Patients with non-small-cell lung cancer harbouring a BRAF mutation: a multicentre study exploring clinical characteristics, management, and outcomes in a real-life setting: EXPLORE GFPC 02-14.

Background: Mutations in BRAF are rare oncogene mutations, found in 2% of non-small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF-mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting. Methods: This retrospective multicentre observational study included all patients with BRAF-mutated nsclc diagnosed between January 2012 and December 2014. Results: Patients (n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 ± 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti-BRAF), and 48% received second-line treatment (23.8% anti-BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations (n = 32) did not differ significantly from those of patients with other BRAF mutations. Conclusions: In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF-mutated patients than in nsclc patients without an oncogenic driver.

Estudio descriptivo de la incapacidad temporal en el sector sanitario de Cataluña (2009-2012) / Descriptive study of sickness absence in the health care sector of Catalonia (2009-2012)

Objetivo: Describir la incidencia y evolución de la incapacidad temporal (IT) por contingencias comunes y profesionales en la población trabajadora de los centros sanitarios de Cataluña. Métodos: La población de estudio estuvo constituida por los 25.964 trabajadores de 30 centros sanitarios de Cataluña, durante el período 2009-2012. La información sobre los episodios de IT se obtuvo de los registros de las Direcciones de Recursos Humanos. Se definieron unos indicadores de IT, y se calcularon las tasas de incidencia de IT y la evolución temporal, según la duración y tipo de episodio, y el tamaño y actividad de los centros sanitarios. Resultados: La evolución temporal de las tasas de incidencia de IT por contingencia común mostró una tendencia a la disminución en el período 2009-2012. Los centros de pequeño tamaño tuvieron tasa de IT por contingencia común inferior que los de mayor tamaño (p<0,001). Los centros sociosanitarios son los que presentaron mayores tasas de IT por contingencia común, especialmente la de muy corta duración (p<0,001). . Los centros de atención primaria tuvieron las tasas más bajas de IT por contingencia profesional siendo la más elevada la de los centros sociosanitarios, especialmente la de larga duración (p<0.01). Conclusiones: Las diferencias observadas en las tasas de incidencia de IT según el tipo de actividad del centro sanitario podrían deberse a diferencias en las condiciones de trabajo

Objective: To describe the incidence and evolution of sickness absence (SA) for non-occupational and occupational illness/injury in the population of workers in Catalonian Health Centers based on the definition of a set of common indicators. Methods: The study population consisted of 25,964 workers from 30 health centers in Catalonia, during 2009-2012. Information on SA episodes was obtained from records of the Directorate of Human Resources. SA indicators were defined, and SA incidence rates and temporal evolution were calculated, depending on the length and type of episode, and the size and activity of health centers. Results: SA incidence rates for non-occupational illness and injury showed a decreasing trend during 2009-2012. Smaller centers had lower SA rates for non-occupational conditions than larger centers (p<0,001). . Social health centers had higher SA rates of non-occupational illness and injury, especially those with a very short duration (p<0.001). Primary care centers had the lowest SA occupational illness and injury rates, with the highest rates occurring in the social health centers, especially long-term centers (p<0.01). Conclusions: The differences in incidence rates of SA detected by type of activity of the health centers could be due to differences in working conditions

Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study.

UNLABELLED: Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients. CLINICAL TRIAL INFORMATION: NCT02293733.

[IMRT combined to IGRT: increase of the irradiated volume. Consequences?]. / Radiothérapie conformationnelle avec modulation d'intensité (RCMI) guidée par l'image: impact de l'augmentation du volume irradié à faible dose?

Image-guided radiotherapy (IGRT) combined or not with intensity-modulated radiation therapy (IMRT) are new and very useful techniques. However, these new techniques are responsible of irradiation at low dose in large volumes. The control of alignment, realignment of the patient and target positioning in external beam radiotherapy are increasingly performed by radiological imaging devices. The management of this medical imaging depends on the practice of each radiotherapy centre. The physical doses due to the IGRT are however quantifiable and traceable. In one hand, these doses appear justified for a better targeting and could be considered negligible in the context of radiotherapy. On the other hand, the potential impact of these low doses should deserve the consideration of professionals. It appears important therefore to report and consider not only doses in target volumes and in "standard" organs at risk, but also the volume of all tissue receiving low doses of radiation. The recent development of IMRT launches the same issue concerning the effects of low doses of radiation. Indeed, IMRT increases the volume of healthy tissue exposed to radiation. At low dose (<100mGy), many parameters have to be considered for health risk estimations: the induction of genes and activation of proteins, bystander effect, radio-adaptation, the specific low-dose radio-hypersensitivity and individual radiation sensitivity. With the exception of the latter, the contribution of these parameters is generally protective in terms of carcinogenesis. An analysis of secondary cancers arising out of field appears to confirm such notion. The risk of secondary tumours is not well known in these conditions of treatment associating IMRT and IGRT. It is therefore recommended that the dose due to imaging during therapeutic irradiation be reported.

Mirtazapina en combinación / Mirtazapine in combination

La depresión es sin duda una enfermedad especialmente relevante en términos de sufrimiento personal, mortalidad y costes sociales, familiares y económicos. El tratamiento farmacológico supone un abordaje terapéutico razonablemente eficaz. Sin embargo el retraso en la aparición de la respuesta terapéutica y la persistencia de síntomas depresivos constituyen serios inconvenientes para la recuperación clínica. Aunque la acción farmacológica de los antidepresivos se inicia a las pocas horas de iniciar el tratamiento, la respuesta antidepresiva suele demorarse entre dos y seis semanas. La persistencia de síntomas depresivos después de las seis primeras semanas de tratamiento constituye un factor de mal pronóstico en términos de cronicidad y de una función social que no alcanzará la normalidad. La combinación de otros antidepresivos con mirtazapina puede paliar de forma significativa estos inconvenientes. Su efecto antagonista sobre los receptores presinápticos reduce la latencia de respuesta antidepresiva. Por otra parte su robusto efecto noradrenérgico potencia los efectos predominantemente serotoninérgicos de los antidepresivos mas corrientes. Finalmente los efectos secundarios de la mirtazapina pueden ser parcialmente neutralizados por la actividad fármaco dinámica de otros antidepresivos, así como esta puede mejorar efectos adversos de otros medicamentos tan críticos como lo puede ser la disfunción sexual (AU)

Depression is undoubtedly a particularly important disease in terms of personal suffering and death as well as social, family, and economic costs. Pharmacological treatment is a reasonably effective therapeutic approach; however, a delayed therapeutic response and the persistence of depressive symptoms represent serious draw backs to clinical recovery. Although the pharmacological action of antidepressants begins a few hours after the start of treatment, an antidepressant response usually takes between 2 and 6 weeks. The persistence of depressive symptoms after the fi rst6 weeks of treatment is indicative of a poor prognosis in terms of chronicity and a return to normal social function. The combination of mirtazapine with other antidepressants may significantly lessen these draw backs. Its antagonist effect on the presynaptic receptors reduces the latency of the antidepressant response. Moreover, its robust noradrenergic effect enhances the serotoninergic effects of the most common antidepressants. In addition, the side effects of mirtazapine can be partially neutralized by the pharmaco dynamic activity of other antidepressants, while mirtazapine can ameliorate the serious adverse effects, such as sexual dysfunction, of other medications (AU)

Mirtazapine in combination.

INTRODUCTION: Depression is undoubtedly a particularly important disease in terms of personal suffering and death as well as social, family, and economic costs. Pharmacological treatment is a reasonably effective therapeutic approach;however, a delayed therapeutic response and the persistence of depressive symptoms represent serious drawbacks to clinical recovery.Although the pharmacological action of anti depressants begins a few hours after the start of treatment, an antidepressant response usually takes between 2 and 6 weeks.The persistence of depressive symptoms after the first weeks of treatment is indicative of a poor prognosis in terms of chronicity and a return to normal social function.The combination of mirtazapine with other antidepressants may significantly lessen these drawbacks.Its antagonist effect on the presynaptic receptors reduces the latency of the antidepressant response. Moreover, its robust noradrenergic effect enhances the serotoninergic effects of the most common antidepressants. In addition, the side effects of mirtazapine can be partially neutralized by the pharmacodynamic activity of other antidepressants, while mirtazapine can ameliorate the serious adverse effects, such as sexual dysfunction, of other medications.

Feeding problems in nursery children: prevalence and psychosocial factors.

AIM: In this study we analyze the prevalence of feeding problems in a sample of nursery children and examine the environmental and psychopathological factors related to such problems. METHODS: We used the Early Childhood Inventory-Parents Checklist to assess 851 Spanish children aged between 3 and 6 years from both urban and rural samples. This screens emotional and behavioural problems and is based on the Diagnostic and Statistical Manual of Mental Disorders-IV. We collected sociodemographic data and information about life events and the psychopathology of the children's parents (General Health Questionnaire-28). RESULTS: Our results showed that the prevalence of feeding problems was 4.8% and that there were no differences between gender. Sample subtype, socioeconomic level and family characteristics were not linked to feeding problems. Children with feeding problems had significantly more symptoms of psychological problems and somatic complaints and had experienced more life events in the previous 12 months. The psychopathology of the mother, especially in terms of anxiety problems, increased the risk of feeding problems in children. CONCLUSION: When there are complaints of feeding problems in preschools, the psychological problems of children and their mothers should be taken into consideration during paediatric consultation, irrespective of gender or socioeconomic status.

La Cultura y Clima Organizacional. Su influencia en la eficacia de la Organización: Ciclo Básico de la Facultad de Ciencias Médicas Dr. Faustino Pérez Hernández de Sancti Spíritus

En la Universidad Médica de Sancti Spíritus se elaboró una metodología para el diagnóstico de Cultura y Clima Organizacional que permita garantizar el cambio en una institución educacional. Esta metodología se aplicó a los integrantes del colectivo del área básica para realizar el diagnóstico en sí, proponer estrategias y acciones que tiendan a su perfeccionamiento. Se utilizaron los métodos teóricos investigación acción, histórico lógico, el análisis de expertos, el análisis y síntesis así como métodos empíricos particulares como encuestas, cuestionario, entrevistas y análisis grupal. Se determinaron los valores compartidos y la actitud global directiva que permita tanto al equipo de dirección como a los miembros de la organización enfrentar el cambio. Se clasificó la Cultura y el Clima Organizacional imperante. Se propusieron las estrategias y un plan de acción según el resultado de 21 instrumentos aplicados con vistas a elevar la identidad, la racionalidad y sentido de pertenencia a la Facultad, lo cual propiciará desarrollar la Cultura Organizacional.

Burr hole cover for ventriculoperitoneal shunts and ventriculostomy: technical note.

In patients who have undergone intracranial procedures, bone gaps or burr holes often result in small but undesirable scalp or skin depressions. The authors designed a burr hole cover for hydrocephalus shunt system or external ventricular drainage, which is shaped to alleviate the deformity of the burr hole by filling the bone defect and allowing the passage of the ventricular catheter. The specifications of this device and its clinical application are described.

Diagnosis and management of neurosarcoidosis.

Sarcoidosis is a multisystemic disorder characterised by the presence of multiple noncaseating granulomas. Clinically recognisable nervous system involvement occurs in 5-16% of patients with sarcoidosis. However, the incidence of subclinical neurosarcoidosis may be higher. The following article presents a review of the disease, including its pathophysiology, clinical and radiological characteristics and treatment. Neurosarcoidosis should be included in the differential diagnosis of infectious and noninfectious neurological syndromes.

The spontaneous resorption of herniated cervical discs.

The spontaneous resolution of herniated cervical discs has not been previously well documented. The authors analysed four cases who underwent spontaneous resolution of herniated cervical discs, and all other cases reported in the literature. A complex physiopathologic mechanism that includes the release of basic fibroblast grow factors, endothelial cell proliferation, chemotaxis of inflammatory cells into the disc fragment, foreign body inflammatory reaction, neovascularization and phagocytosis and accounts for the resorption of herniated discs is reviewed.

Hyperacute measurement of intracranial pressure, cerebral perfusion pressure, jugular venous oxygen saturation, and laser Doppler flowmetry, before and during removal of traumatic acute subdural hematoma.

OBJECT: The poor prognosis for traumatic acute subdural hematoma (ASDH) might be due to underlying primary brain damage, ischemia, or both. Ischemia in ASDH is likely caused by increased intracranial pressure (ICP) leading to decreased cerebral perfusion pressure (CPP), but the degree to which these phenomena occur is unknown. The authors report data obtained before and during removal of ASDH in five cases. METHODS: Five patients who underwent emergency evacuation of ASDH were monitored. In all patients, without delaying treatment, a separate surgical team (including the senior author) placed an ICP monitor and a jugular bulb catheter, and in two patients a laser Doppler probe was placed. The ICP prior to removing the bone flap in the five patients was 85, 85, 50, 59, and greater than 40 mm Hg, resulting in CPPs of 25, 3, 25, 56, and less than 50 mm Hg, respectively. Removing the bone flap as well as opening the dura and removing the blood clot produced a significant decrease in ICP and an increase in CPP. Jugular venous oxygen saturation (SjvO2) increased in four patients and decreased in the other during removal of the hematoma. Laser Doppler flow also increased, to 217% and 211% compared with preevacuation flow. CONCLUSIONS: Intracranial pressure is higher than previously suspected and CPP is very low in patients with ASDH. Removal of the bone flap yielded a significant reduction in ICP, which was further decreased by opening the dura and evacuating the hematoma. The SjvO2 as well as laser Doppler flow increased in all patients but one immediately after removal of the hematoma.

Microsurgical anatomy of the Liliequist's membrane and surrounding neurovascular territories.

Since the original description by Liliequist only a few microanatomical studies of the Liliequist membrane have been performed. These studies contain some discrepancies in the description, boundaries, and attachments of the membrane. Using a surgical microscope the authors examined the microsurgical anatomy of Liliequist's membrane and surrounding neurovascular structures in twenty adult brains injected with silicone rubber, with special emphasis given to the analysis of controversial details. This description is intended as an aid for neurosurgeons performing neuroendoscopic procedures.

Spinal cord sarcoidosis: a diagnostic dilemma.

Sarcoidosis is a chronic disorder of unknown etiology characterized by the development of non-caseating granulomas with derangement of the normal tissue architecture. Compromise of the spinal cord is one of the rarest neurologic manifestations of the disease, which may be clinically and radiologically indistinguishable from a spinal cord malignant tumor. However, neurosarcoidosis can be treated with steroids. This study reviews the clinical, radiological, and pathological features of the sarcoid compromise of the spinal cord, emphasizing the difficulties commonly encountered in making a diagnosis.

Safety and feasibility of craniectomy with duraplasty as the initial surgical intervention for severe traumatic brain injury.

BACKGROUND: Decompressive craniectomy has historically served as a salvage procedure to control intracranial pressure after severe traumatic brain injury. We assessed the safety and feasibility of performing craniectomy as the initial surgical intervention. METHODS: Of 29 consecutive patients undergoing emergent decompression for severe traumatic brain injury with horizontal midline shift greater than explained by a removable hematoma, 17 had traditional craniotomy with or without brain resection and 12 underwent craniectomy. RESULTS: The craniectomy group had lower Glasgow Coma Scale scores at surgery (median, 4 vs. 7; p = 0.04) and more severe radiographic injuries (using specific measures). Mortality, Glasgow Outcome Scale scores, Functional Independence Measures, and length of stay in both the acute care setting and the rehabilitation phase were similar between the surgical groups. CONCLUSION: Despite more severe injury severity, patients undergoing initial craniectomy had outcomes similar to those undergoing traditional surgery. A randomized evaluation of the effect of early craniectomy on outcome is warranted.

Bedside invasive monitoring techniques in severe brain-injured patients.

In patients with severe brain injury, brain edema, elevated intracranial pressure, and cerebral ischemia are accountable for a significant morbidity and mortality. New invasive methods of monitoring attempt to foresee the physiopathological mechanisms responsible for the production of secondary brain injuries. The available methods for monitoring severely brain-injured patients, their potential usefulness, advantages, and disadvantages are reviewed.

Spontaneous resolution of a syrinx.

Syrinx are often related to trauma, tumours or abnormalities of the craniocervical junction. Only a few cases of spontaneous resolution have been reported in the literature. The authors present a case of spontaneous resolution of a cervical syrinx, and analyse the possible physiopathological mechanisms leading to resolution. Other similar cases reported in the literature were collected and analysed.

Impaired cerebral mitochondrial function after traumatic brain injury in humans.

OBJECT: Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported. METHODS: Using tissue fractionation procedures, living mitochondria derived from therapeutically removed brain tissue were analyzed in 16 patients with head injury (Glasgow Coma Scale Scores 3-14) and two patients without head injury. Results revealed that in head-injured patients mitochondrial function was impaired, with subsequent decreased ATP production. CONCLUSIONS: Decreased oxygen metabolism due to mitochondrial dysfunction must be taken into account when clinically defining ischemia and interpreting oxygen measurements such as jugular venous oxygen saturation, arteriovenous difference in oxygen content, direct tissue oxygen tension, and cerebral blood oxygen content determined using near-infrared spectroscopy. Restoring mitochondrial function might be as important as maintaining oxygen delivery.

Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury.

OBJECT: Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction. Because mitochondrial dysfunction is easy to assess compared with neurobehavioral endpoints, it might prove useful as an outcome measure to establish therapeutic time windows and dose-response curves in preclinical drug testing. This idea was tested in a model of TBI in rats. METHODS: Animals treated with the selective N-type voltage-sensitive calcium channel blocker Ziconotide (also known as SNX-111 and CI-1009) after cortical impact displayed significant improvement in brain mitochondrial function. When a single intravenous bolus injection of 4 mg/kg Ziconotide was given at different time intervals, ranging from 15 minutes before injury to 10 hours after injury, mitochondrial function was improved at all time points, but more so between 2 and 6 hours postinjury. The authors evaluated the effects on mitochondrial function of Ziconotide at different doses by administering 0.5 to 6 mg/kg as a single bolus injection 4 hours after injury, and found 4 mg/kg to be the optimum dose. CONCLUSIONS: The authors established these time-window profiles and dose-response curves on the basis of mitochondrial outcome measures in a total of 42 rats because there were such low standard deviations in these tests. Establishing similar time-window profiles and dose-response curves by using neurobehavioral endpoints would have required using 114 rats in much more elaborate experiments.