguimiento. Se apreciaron efectos adversos gastrointestinales en el 33,3% de los enfermos y nefrotoxicidad aguda transitoria en el 14,8%. El 22,2% de los enfermos precisó un incremento en la dosis y/o número de hipotensores durante los 12 meses de tratamiento. Conclusiones: En enfermos con GSF resistente a ciclosporina, el tratamiento con asociación de CsA y MMF durante 12 meses, aunque puede inducir reducciones parciales de la proteinuria, no modifica significativamente el curso evolutivo de la función renal (AU)

Introduction: The combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission of nephrotic syndrome in patients with steroid- and CsA-resistant focal segmental glomerulosclerosis (FSGS). Objective: To analyse the efficacy and safety of the combined CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. Patients and methods: Twenty-seven patients with CsA-resistant FSGS were treated for 12 months with CsA (4 mg/kg/day) combined with MMF (2 g/day). The overall follow-up was 5 years. The proportion of patients with remission of proteinuria and the evolution of kidney function after 5 years were used to measure the outcome. Results: At the end of the treatment period, no patients were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, P=.042), significantly lower GFR (-0.08 compared to -0.69±0.38; P=.003) and higher baseline kidney function (99.6±12.9 compared to 85.05±15.5ml/min; P=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients and acute transitory nephrotoxicity in 14.8%. The dosage and/or number of anti-hypertensive drugs had to be increased in 22.2% of patients during the 12 months of treatment. Conclusions: Twelve months of combined CsA and MMF therapy does not significantly alter the evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial reductions in proteinuria (AU)

Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis.

INTRODUCTION: The combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission of nephrotic syndrome in patients with steroid- and CsA-resistant focal segmental glomerulosclerosis (FSGS). OBJECTIVE: To analyse the efficacy and safety of the combined CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. PATIENTS AND METHODS: Twenty-seven patients with CsA-resistant FSGS were treated for 12 months with CsA (4mg/kg/day) combined with MMF (2g/day). The overall follow-up was 5 years. The proportion of patients with remission of proteinuria and the evolution of kidney function after 5 years were used to measure the outcome. RESULTS: At the end of the treatment period, no patients were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, P=.042), significantly lower GFR (-0.08 compared to -0.69±0.38; P=.003) and higher baseline kidney function (99.6±12.9 compared to 85.05±15.5ml/min; P=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients and acute transitory nephrotoxicity in 14.8%. The dosage and/or number of anti-hypertensive drugs had to be increased in 22.2% of patients during the 12 months of treatment. CONCLUSIONS: Twelve months of combined CsA and MMF therapy does not significantly alter the evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial reductions in proteinuria.

Prophylaxis with a cream containing urea reduces the incidence and severity of radio-induced dermatitis

INTRODUCTION: Radio-induced dermatitis is one of the most frequent side effects of radiotherapy. Among the commercially available products for the care of irradiated skin is a hydrating lotion containing 3% urea, polidocanol and hyaluronic acid. Its effectiveness for preventing the appearance of radiodermatitis or reducing its severity has been studied on a number of occasions. OBJECTIVE: To evaluate the effectiveness of "intensive use" of the lotion containing 3% urea, polidocanol and hyaluronic acid for preventing the appearance of acute radiodermatitis and controlling its severity. MATERIAL AND METHODS: Prospective observational study in 98 patients with breast cancer with a 10-week follow-up period. Skin toxicity (RTOG/EORTC scale) was evaluated weekly. To study the effectiveness we compared incidence and grade of toxicity with a sample of 174 breast cancer patients (control sample) treated in our centre during 2006 who used skin-support measures at the start of the radiotherapy or the occurrence of radiodermatitis. RESULTS: The proportion of patients who did not develop radiodermatitis was significantly higher in the intensive use group (27.6% vs. 15.5%; p<0.05; OR: 2.07). Compared with the same lotion in standard conditions, the intensive use group showed lower incidence of radiodermatitis (p<0.01), lower grade of toxicity (p<0.001) and lower proportion of radiodermatitis grade 2 or higher (p<0.01). CONCLUSIONS: Intensive use of the lotion doubles the likelihood that breast cancer patients will not develop radiodermatitis during radiotherapy. Furthermore, compared with standard use, intensive use is more effective in reducing the incidence of skin toxicity and skin toxicity grade 2 or higher (AU)

Combination therapies that inhibit cyclooxygenase-2 and leukotriene synthesis prevent disease in murine collagen induced arthritis.

OBJECTIVE AND DESIGN: To determine the effect of combinations of cyclooxygenase (COX) inhibitors and inhibitors of leukotriene (LT) syntheses on collagen induced arthritis (CIA) in mice. METHODS: The CIA model was evaluated for the presence of eicosanoids in the paw tissue. Several selective cyclooxygenase 2 (COX-2) inhibitors or non-selective non-steroidal anti inflammatory drugs (NSAIDs) were evaluated alone or in combination with leukotriene (LT) synthesis inhibitors in the CIA model. RESULTS: Arthritic paw tissue showed increased levels of prostaglandins and leukotrienes in comparison to normal paws. Analysis of mRNA levels indicated the inducible form of the COX-2 enzyme to be the source of prostaglandins. NSAIDs, COX-2 or leukotriene synthesis inhibitors administered alone in CIA decreased severity but had little effect on disease incidence. However, the combination of selective COX-2 inhibitors with leukotriene synthesis inhibitors produced significant decreases in both incidence and severity, suggesting an additive or synergistic effect. This effect was reversible with removal of drug. Little decrease in incidence was observed with the NSAID/5-LO inhibitor combinations. CONCLUSIONS: These results suggest that the induction of the disease in CIA is mediated by products of the COX-2 enzyme and LTB4 production, and that blockade of both pathways is required to prevent CIA.

Evaluación del riesgo nutricional e instauración de soporte nutricional en pacientes oncológicos, según el protocolo del grupo español de Nutrición y Cáncer / Nutricional risk evaluation and establishment of nutricional support in oncology patients according to the protocol of the spanish nutrition and cancer group

Introducción: El cáncer, los tratamientos que lo acompañan y los síntomas consecuentes que a su vez generan, aumentan en los pacientes el riesgo de sufrir malnutrición. La cual produce un gran deterioro del estado de salud, con el consecuente aumento de complicaciones, disminución de la tolerancia al tratamiento oncológico y una disminución de la calidad de vida del paciente. Por este motivo, un grupo de profesionales sanitarios de diferentes puntos de España se reunieron con el objetivo de mejorar la intervención nutricional en pacientes oncológicos, con el apoyo de la Sociedad Española de Nutrición Básica y Aplicada (SENBA). Metodología: Este grupo multidisciplinar de profesionales elaboró un documento de consenso basado en la literatura y en la experiencia personal, creando un protocolo de evaluación y de intervención nutricional en forma de algoritmos. Se clasifican los pacientes en tres pasos: 1. según el tipo de tratamiento oncológico que reciben, ya sea de tipo curativo o paliativo; 2. riesgo nutricional de la terapia antineoplásica (bajo, mediano, o alto riesgo), y 3. de acuerdo a la Valoración Global Subjetiva-Generada por el paciente (VGS-gp), que clasifica a los pacientes en: A. pacientes con adecuado estado nutricional, B. pacientes con malnutrición o a riesgo de malnutrición y C. pacientes con malnutrición severa. Durante un año el protocolo se puso en marcha en 226 pacientes mayores de 18 años de ambos sexos, escogidos al azar en las consultas externas de Radioterapia Oncológica y Oncología Médica. Resultados: Más de la mitad sufren malnutrición (64%), y este valor se incrementa llegando hasta un 81% en pacientes con tratamiento paliativo. La mayoría de los pacientes tienen tratamiento de intención curativa (83%) y reciben tratamiento oncológico de intensidad moderada o de alto riesgo nutricional (69%). Un 68% de los pacientes tienen algún tipo de dificultad en la alimentación. La media en el porcentaje de pérdida de peso es del 6,64% ± 0,87 (min 0, máx 33%). El 32% de la población presenta cifras de albúmina entre 3 y 3,5 g/dl, existiendo una correlación negativa entre ésta y las dificultades con la alimentación p = 0,001. El IMC no mostró ser un parámetro significativo para detectar malnutrición (sólo un 10% se encontraba por debajo de 19,9 kg/m2), pero tiene una tendencia lineal significativa con las dificultades en la alimentación, de forma tal que a medida que disminuye el IMC aumentan las dificultades p = 0,001. Más de la mitad de la población, requirió recomendaciones dietéticas específicas para el control de los síntomas que dificultaban la ingesta y una tercera parte de la población necesitó la indicación de suplementos nutricionales. Tras la intervención nutricional más de la mitad (60%) mantuvo su peso y una sexta parte lo aumentó. Conclusión: La aplicación de este protocolo es útil, sencillo y podría facilitar la detección de malnutrición en los pacientes oncológicos. Seleccionando a los pacientes que realmente se podrían beneficiar de una intervención nutricional específica, pero debería aplicarse al inicio coincidiendo si fuera posible con el diagnóstico de la enfermedad. El soporte nutricional resulta eficaz en la mayoría de los pacientes (AU)

Introduction: Cancer and its oncological treatment cause symptoms which increase the patients risk to suffer from malnutrition. This affects the patients health status negatively by increasing the number of complications, reducing the tolerance to the oncology treatment and a decrease of the patients quality of life. Motivated by this, a group of health professionals from several spanish regions met with the backing of the Sociedad Española de Nutrición Básica y Aplicada (SENBA) to address strategies to improve the quality of nutritional intervention in cancer patients. Methods: This multidisciplinary group developed a protocol describing nutritional assessment and intervention in form of algorithms based on literature and personal experience. The patients are classified in a three step process: 1. type of their oncology treatment (curative or palliative); 2. nutritional risk of the antineoplastic therapy (low, medium or high risk) and 3. depending on the Subjective Global Assessment patient-generated (SGApg). The patients are classified as: A. patients with adequate nutritional state, B. patients with malnutrition or risk of malnutrition and C. patients suffering from severe malnutrition. During one year, the protocol has been used for 226 randomly chosen female and male patients older than 18 years. They were treated by the Medical and Radiotherapy Oncology outpatient clinic. Results: More than a half of the patients were suffering from malnutrition (64%) increasing up to 81% for patients undergoing palliative treatment. Most of them were treated curatively (83%) and received oncology treatment with moderate or high nutritional risk (69%). 68% of patients were affected by some feeding difficulty. The mean percentage of weight loss has been 6.64% ± 0.87 (min 0%, max 33%). Albumin values of 32% of the patients were between 3 and 3.5 g/dl and negatively correlated with feeding difficulties (p = 0.001). The body mass index (BMI) has not found to be a significant parameter for detecting malnutrition (only in 10% of the patients, the value was below 19.9 kg/m2). But a significant linear tendency when compared to feeding problems could be shown, such that in patients with less feeding problems a higher BMI has been found (p = 0.001). More than a half of the patients required nutritional counselling to control symptoms which made food intake difficult. One third of the patients needed oral nutritional supplementation. Following the nutritional intervention the weight of about 60% of the patients could be maintained and of one sixth it could be increased. Conclusion: The application of this protocol is useful, easy and could help detecting malnutrition in oncology patients. It provides the possibility to select those patients who can benefit from a specific nutritional intervention. If possible, the application of the protocol should be started immediatly after cancer is diagnosed. Nutritional support proves efficient for most of the patients (AU)

[Nutritional risk evaluation and establishment of nutritional support in oncology patients according to the protocol of the Spanish Nutrition and Cancer Group]. / Evaluación del riesgo nutricional e instauración de soporte nutricional en pacientes oncológicos, según el protocolo del grupo Español de Nutrición y Cáncer.

INTRODUCTION: Cancer and its oncological treatment cause symptoms which increase the patients risk to suffer from malnutrition. This affects the patients health status negatively by increasing the number of complications, reducing the tolerance to the oncology treatment and a decrease of the patients quality of life. Motivated by this, a group of health professionals from several spanish regions met with the backing of the Sociedad Española de Nutrición Básica y Aplicada (SENBA) to address strategies to improve the quality of nutritional intervention in cancer patients. METHODS: This multidisciplinary group developed a protocol describing nutritional assessment and intervention in form of algorithms based on literature and personal experience. The patients are classified in a three step process: 1. type of their oncology treatment (curative or palliative); 2. nutritional risk of the antineoplastic therapy (low, medium or high risk) and 3. depending on the Subjective Global Assessment patient-generated (SGA-pg). The patients are classified as: A. patients with adequate nutritional state, B. patients with malnutrition or risk of malnutrition and C. patients suffering from severe malnutrition. During one year, the protocol has been used for 226 randomly chosen female and male patients older than 18 years. They were treated by the Medical and Radiotherapy Oncology outpatient clinic. RESULTS: More than a half of the patients were suffering from malnutrition (64%) increasing up to 81% for patients undergoing palliative treatment. Most of them were treated curatively (83%) and received oncology treatment with moderate or high nutritional risk (69%). 68% of patients were affected by some feeding difficulty. The mean percentage of weight loss has been 6.64% +/- 0.87 (min 0%, max 33%). Albumin values of 32% of the patients were between 3 and 3.5 g/dl and negatively correlated with feeding difficulties (p = 0.001). The body mass index (BMI) has not found to be a significant parameter for detecting malnutrition (only in 10% of the patients, the value was below 19.9 kg/m2). But a significant linear tendency when compared to feeding problems could be shown, such that in patients with less feeding problems a higher BMI has been found (p = 0.001). More than a half of the patients required nutritional counselling to control symptoms which made food intake difficult. One third of the patients needed oral nutritional supplementation. Following the nutritional intervention the weight of about 60% of the patients could be maintained and of one sixth it could be increased. CONCLUSION: The application of this protocol is useful, easy and could help detecting malnutrition in oncology patients. It provides the possibility to select those patients who can benefit from a specific nutritional intervention. If possible, the application of the protocol should be started immediatly after cancer is diagnosed. Nutritional support proves efficient for most of the patients.

Activation of the signal transducer and activator of transcription-1 in diffuse proliferative lupus nephritis.

Difuse proliferative lupus nephritis (DPLN) is the most common and severe form of lupus nephritis. A predominance of IFN-gamma-producing T cells in both peripheral and renal tissues of patients with DPLN has been identified which suggests an important role for cell-mediated immunity in the pathogenesis of this complication in SLE. The biological effects of IFN-gamma rely mainly on the activity of the transcription factor called signal transducer and activator of transcription (STAT)-1. To assess the IFN-gamma/STAT-1 pathway in DPLN, we examined the expression of STAT-1 in renal biopsies from 15 DPLN patients by immunohistochemical staining with an anti-STAT-1 antibody. The expression of STAT-1 in renal tissues was correlated with several clinical and laboratory findings in these DNPN patients.STAT-1 was activated in the tubular cells in all DPLN patients. Seven of 15 DPLN biopsies (46.7%) showed positive cells in glomeruli. Five of these seven DPLN biopsies (71.4%) with positive glomerular cells showed a serum creatinine >1.5 mg/mL at the time the biopsy was carried out whereas only one of eight DPLN biopsy specimens (12.5%) without positive glomerular cells, showed a serum creatinine >1.5 mg/mL (P = 0.041). Moreover, the percentage of DPLN patients with a worse renal outcome in those who showed expression of STAT-1 in glomerulari were higher in comparison to those without STAT-1 expression (P = 0.041). Our results show that STAT-1 is activated in DPLN suggesting that biological effects of IFN-gamma in renal tissues depend, at least in part, on the activation of STAT-1.

Polymyositis/dermatomyositis-associated lung disease: analysis of a series of 81 patients.

The objective of this study was to assess the prevalence, clinical, histological and immunological characteristics, and the long-term outcome of polymyositis- (PM) and dermatomyositis- (DM) associated lung disease, and to define subgroups of lung-associated inflammatory myopathies. This retrospective study included 81 consecutive patients diagnosed with PM/DM. Pulmonary involvement was systematically investigated in relation to clinical symptoms by chest radiography, high resolution computed tomography and pulmonary function testing. Anti-synthetase autoantibodies (ASA) were analysed by ELISA and confirmed by protein and RNA immunoprecipitation methods. Statistical analyses were done with the Student t-test and Fisher exact test. Cumulative survival probabilities were estimated by the Kaplan-Meier method and Cox regression analysis. Fifty patients (61%) presented pulmonary involvement. Thirty-two (39%) had interstitial lung disease and five of them had devastating acute interstitial pneumonia with pneumomediastinum and an unfavorable prognosis. Histology showed diffuse alveolar damage in this subgroup and ASA were negative. Eighteen patients (22%) presented restrictive myopathic lung disease; in three of them respiratory muscles could not maintain ventilation. ASA were positive in 17 of the 50 patients (34%) and were significantly associated with interstitial lung disease (OR: 4.5 [95% CI: 1.3-15.3]), arthritis (OR: 6.0 [95% CI: 1.3-29.2]) and 'mechanic hands' (OR: 8.5 [95% CI: 1.7-41.4]); the presence of these autoantibodies did not imply worse survival prognosis. We concluded that clinical and immunological characteristics allowed the grouping of patients into different types of PM/DM lung-associated disease. Presence of ASA did not affect survival. ASA-negative patients with acute interstitial pneumonitis and pneumomediastinum had an unfavorable prognosis.

Introduccion

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Characterization of cyclooxygenase-2 (COX-2) during tumorigenesis in human epithelial cancers: evidence for potential clinical utility of COX-2 inhibitors in epithelial cancers.

Increased prostaglandins (PGs) are associated with many inflammatory pathophysiological conditions; and are synthesized from arachidonic acid by either of 2 enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2). Recent epidemiologic, expression, and pharmacologic studies suggest COX-2 derived metabolites also play a functional role in the maintenance of tumor viability, growth and metastasis. Archival and/or prospectively collected human tissues were prepared for immunohistochemistry, and representative cases assayed via Western blot, RT-PCR, or TAQman analysis. Consistent overexpression of COX-2 was observed in a broad range of premalignant, malignant, and metastatic human epithelial cancers. COX-2 was detected in ca. 85% of the hyperproliferating, dysplastic, and neoplastic epithelial cells, and in the existing and angiogenic vasculature within and adjacent to hyperplastic/neoplastic lesions. These data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers.

Nutrición en el paciente con radioterapia / No disponible

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Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon.

BACKGROUND: The cyclooxygenase (COX) enzymes exist in two related but unique isoforms (COX-1 and COX-2) and catalyze the formation of prostaglandins (PGs). COX-1 is constitutively expressed, and is responsible for the synthesis of PGs necessary for gastroprotection and normal renal function. The COX-2 isoform is important in a variety of pathophysiological conditions such as inflammation and tumorigenesis. Numerous studies report that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the incidence of some tumor types, including gastrointestinal polyposis. METHODS: In this study, we evaluated COX-1 and COX-2 expression in 30 polyps collected from 10 patients with familial adenomatous polyposis (FAP) and in 18 polyps collected from 18 patients with sporadic adenomatous polyposis (SAP) using COX-1 or COX-2 isoform-specific antibodies. All tissues were formalin-fixed and paraffin-embedded. Immunoreactivity was detected using tyramide signal amplification and evaluated utilizing an immunohistochemical scoring system. RESULTS: COX-2 was minimally detected in the distant non-neoplastic epithelium, which also served as an internal negative control. In comparison, all polyps collected from SAP or FAP patients overexpressed COX-2 in the neoplastic epithelial cells (P < or = 0.002). Additionally, pronounced COX-2 expression was observed in the stromal cells underlying and adjacent to adenomatous lesions. COX-1 immunoreactivity was weak to mild throughout each tissue evaluated and did not change in the neoplastic or stromal cells of the polyps. CONCLUSIONS: COX-2 expression is upregulated in the adenomatous epithelium of SAP and FAP, while the COX-1 isoform appears to be constitutively expressed at low levels in both neoplastic and non-neoplastic regions. The differential expression of COX-1 and COX-2 in these neoplasms suggests that COX-2 rather than COX-1 may play a role in adenoma formation and/or growth in cases of SAP and FAP in humans.

Cyclooxygenase-2 is overexpressed in human cervical cancer.

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.

Approach to angiogenesis inhibition based on cyclooxygenase-2.

Two cyclooxygenase (COX) isoforms have been identified: COX-1 and COX-2. COX-1 is the constitutively expressed form of the enzyme and is ubiquitous in its distribution. COX-2 is inducible and is present in inflammatory foci, tumors, and neovasculature. Expression of COX-2 appears to be important in tumor promotion, growth, and metastasis. It is up-regulated in a variety of premalignant disorders and malignancies. COX inhibitors have a major role in the treatment of inflammation and pain. Epidemiologic evidence in patients who take nonsteroidal anti-inflammatory drugs links COX inhibition with decreases in malignant esophageal, stomach, colon, lung, and breast tumors. Nonselective COX inhibitors have demonstrated efficacy in control of familial adenomatous polyposis, a disorder associated with the development of thousands of benign intestinal polyps. The selective COX-2 inhibitor celecoxib (Celebrex, Pharmacia) has been shown to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care. Celecoxib has recently been approved for this indication and offers the potential for equivalent or greater efficacy than that seen with nonselective COX inhibitors but without the gastrointestinal mucosal toxicity and the inhibition of platelet function associated with those agents. Angiogenesis is a feature of both benign and malignant disease. Because COX-2 is up-regulated in the neovasculature of the rheumatoid pannus and in malignant tumors and their surrounding stroma, selective COX-2 inhibitors may be able to modify the progression of these disorders through the control of angiogenesis.

Dose-response effects of the COX-2 inhibitor, celecoxib, on the chemoprevention of mammary carcinogenesis.

Recent chemopreventive studies in our laboratories showed that the COX-2 inhibitor, celecoxib, inhibited the induction of mammary cancer by 7,12-dimethylbenz(a)anthracene (DMBA). In this study, we examined the relative chemopreventive effect of varying doses of celecoxib on the development and growth of DMBA-induced rat mammary tumors. At 10 days prior to receiving a single intragastric dose of 15 mg DMBA/rat, female Sprague-Dawley rats were fed a control chow diet or diets containing 250, 500, 1000 or 1500 ppm celecoxib until termination of the experiment. Administration of increasing doses of celecoxib inhibited mammary tumor incidence and multiplicity as well as tumor volume in a dose-dependent manner. At 122 days post DMBA-intubation, mammary tumor incidence was 100% in the control rats compared to 80%, 50%, 45% and 25% in rats receiving 250, 500, 1000 or 1500 ppm celecoxib, respectively (p<0.001). Similarly, tumor multiplicity and tumor volume were significantly reduced by increasing the dose of celecoxib from 250 to 1500 ppm in the diet. The control rats had an average of 3.46 tumors/rat compared to 1.80, 1.00, 0.75 and 0.50 tumors/rat in animals receiving 250, 500, 1000 or 1500 ppm celecoxib, respectively (p<0.001). Average tumor volumes in rats fed 250, 500, 1000 or 1500 ppm celecoxib were 0.42, 0.34, 0.31 and 0.16 cm3 compared to 1.29 cm3 in the control rats (p<0.001). There was a concomitant increase in the steady-state serum concentration of celecoxib with the dose. These results indicate that, in this rat model, the chemopreventive effect of celecoxib against breast cancer is dose-dependent and that celecoxib is effective even at lower dose levels.