A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.

PURPOSE: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. MATERIALS AND METHODS: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. RESULTS: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). CONCLUSION: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

Mastocitosis cutánea: tres manifestaciones clínicas diferentes / Cutaneous mastocytosis: three different clinical manifestations

La mastocitosis cutánea es una enfermedad heterogénea, caracterizada por el infiltrado de mastocitos en la piel. Puede iniciarse en la infancia o en la edad adulta, con distintas manifestaciones clínicas y evolución. Las formas pediátricas generalmente se inician en los primeros 2 años de vida, afectan exclusivamente a la piel y su curso clínico es variable con tendencia a la desaparición en la edad adulta. Se exponen 3 casos de mastocitosis cutánea con diferentes formas de presentación clínica

Cutaneous mastocytosis is a heterogeneous disease characterized by the accumulation of mast cells in the skin. It can start in paediatric or adult age, with different clinical manifestations and disease course. The childhood-onset mastocytosis usually starts before the age of two, it affects only the skin and it has a variable course tending to dissapear in the adult age. This article presents 3 cases of cutaneous mastocytosis with different forms of clinical presentation

New clinical trials regulation in Spain: analysis of royal decree 1090/2015.

The coming into force of Directive 2001/20/EC represented a step forward in harmonising clinical trial regulation in European countries, guaranteeing a uniform protection of subjects participating in clinical research across Europe. However, it led to a disproportionate increase in the bureaucratization, and thus, it became evident that procedures needed to be simplified without detriment to patient's safety. Thus, Regulation 536/2014, that repealed Directive 2001/20/EC, with the aim of decreasing the growing bureaucratization and stimulating clinical research in Europe, established simplified procedures, such as regulating a common procedure for authorising trials in Europe, the institution of strict assessment timelines, or the definition of new concepts, such as "low-intervention clinical trial". The legal form of a Regulation allowed the norm to be directly applied to Member States without the need for transposition. By means of the new Royal Decree, the national legislation is adapted to make the application of the regulation feasible and it allows the development of the aspects that the Regulation leaves to national legislation. Both documents seek to stimulate clinical research with medicinal products to foster knowledge, facilitate transparency, and reinforce subjects' safety. This will surely be the case, but with this revision, we will look at the novelties and key aspects that are most relevant to investigators and we will analyse the consequences for all parties involved in clinical research.

Control and automation of the Pegasus multi-point Thomson scattering system.

A new control system for the Pegasus Thomson scattering diagnostic has recently been deployed to automate the laser operation, data collection process, and interface with the system-wide Pegasus control code. Automation has been extended to areas outside of data collection, such as manipulation of beamline cameras and remotely controlled turning mirror actuators to enable intra-shot beam alignment. Additionally, the system has been upgraded with a set of fast (∼1 ms) mechanical shutters to mitigate contamination from background light. Modification and automation of the Thomson system have improved both data quality and diagnostic reliability.

A novel, cost-effective, multi-point Thomson scattering system on the Pegasus Toroidal Experiment (invited).

A novel, cost-effective, multi-point Thomson scattering system has been designed, implemented, and operated on the Pegasus Toroidal Experiment. Leveraging advances in Nd:YAG lasers, high-efficiency volume phase holographic transmission gratings, and increased quantum-efficiency Generation 3 image-intensified charge coupled device (ICCD) cameras, the system provides Thomson spectra at eight spatial locations for a single grating/camera pair. The on-board digitization of the ICCD camera enables easy modular expansion, evidenced by recent extension from 4 to 12 plasma/background spatial location pairs. Stray light is rejected using time-of-flight methods suited to gated ICCDs, and background light is blocked during detector readout by a fast shutter. This ∼103 reduction in background light enables further expansion to up to 24 spatial locations. The implementation now provides single-shot Te(R) for ne > 5 × 1018 m-3.

Diagnóstico y tratamiento del dolor irruptivo oncológico: recomendaciones de consenso / Diagnosis and treatment of breakthrought pain: consensus document

Introducción y objetivos: el dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los distintos especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de cuatro sociedades científicas implicadas en el manejo del paciente oncológico handiseñado este documento. Métodos: tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan® en la que se debatieron las recomendaciones que incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: el manejo del DIO requiere una anamnesis completa tanto del DIO como del dolor basal y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio, de efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO (AU)

Introduction and objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved in its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publicationsin BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology -a structured brainstorming technique- that produced a first version of theConsensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish IntercollegiateGuidelines Network) system. Results: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain. Conclusion: This Consensus can be a very useful tool to improve the quality of life in cancer patients, because it guidesthe clinician towards a better diagnose and treatment of BTcP (AU)

Diagnóstico y tratamiento del dolor irruptivo oncológico: recomendaciones de consenso / No disponible

Introducción y objetivos: El dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los diferentes especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de 4 sociedades científicas implicadas en el manejo del paciente oncológico, han diseñado este documento de consenso. Métodos: Tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO, se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan®, donde se debatieron las recomendaciones a incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: El manejo del DIO requiere de una anamnesis completa, tanto del DIO como del dolor basal, y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio de acción, efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: Este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO (AU)

Introduction objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved n its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publications in BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology –a structured brainstorming technique– that produced a first version of the Consensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish Intercollegiate Guidelines Network) system. Outcomes: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain (AU)

Professional survey on knowledge and clinical patterns of pain management in Spanish medical oncology

Cancer pain is still not treated adequately. The barriers impeding its appropriate treatment include lack of knowledge, erroneous beliefs and inappropriate attitudes with regard to pain, which are sustained by some or all of those involved in the problem. The present study shows the results of an exploratory survey using a large sample of specialists in clinical oncology. Its main objective is to evaluate daily analgesic practices and compliance with clinical guidelines in order to identify areas that should be improved in this particular therapeutic field. Information collection from the responders was in the form of a self-administered written questionnaire, structured in three thematic areas: clinical patterns and resources used in pain treatment in clinical practice, pain and pain-relief therapy, and theoretical knowledge and decision-making in clinical practice. The study identified those skills that most need improvement in the treatment of pain (scientific and technical knowledge and clinical decision-making capacity of professionals) in order to reduce the unjustified variability in current clinical practice (AU)

A reconfigurable, wearable, wireless ECG system.

New emerging concepts as "wireless hospital", "mobile healthcare" or "wearable telemonitoring" require the development of bio-signal acquisition devices to be easily integrated into the clinical routine. In this work, we present a new system for Electrocardiogram (ECG) acquisition and its processing, with wireless transmission on demand (either the complete ECG or only one alarm message, just in case a pathological heart rate detected). Size and power consumption are optimized in order to provide mobility and comfort to the patient. We have designed a modular hardware system and an autonomous platform based on a Field-Programmable Gate Array (FPGA) for developing and debugging. The modular approach allows to redesign the system in an easy way. Its adaptation to a new biomedical signal would only need small changes on it. The hardware system is composed of three layers that can be plugged/unplugged: communication layer, processing layer and sensor layer. In addition, we also present a general purpose end-user application developed for mobile phones or Personal Digital Assistant devices (PDAs).

Recommendation of the scientific societies on the treatment of anaemia in cancer patients.

At present, anaemia in the patients with cancer remains a problem of the first magnitude and of increasing interest due to the high incidence, the major knowledge of its physiopathology, the negative impact on the quality of life of the patient, the influence on the evolution of the disease and its treatments and, finally to the progressive development of new alternatives of treatment, especially the erythropoietic agents. For all this, it becomes necessary to consider the treatment of the anemia of the patients with cancer as a basic part of their support treatment. The erythropoietic agents have demonstrated in the last years that constitute a therapeutic alternative to obtain an increase of the levels of hemoglobin in the patients with anticancer treatments, considering specially that the correction of the anemia not only represents the improvement of an analytical value but also has a significant impact on the quality of life of the patients and diminishes the transfusion requirements. Erythropoietic proteins available for the treatment of the anemia of the patients with cancer are Epoetin-alpha, Epoetin-beta and Darbepoetin-alpha. The existence of different drugs, different doses and intervals of administration, clinical different situations and heterogeneous studies, made necessary the development of documents of consensus and guides of clinical recommendations which provide information on the scientific evidence that supports the use of these agents in medical care. This paper summarizes the main recommendations from panels of experts and scientific societies published so far.

Adjuvant endocrine therapies for premenopausal women.

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease- free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient.

Adjuvant endocrine therapies for premenopausal women

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease- free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient (AU)

Relación entre estrés oxidativo y ciclo celular en la etiología de la muerte neuronal en la enfermedad de Parkinson. Efectos de los antioxidantes / Oxidative stress and cell cycle in the ethiology of neuronal cell death in Parkinson disease

La enfermedad de Parkinson es un trastorno neurodegenerativo caracterizado por la pérdida progresiva de las neuronas dopaminérgicas de la Sustancia Negra. Recientes trabajos relacionan al estrés oxidativo, implicado en la etiología de esta patología, con una sobreexpresión en las neuronas de proteínas reguladoras del ciclo celular. Las células postmitóticas, en respuesta a esta sobreexpresión, mueren por apoptosis en lugar de progresar a través de un ciclo celular descoordinado y por ello fatal. En este trabajo hemos comprobado el efecto neuroprotector de la melatonina frente a la muerte inducida por las neurotoxinas catecolinérgicas, MPP+ y 6-0HDA, en dos líneas celulares dopaminérgicas diferenciadas (UR61 y PC12), observando una prevención de entre el 10-20% (p<0.05). Un efecto similar fue observado con el empleo de antioxidantes y de inhibidores del ciclo celular, por lo que la neuroprotección mostrada por la melatonina podría estar mediada tanto por su actividad antioxidante, como su capacidad para impedir la reentrada en el ciclo celular

Parkinson's disease is a neurodegenerative disorder that leads to a progressive death of dopaminergic neurons in the Substantia Nigra. The generation of reactive oxygen species is considered to be implicated in its etiology. Recent works connect oxidative stress with the overexpresion of cell cycle proteins in neurons. Postmitotic neurons, because of said overexpresion, undergo apoptosis instead of going through a deregulated, therefore fatal, cell cycle. Our work shows the neuroprotector etTect of melatonin against neuronal death induced by the catecolinergic toxins MPP+ and 6-0HDA on two ditTerentiated dopaminergic celllines (UR61 and PC12). Melatonin was able to reduce cell death over a 10-20% (p<0.05). Other antioxidants, as well as other cell cycle inhibitors tested, produced a similar effect. Thus, it appears that either melatonin antioxidant properties or cell cycle reentry inhibiting properties may mediate its neuroprotector effect

Adenocarcinoma de intestino delgado asociado con cáncer colorrectal: a propósito de dos casos / Small bowel adenocarcinoma associated with colorectal cancer: report of two cases

- Propósito: destacar el difícil manejo terapéutico de los tumores de intestino delgado y su poco frecuente asociación con el cáncer de colon.- Material y métodos: se presenta el caso de dos pacientes con un tumor de intestino delgado que también desarrollaron un cáncer de colon.- Conclusiones: la quimioterapia adyuvante en el cáncer de intestino delgado no está claramente establecida. La asociación de ambos tumores es poco frecuente y se desconocen los mecanismos genéticos (AU)

[Radiotherapy alone versus neo-adjuvant chemotherapy and irradiation in the treatment of carcinoma of the cavum]. / Radioterapia exclusiva frente a quimioterapia neoadyuvante más radioterapia en el tratamiento de los carcinomas de cávum.

Radiation therapy is the usual treatment for nasopharyngeal carcinoma. However, in recent years the use of neoadyuvant chemotherapy in the treatment of local and regionally advanced carcinoma has been investigated. We report the results of a retrospective study of two treatments used in our center. The study included 68 patients: 34 (group A) who received radiotherapy alone and 34 (group B) who received neoadyuvant chemotherapy before radiotherapy. In group A, 70.6% achieved a complete clinical response: 23.5% relapsed: 5 patients presented distant metastases. Survival rates at 5 and 10 years were 53% and 27% respectively; the disease-free survival was 71.4% at 5 years and 54% at 10 years. In group B, the complete clinical response rate to neoadyuvant chemotherapy was 35.3%, which increased to 73.5% when the treatment was complemented with radiotherapy. The relapse rate was 14.7%; the survival rates at 5 and 10 years were 49.5% and 49%, respectively; and the disease-free survival was 77.2% at 5 and 10 years.

[Importance of the early diagnosis of malignant neuroleptic syndrome: report of 2 cases]. / Importancia del diagnóstico precoz del síndrome neuroléptico maligno a propósito de dos casos.

Two cases of neuroleptic malignant syndrome presented in a psychiatry inpatient unit are commented, as well as their positive evolution.

Ultrastructural study of neuromuscular junction in rectus femoris muscle of streptozotocin-diabetic rats.

The neuromuscular junctions (NMJ) from rectus femoris muscle in streptozotocin (STZ)-induced diabetic rats were examined by electron microscopy eight weeks after the STZ injection. When compared to controls and vehicle-injected groups, both the axon terminal and the junctional sarcoplasm showed serious alterations including mitochondrial degeneration, presence of myeloid bodies, breakdown of presynaptic membrane and changes in the form of the synaptic vesicles. The results suggest that NMJ can contribute to the pathogenesis of diabetic proximal myopathy.

Proximal skeletal muscle alterations in streptozotocin-diabetic rats: a histochemical and morphometric analysis.

The response of rat quadriceps muscle fibers to chronic streptozotocin (STZ) diabetes was studied. Transverse sections of rectus femoris muscle from diabetic and weight-matched control rats were assayed for myofibrilar adenosine triphosphatase (ATPase) and nicotinamide adenine dinucleotide-tetrazolium reductase (NADH-TR). A quantitative analysis was carried out by an automatic interactive analysis system focused on the fiber type size and distribution. STZ-induced diabetes caused important effects in this muscle, with changes in the distribution of oxidative enzyme reactions, type I fiber hypertrophy, and type II fiber atrophy, which was greater in type IIB than in type IIA. It is concluded that hypoinsulinism produces morphological alterations in proximal skeletal muscle fibers that are similar to those of neurogenic myopathy. Thus the pathological changes in these mammalian muscle fibers could explain the clinical syndrome seen in diabetic patients called "diabetic symmetrical proximal motor neuropathy," perhaps the least understood of the major neuropathic complications of diabetes.

Morphological abnormalities in the sural nerve from patients with peripheral vascular disease.

The present paper has been written in order to determine the morphological alterations in the sural nerve from patients with chronic arteriosclerotic occlusive disease. Eight patients with Peripheral Vascular Disease (PVD) and six age-matched control subjects were studied. Morphometric data revealed two groups of patients, one of them with mild disease (n = 5), and the other one with severe damage (n = 3), consisting in loss of myelinated fibres and increase in the number of small fibres (p less than 0.05). Teased nerve fibres and electron microscopic studies also showed two types of patients, with respect to the myelin or the axonal alterations. The unmyelinated fibre population was affected equally in both groups. In conclusion, this study supports the idea that ischemia is able to cause structural alterations in the peripheral nerve, and that it can play a role in the development of neuropathy.