Phase I and pharmacological trial of lapatinib in combination with gemcitabine in patients with advanced breast cancer.

BACKGROUND: Lapatinib has proven efficacy as monotherapy and in combination with capecitabine in patients with metastatic breast cancer (MBC) overexpressing HER2 and/or EGFR. Gemcitabine also has anti-tumor activity in MBC and a favourable toxicity profile. In this phase I study lapatinib and gemcitabine were combined. METHODS: Female patients with advanced BC were given lapatinib once daily (QD) in 28-day cycles with gemcitabine administered on day 1, 8 and 15. Physical examinations, vital signs and blood sampling for hematology, clinical chemistry and pharmacokinetics (PK) and radiological assessments of disease were performed at regular intervals. RESULTS: In total, 33 patients were included. Six dose-limiting toxicities were observed, mostly grade 3 increases in liver function tests. Most common toxicities were fatigue (73%), nausea (70%), diarrhea (58%), increases in ALAT and ASAT (55 and 52%, respectively) and rash (46%). The maximum tolerated dose was lapatinib 1250 mg QD with gemcitabine 1000 mg/m(2). Lapatinib and gemcitabine PK did not appear to be influenced by each other. Anti-tumor activity was observed with one patient (4%) showing complete response and six (23%) partial response. CONCLUSION: Despite a slightly increased toxicity profile compared to their respective monotherapies, lapatinib and gemcitabine can be safely combined while showing signs of anti-tumor activity.

Relación entre puntaje de prueba de selección universitaria y nota enseñanza media, y el rendimiento académico de la asignatura de morfología en alumnos de primer año de odontología de la Universidad de los Andes / Relationship between university selection test scores, high school grade point average (GPA) and academic performance in the subject of morphology in dentistry freshmen at the Universidad de los Andes

El estudio de predictores de rendimiento académico presenta gran relevancia en el área de la salud. El objetivo de este trabajo fue evaluar la relación entre el puntaje de Prueba de Selección Universitaria (PSU) y notas de enseñanza media (puntaje nota de enseñanza media) en la asignatura de Morfología en alumnos de primer año de odontología, en la Universidad de los Andes. Estudio descriptivo con 312 estudiantes admitidos en el primer año de la carrera de odontología de la Universidad de los Andes de Chile, de forma regular y que terminaron el año universitario sin deserción los años 2005 a 2008 y 2010. Las variables estudiadas fueron género, promedio puntaje de notas de enseñanza media, puntaje PSU, tipo de colegio de procedencia según sistema de financiamiento (municipal, particular subvencionado y particular) y nota final de la asignatura de morfología de los alumnos del primer año de estudio, en la carrera de odontología. De los 312 alumnos, la mediana de PSU, notas de enseñanza media y nota de morfología fueron 692,6, 702 y 4,4 respectivamente. Del total de la muestra, 221 alumnos (71%) correspondieron al sexo femenino. Del total de la muestra, 290 alumnos (93%) provenían de colegios particulares, 15 alumnos (5%) de colegios particulares subvencionados y 6 alumnos (2%) de colegios municipales. La relación entre puntaje nota de enseñanza media y nota de morfología muestra una correlación de 0,35 (Rho de Spearman, valor-p <0,0001), y puntaje de PSU con nota de Morfología una correlación de 0,39 (Rho de Spearman, valor-p <0,0001). Existe asociación entre nota morfología, puntaje de notas de enseñanza media y PSU, de tal manera, que los mejores puntajes de nota de enseñanza media y PSU, muestran mejor rendimiento en la asignatura de morfología.

The study of predictors of academic performance is of great importance in the area of health. The objective of this study was to assess the relationship between PSU (University selection admission scores) and Secondary Education (High school grade point average score) in the freshmen morphology course in dentistry, at the Universidad de los Andes. A descriptive study of 312 students admitted to the first year of dental school at the Universidad de los Andes in Chile, on a regular basis and who have completed the academic year without dropping out, the years 2005-2008 and 2010. The variables studied were sex, grade point average in high school, PSU score, type of school of origin as financing system (municipal, private subsidized and private) and final grade received in morphology for dentistry students during their freshmen year. Of the 312 students, the median PSU, high school grades and morphology were as follows: 692.6, grade 702, and 4.4 respectively. Of the total sample, 221 students (71%) were female. Of the total sample, 290 students (93%) had attended private schools, 15 students (5%) private subsidized schools and 6 students (2%) municipal schools. The relationship between scores and high school grade point average and grade attained in the morphology course, shows a correlation of 0.35 (Spearman rho, p-value <0.0001) and PSU score with the morphology course grade, a correlation of 0.39 (Spearman rho, p-value <0.0001). There is a relationship between morphology grade scores, high school grades and university selection test scores, indicating that the best high school grades and university selection scores show better student performance in the subject of morphology.

Current approaches, challenges and future directions for monitoring treatment response in prostate cancer.

Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm in men in the United States and the second leading cause of cancer mortality. One in 7 men will be diagnosed with prostate cancer during their lifetime. As a result, monitoring treatment response is of vital importance. The cornerstone of current approaches in monitoring treatment response remains the prostate-specific antigen (PSA). However, with the limitations of PSA come challenges in our ability to monitor treatment success. Defining PSA response is different depending on the individual treatment rendered potentially making it difficult for those not trained in urologic oncology to understand. Furthermore, standard treatment response criteria do not apply to prostate cancer further complicating the issue of treatment response. Historically, prostate cancer has been difficult to image and no single modality has been consistently relied upon to measure treatment response. However, with newer imaging modalities and advances in our understanding and utilization of specific biomarkers, the future for monitoring treatment response in prostate cancer looks bright.

Metabolic efficiency of volitional and electrically stimulated cycling in able-bodied subjects.

This study compared the metabolic efficiency of volitional cycling and functional-electrical-stimulation (FES) cycling within a subject group of able-bodied individuals, with a view to further elucidating the mechanisms underlying the low efficiency of FES cycling. Previous studies estimated the metabolic efficiency of volitional cycling and anaesthetised FES cycling in able-bodied subjects, and of FES cycling in subjects paralysed by spinal cord injury. The rationale for the experimental model chosen here, i.e. non-anaesthetised able-bodied subjects, was that this lies between normal cycling and paralysed cycling: while using FES, this group has artificial muscle activation and timing like the paralysed group; but it does not have disrupted sensory feedback and vasomotor control; this measurement therefore allows delineation of the magnitude of reduction in metabolic efficiency resulting from: (i) the FES itself and (ii) paralysis (where there is disrupted sensory feedback and vasomotor control). Furthermore, we used the same methods employed previously for estimation of metabolic efficiency in subjects with motor- and sensory-complete paraplegia. The mean metabolic efficiency of volitional cycling was found to be 29.8% and that of FES cycling was 16.4% (n=11). The low efficiency of FES cycling can be explained in large part by the crude timing of muscle activation and by non-physiological muscle fibre recruitment. In FES cycling with paralysed subjects, disrupted sensory feedback and vasomotor control may play a further, albeit smaller, role in the reduced efficiency.

On the efficiency of FES cycling: a framework and systematic review.

Research and development in the art of cycling using functional electrical stimulation (FES) of the paralysed leg muscles has been going on for around thirty years. A range of physiological benefits has been observed in clinical studies but an outstanding problem with FES-cycling is that efficiency and power output are very low. The present work had the following aims: (i) to provide a tutorial introduction to a novel framework and methods of estimation of metabolic efficiency using example data sets, and to propose benchmark measures for evaluating FES-cycling performance; (ii) to systematically review the literature pertaining specifically to the metabolic efficiency of FES-cycling, to analyse the observations and possible explanations for the low efficiency, and to pose hypotheses for future studies which aim to improve performance. We recommend the following as benchmark measures for assessment of the performance of FES-cycling: (i) total work efficiency, delta efficiency and stimulation cost; (ii) we recommend, further, that these benchmark measures be complemented by mechanical measures of maximum power output, sustainable steady-state power output and endurance. Performance assessments should be carried out at a well-defined operating point, i.e. under conditions of well controlled work rate and cadence, because these variables have a strong effect on energy expenditure. Future work should focus on the two main factors which affect FES-cycling performance, namely: (i) unfavourable biomechanics, i.e. crude recruitment of muscle groups, non-optimal timing of muscle activation, and lack of synergistic and antagonistic joint control; (ii) non-physiological recruitment of muscle fibres, i.e. mixed recruitment of fibres of different type and deterministic constant-frequency stimulation. We hypothesise that the following areas may bring better FES-cycling performance: (i) study of alternative stimulation strategies for muscle activation including irregular stimulation patterns (e.g. doublets, triplets, stochastic patterns) and variable frequency stimulation trains, where it appears that increasing frequency over time may be profitable; (ii) study of better timing parameters for the stimulated muscle groups, and addition of more muscle groups: this path may be approached using EMG studies and constrained numerical optimisation employing dynamic models; (iii) development of optimal stimulation protocols for muscle reconditioning and FES-cycle training.

Quality of life after severe hand injury.

This study explores the quality of life in 118 patients following severe and major hand injury with a Hand Injury Severity Score >50. Each patient answered five different validated outcome measures (DASH (Disability of the Arm, Shoulder, and Hand), FLZ(M) ('Fragen zur Lebenszufriedenheit'), HADS (Hospital Anxiety and Depression Score), BDDE-SR (Body Dysmorphic Disorder Examination-Self Report) and FBeK ('Fragebogen zur Beurteilung des eigenen Körpers'), which were incorporated into a single questionnaire. Each of these questionnaires covered one or more of the established quality-of-life domains. Patients with pain and pressure sensations were significantly less satisfied in life, showed lower levels of health satisfaction, had higher levels of anxiety and depression and showed higher body dysmorphic disorder levels (all p < 0.001). General life satisfaction in this hand-injury study group is highly dependent on the patients` satisfaction with their health and appearance as well as self-confidence. The quality-of-life outcomes improve with time, and despite evidence of continued impairment in the injured hand, the majority of patients had a normal quality of life.

Use of the earlobe in auricular reconstruction post tumour extirpation.

The exact location and topography of defects resulting from surgical excision of cutaneous malignancies of the auricle demand a customized approach based on an awareness of locally redundant tissue. With advancing age, the earlobe becomes ideal for this reconstructive role and we describe an earlobe flap created along the longitudinal axis of lobular tissue. This reliable, simple, one-step procedure provides adequate tissue cover for defects of the antitragus and adjoining concha. Flap vascularity is satisfactory and although the overall size of the ear is reduced, this is accepted for a rejuvenated shape and minimal morbidity.

The psychological impact of severe hand injury.

The final outcome of severe hand injuries is not solely determined by the residual functional impairment, but is also a function of non-functional criteria, including the sequelae of the accompanying psychological trauma. This paper reviews the literature with respect to the psychological impact of severe hand injuries, including the special impact of amputations, adaptation processes, adaptation stages, prognostic criteria and aesthetic issues influencing the final individual outcome, including present recommendations for promoting a positive outcome. Motivated and psychologically stable people are reported to do well irrespective of the severity of a hand injury. In patients who find it difficult to cope mentally, successful treatment strategies have been proposed. Their implementation is in a constant state of evolution and includes not only improved surgical techniques and advanced pharmacological pain management but also early psychotherapeutic input and involvement of patients in decision making for treatment.

[The use of a foldable, iris-fixated, phakic intraocular lens for the correction of myopia]. / Implantation einer faltbaren, iris-fixierten, phaken Intraokularlinse für die Korrektur von Kurzsichtigkeit.

BACKGROUND: The aim of this study was to evaluate the predictability and visual outcome of a foldable silicone iris-fixated phakic intraocular lens (Artiflex, Ophtec) for the correction of moderate to high myopia. PATIENTS AND METHODS: A retrospective cohort study with 34 eyes of 20 patients was undertaken. All patients underwent similar lens implantation with iris enclavation. The follow-up was 6 months. RESULTS: At the final visit, 81% of eyes were within 0.5 D of the target spherical equivalent. Intraocular lenses with -12.0 to -14.5 D power showed a mean overcorrection of +0.81 D. The highest mean overcorrection of +1.45 D was shown by the Artiflex lenses with -14.5 D of power. The postoperative refraction remained stable, but the postoperative uncorrected and best-corrected visual acuity increased over time. 56% of eyes gained 1 or more Snellen lines of best-corrected visual acuity; one eye lost one line. No intraoperative complication was noticed. Two eyes showed prolonged intraocular inflammation. CONCLUSIONS: The implantation of the phakic Artiflex intraocular lens was safe and showed a good predictability and safety for the correction of moderate to high myopia. It is an efficient alternative for laser in-situ keratomileusis, especially in high myopia, leading to a stable refraction one month postoperatively.

[Balloon dilatation and Stentimplantation of the nasolacrimal duct for chronic epiphora]. / Minimal-invasive Therapie der Epiphora durch Ballonkatheterdilatation und Stentimplantation.

PURPOSE: To examine the clinical outcome of the ballon dilatation in stenosis and obstruction of the nasolacrimal duct. MATERIAL AND METHODS: 63 patients (69 nasolacrimal duct systems) with epiphora and proven obstruction of the nasolacrimal duct were treated with ballon dilatation, respectively Stentimplantation. In 55 cases there was a pre- or postsaccal stenosis, in 14 cases an occlusion of the nasolacrimal duct system. The diagnosis was established by dacryocystography. RESULTS: Technical success was obtained in 61 cases (n=50/55 stenosis; n=11/14 occlusions). Over a mean follow-up of 6 months patency of the nasolacrimal duct system was achieved in 83,6% (46/55) in stenosis. In occlusion the clinical outcome was 42,9% (6/14). CONCLUSION: Balloon dacryocystoplasty and Stentimplantation are minimal-invasive alternatives, performed in local anesthesia that recover the normal anatomy of the nasolacrimal duct system. They are a good alternative in the treatment of epiphora caused by nasolacrimal duct obstructions.

Routine histological examination of the mastectomy scar at the time of breast reconstruction: important oncological surveillance?

This retrospective study assesses whether the routine submission of mastectomy scars for histological examination at the time of delayed breast reconstruction is useful.

Characterization of the neurochemical content of neuronal populations of the lamina terminalis activated by acute hydromineral challenge.

The lamina terminalis (LT) contains three main regions, namely the subfornical organ (SFO), the median preoptic nucleus (MnPO) and the vascular organ of the LT (OVLT). Although LT is recognized of paramount importance in the regulation of hydromineral homeostasis, identity of the neurocircuits interconnecting the SFO and OVLT to the MnPO is not known. Furthermore, the phenotype of neuronal populations activated during acute hydromineral challenge is not yet determined. By using the high cellular resolution of the in situ hybridization histochemistry (ISHH), we investigated whether a furosemide-induced fluid and electrolyte depletion might modify both putative GABAergic and glutamatergic systems within the LT. We show that acute furosemide treatment (4 h) significantly reduced the expression of GAD67 mRNA, the active holoenzyme predictive of GABA synthesis, within the SFO. A strong tendency toward a reduction of GAD67 signal was also observed in the OVLT and MnPO. The hydromineral challenge did not alter the expression of GAD65 and type 2 vesicular glutamate transporter (vGlut2) mRNA in all the structures of the LT. Furosemide treatment was associated with a reduction in the population of GAD67-containing neurons in the periphery of the SFO and dorsal part of the MnPO. Contrastingly, GAD65-containing cells were shown to be increased in the OVLT and no change was observed for the vGlut2-containing neurons in the whole LT. By combining ISHH with immunohistochemistry (Fos immunoreactivity), we report that furosemide-induced water and sodium depletion did essentially recruit a glutamatergic network throughout the LT, although GABAergic neurons were specifically activated in the ring of the SFO and in the OVLT. The MnPO, the region of the LT that is considered as being an integrative area for sensory inputs arising from the SFO and OVLT, showed exclusive activation of excitatory neuronal populations. Taken together these results suggest that acute water and Na(+) depletion diminish the efficacy of the GABAergic system and mainly activates excitatory neuronal pathways in the regions of the LT.

Paediatric friction hand injuries caused by domestic vacuum cleaners-a review from one unit.

The management of seven children with vacuum cleaner friction burns is described. Six of the children sustained full thickness burns. Four were treated operatively. Indications for surgery are outlined and important accident prevention strategies are highlighted.

Altered intracellular expression of the chemokines MIP-1alpha, MIP-1beta and IL-8 by peripheral blood CD4+ and CD8+ T cells in mild allergic asthma.

BACKGROUND: The ability of chemokines to regulate Th1 and Th2 responses suggests a role in the pathogenesis of atopic disorders such as allergic asthma where Th2 response dominance has been observed. Although the impact of allergic asthma on local chemokine production in the lung has been the subject of investigation, little is know about the influence of disease progression on peripheral chemokine production. We now report use of whole blood culture and flow cytometry to assess the influence of mild allergic asthma on peripheral T-cell chemokine expression. METHODS: Study participants included patients with mild allergic asthma (n = 7) and nonasthmatic controls (n = 7). Following in vitro stimulation of peripheral venous blood with phorbol 12-myristate acetate (PMA) and ionomycin, flow cytometry was used to estimate the percentage of CD4+ and CD8+ T cells producing a number of chemokines, including macrophage inflammatory proteins MIP-1alpha and MIP-1beta, RANTES (regulated on activation, T-cell expressed and secreted), monocytic chemotactic protein-1 (MCP)-1, and interleukin (IL)-8, or the cytokines interferon (IFN)-gamma and IL-4. Serum levels of MIP-1alpha, MIP-1beta, RANTES, MCP-1, IL-8, IFN-gamma and IL-4 were also assessed by quantitative ELISA. RESULTS: Intracellular expression of MIP-1beta by CD4+ and CD8+ T cells from allergic asthmatics was significantly reduced in comparison to that observed for nonasthmatics (median = 2.29% (1.75-3.50) vs 4.57% (3.38-6.64), P = 0.05; 14.20% (13.18-17.88) vs 44.10% (30.38-48.70), P = 0.01). Similarly, intracellular expression of MIP-1alpha by CD8+ T cells from allergic asthmatics was also significantly lower (3.67% (1.17-5.42) vs 17.10% (4.97-20.43), P = 0.05). Conversely, IL-8 expression by both CD4+ and CD8+ T cells from allergic asthmatics demonstrated significant enhancement (9.93% (7.77-11.28) vs 4.14% (3.61-7.11), P = 0.05; 8.40% (6.97-10.04) vs 4.98% (3.37-6.08), P = 0.05). Examination of intracellular IFN-gamma and IL-4 revealed no significant difference in the expression of either cytokine by CD4+ T-cells from allergic asthmatics and nonasthmatics. In contrast, expression of IFN-gamma was significantly reduced in CD8+ T-cells from allergic asthmatics (24.60% (21.08-32.50) vs 48.40% (41.50-55.28), P = 0.01). CONCLUSIONS: The occurrence in mild allergic asthma of peripheral T-cell chemokine expression suggestive of a diminished Th1 response, coinciding with marginal change in cytokine profiles indicative of a Th2 response bias, confirms the importance of chemokine involvement in the etiology of allergic asthma. The ability to use whole blood culture to estimate chemokine expression in T cell subsets may ultimately provide a practical means to evaluate disease status and to monitor early intervention therapies which target chemokines.

Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism.

In the vertebrate spinal cord, oligodendrocytes arise from the ventral part of the neuroepithelium, a region also known to generate somatic motoneurons. The emergence of oligodendrocytes, like that of motoneurons, depends on an inductive signal mediated by Sonic hedgehog. We have defined the precise timing of oligodendrocyte progenitor specification in the cervico-brachial spinal cord of the chick embryo. We show that ventral neuroepithelial explants, isolated at various development stages, are unable to generate oligodendrocytes in culture until E5 but become able to do so in an autonomous way from E5.5. This indicates that the induction of oligodendrocyte precursors is a late event that occurs between E5 and E5.5, precisely at the time when the ventral neuroepithelium stops producing somatic motoneurons. Analysis of the spatial restriction of oligodendrocyte progenitors, evidenced by their expression of O4 or PDGFR(&agr;), indicate that they always lie within the most ventral Nkx2.2-expressing domain of the neuroepithelium, and not in the adjacent domain characterized by Pax6 expression from which somatic motoneurons emerge. We then confirm that Shh is necessary between E5 and E5.5 to specify oligodendrocyte precursors but is no longer required beyond this stage to maintain ongoing oligodendrocyte production. Furthermore, Shh is sufficient to induce oligodendrocyte formation from ventral neuroepithelial explants dissected at E5. Newly induced oligodendrocytes expressed Nkx2.2 but not Pax6, correlating with the in vivo observation. Altogether, our results show that, in the chick spinal cord, oligodendrocytes originate from Nkx2.2-expressing progenitors.

Mental stress increases right heart afterload in severe pulmonary hypertension.

Little is known about mental stress effects on the pulmonary circulation in health and disease. The current study was conducted to investigate whether pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) would further increase during standardized mental stress testing in patients with severe pulmonary hypertension. The study was a prospective analysis of seven patients (average age: 40 years, range from 21 to 56 years) with severe pulmonary hypertension (primary: n = 4, secondary forms: n = 3; resting mean pulmonary artery pressure ranged between 48 and 65 mmHg). Right heart catheterization for the determination of PAP, pulmonary capillary wedge pressure (PCW) and cardiac output (CO) was clinically indicated (diagnostic workup, acute drug testing). Patients accomplished a standardized 10 min mental stress test (computer based, adaptive complex reaction-time task). Pulmonary haemodynamics during stress were compared to resting baseline. During mental stress mean PAP (+/- SEM) increased by 9.4 +/- 2.1 mmHg (P < 0.005). Pulmonary vascular resistance increased by 149 +/- 25 dyne s cm-5 (P < 0.001). Stroke volume decreased by 6.6 +/- 2.2 ml (P < 0.03). The data show that moderate mental stress increases right heart afterload in patients with severe pulmonary hypertension owing to elevation of PVR.

[Delay of the diagnosis of an amelanotic malignant melanoma due to CO2-laser treatment--case report and discussion]. / Diagnoseverzögerung bei einem amelanotischen Melanom durch CO2-Laserung. Fallbericht und Diskussion.

The incidence of malignant melanoma is steadily increasing. The best prognostic indicator of melanoma is the vertical tumor thickness. Early recognition of melanoma by the naked eye is often difficult, because many lesions simulate its clinical presentation. We report on a 47-year-old man with a red papular skin lesion treated by CO2 laser. The histological diagnosis of an amelanotic malignant melanoma was thus delayed for one year. Clinically ambiguous skin tumors should never be treated by laser prior to a diagnostic biopsy.