Permutation entropy and irreversibility in gait kinematic time series from patients with mild cognitive decline and early alzheimer’s dementia

Gait is a basic cognitive purposeful action that has been shown to be altered in late stages of neurodegenerative dementias. Nevertheless, alterations are less clear in mild forms of dementia, and the potential use of gait analysis as a biomarker of initial cognitive decline has hitherto mostly been neglected. Herein, we report the results of a study of gait kinematic time series for two groups of patients (mild cognitive impairment and mild Alzheimer’s disease) and a group of matched control subjects. Two metrics based on permutation patterns are considered, respectively measuring the complexity and irreversibility of the time series. Results indicate that kinematic disorganisation is present in early phases of cognitive impairment; in addition, they depict a rich scenario, in which some joint movements display an increased complexity and irreversibility, while others a marked decrease. Beyond their potential use as biomarkers, complexity and irreversibility metrics can open a new door to the understanding of the role of the nervous system in gait, as well as its adaptation and compensatory mechanismsThis research was funded through the Premio del Ilustre Colegio Profesional de Fisioterapeutas de la Comunidad De Madrid, prize number ICPFM-IX-201

Multiple cycles of dose-intensive chemotherapy with repeated stem cell support as induction treatment in metastatic breast cancer: a feasibility study

The purpose of this trial was to study feasibility and tolerance of a dose-intensive multicyclic alternating induction chemotherapy with repeated stem cell support in a series of 43 metastatic breast cancer patients. Anthracycline-naive patients (n = 21) received cyclophosphamide 2.5 g/m2 plus doxorubicin 80 mg/m2 alternating every 14 days with paclitaxel 200-350 mg/m2 plus cisplatin 120 mg/m2. Patients who had previously received anthracyclines (n = 22) received cisplatin 120 mg/m2 plus etoposide 600 mg/m2 alternating with paclitaxel 200-350 mg/m2 plus ifosfamide 8 g/m2. Peripheral blood stem cells were infused after every course except the first, with a median CD34+ dose of 2.1 ´ 106/kg per cycle. Positive selection of CD34+ cells was performed in good mobilizers. The median number of cycles administered was six (4-8), and the time interval between them was 17 days. Median summation dose intensities (SDI) actually administered for the CA-TP and PE-TI protocol were 4.95 and 4.69, respectively (87% of scheduled SDI). There were 15 complete (35%) and 21 partial responses (49%), for an overall response rate of 84% (95% CI, 73%-95%). Infection or neutropenic fever occurred in 50% of the cycles. There was one treatment-related death. After a median follow-up of 26 months, the median event-free-survival was 12 months (95% CI: 10-14) and overall survival was 31 months. These high dose-intensity induction treatments seem to be feasible with sequential stem cell support

Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis

Purpose and Experimental Design: The stem cell factor/ KIT receptor loop may represent a novel target for molecular- based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines. Results: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWSFLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5–20 M) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC50, 12–15 M). However, imatinib administered alone at doses close to IC50 for growth inhibition (10 M) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 M) was able to increase the antitumor in vitro effect of doxorubicin (DXR)and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15–20 and 15–36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs. Conclusions: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor

Acquired potential N-glycosylation sites within the tumor-specific immunoglobulin heavy chains of B-cell malignancies

Background and Objectives. Among B-cell malignancies, follicular lymphomas (FL) more frequently show acquired, potential N-glycosylation sites (AGS) within tumor-specific immunoglobulin. The aim of this study was to extend this observation and to evaluate the pattern of presentation of AGS within five different forms of B-cell lymphoma. Design and Methods. We sequenced the tumor-specific immunoglobulin heavy chain variable region fragment, including complementarity-determining regions 2 and 3, of forty-seven consecutive patients with a B-cell malignancy enrolled in idiotype vaccine clinical trials. This sequencing approach is known to allow the identification of most AGS. We then statistically analyzed differences in presentation pattern, in terms of tumor histology, immunoglobulin isotype, AGS location and amino acid composition. Results. All twenty-four FL cases presented with at least one AGS, whereas the vast majority of four B-cell lymphoma types other than FL did not. The non- FL group of tumors included four cases of Burkitt’s lymphoma, six of diffuse large cell lymphoma, seven mantle cell lymphomas and six small lymphocytic lymphomas. Most IgM-bearing follicular lymphoma cases featured their AGS within complementarity-determining region 2, as opposed to those bearing an IgG, which mostly displayed the AGS within complementarity- determining region 3. The vast majority of AGS located within either complementarity- determining region ended with a serine residue, whereas those located within framework regions mostly featured threonine as the last amino acid residue. Interpretation and Conclusions. In our series, all cases of FL had AGS within their tumor-specific immunoglobulin heavy chain variable regions. In contrast, most B-cell malignancies other than FL did not. Further studies are warranted in order to establish the possible meaning of these findings in terms of disease pathogenesis, their diagnostic value in doubtful cases and their potential implications for immunotherapy

Radioterapia en cáncer de recto localmente avanzado: situación actual y desarrollo terapéutico

La radioterapia es uno de los elementos integrantes del tratamiento radical del cáncer de recto localmente avanzado. La radioterapia preoperatoria y la radioterapia postoperatoria en combinación con quimioterapia han demostrado aumento del control local y la supervivencia. La tendencia actual es el uso de quimioirradiación preoperatoria por su mejor tolerancia y porque a los beneficios en control local y supervivencia se le podrían añadir los de mayor tasa de respuesta (downstaging) y un aumento de cirugía preservadora del esfínter anal. El desarrollo terapéutico en cáncer de recto localmente avanzado se sitúa en conseguir una mayor intensificación terapéutica sobre el tumor y las regiones de riesgo de recidiva sin aumentar la toxicidad sobre los tejidos sanos: esquemas de radioterapia con fraccionamientos modificados, radioterapia intraoperatoria, radioterapia con intensidad modulada de dosis, nuevos agentes quimioterápicos en combinación con radioterapia. En el presente artículo se revisan los datos más relevantes de esta modalidad terapéutica.Radiotherapy is one of the integral elements of the radical treatment of locally advanced rectal cancer. Combined chemotherapy and postoperative radiotherapy or preoperative radiotherapy has demonstrated an increase in local control and survival. The present trend is the use of preoperative chemoradiotherapy: this scheme seems to have a better tolerance and downstaging with an increase in sphincter-preserving surgery rates. Current therapeutic development in locally advanced rectal cancer focuses on obtaining a greater therapeutic ratio: with modified fractionation, intraoperative radiation therapy, intensity modulated radiation therapy, new chemoradiation regimens. The present work reviews the state of the art and the most significant advances in radiation in rectal cancer

Comparison of unidimensional and bidimensional measurements in metastatic non-small cell lung cancer

Tumour response evaluation after chemotherapy has become crucial in the development of many drugs. In contrast to the standard bidimensional WHO criteria, the recently described Response Evaluation Criteria In Solid Tumors are based on unidimensional measurements. The aim of the present study was to compare both methods in patients with metastatic non-small cell lung cancer. One hundred and sixty-four patients treated with two cisplatin-paclitaxel-based chemotherapy schedules between June 1994 and December 2000 were analysed. The measurements were reviewed by an independent panel of radiologists. Patient characteristics were: median age of 55 years (range 24–77 years) and a male to female ratio of 129 : 35. Adenocarcinoma and squamous carcinoma were the most common histologies. Vinorelbine was the third drug used in 77 patients and gemcitabine in 87. The ratio unidimensional/bidimensional was as follows: response 85 : 85; stable disease 32 : 32; progression 47 : 42 and not assessable 0 : 5. Kappa for agreement between responders was 0.951 (95% CI: 0.795–1.0) (P<0.001). Both WHO criteria and Response Evaluation Criteria In Solid Tumors give similar results in assessing tumour response in patients with non-small cell lung cancer after chemotherapy. The unidimensional measurement could replace the more complex bidimensional one

Carcinoma microcítico de pulmón

El cáncer microcítico de pulmón es uno de los tumores sólidos más agresivos, por su rápido crecimiento y por su tendencia a metastatizar desde fases tempranas. Sin embargo, también es uno de los tumores más sensibles a los tratamientos de quimioterapia y radioterapia, con los cuales algunos pacientes con enfermedad limitada pueden sobre- vivir a largo plazo. Estas características han hecho de este tumor un modelo clínico sobre el cual se han probado múltiples estrategias de tratamiento, incluyendo tratamientos concomitantes con quimioterapia y radioterapia, esquemas de quimioterapia alternante o de altas dosis con soporte hematológico o la utilización de radioterapia holocraneal profi láctica. Además en los últimos años el cáncer microcítico de pulmón también se ha empleado como plataforma de desarrollo de tratamientos dirigidos contra dianas específi cas o de inmunoterapia. INGLÉS: Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of whole-brain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches

Farmacogenómica en el cáncer colorrectal

La investigación en el proyecto genoma humano va a favorecer en los próximos años el desarrollo farmacoterapias más personalizadas. La Farmacogenómica es una nueva disciplina que se ha desarrollado en los últimos años y cuyos objetivos se dirigen a conocer aquellos mecanismos que permitan explicar cómo la base genética de cada individuo afecta a la respuesta obtenida a las drogas. La posibilidad de predecir qué terapias son más efectivas para un determinado paciente va a constituir una poderosa herramienta médica, particularmente en el ámbito de la oncología. Es probable que estas predic- ciones deriven de una mejor comprensión de la enfermedad tanto a nivel celular como molecular. Por lo que respecta al cáncer colorrectal, los avances en el conocimiento de la etiología de la enfermedad a nivel molecular no se han asociado con una mejora en el tratamiento del paciente. La eficacia clínica y la toxicidad de las drogas más utilizadas en el tratamiento del cáncer colorrectal de cada paciente son por el momento impredecibles. Entre otras muchas variables, se han descrito determinados polimorfismos en genes implicados en el metabolismo de estas drogas que determinan la variabilidad interindividual tanto en la eficacia terapeútica como en la toxicidad. La investigación de las características moleculares del cáncer colorrectal y el desarrollo de nuevas terapias dirigidas a dianas específicas van a permitir en el futuro predecir la respuesta de la neoplasia y, por tanto, modificar la opción terapeútica buscando aquella que mejor se ajuste al perfil biológico.Advances in human genome research will make it possible to personalize pharmacotherapy. Pharmacogenomics has been defined as the study of mechanisms that explain how an individual's genetic inheritance affects the response to drugs. The ability to predict which therapies are most likely to be effective for certain patients would constitute a powerful medical tool, particularly in oncology. Such predictions would be likely to arise from an understanding of the disease on the cellular and molecular level. For colorectal cancer, our increased knowledge of the molecular etiology of the disease has not yet been paralleled by an improvement in patient care. Clinical efficacy and also toxicity of a given chemotherapy are still largely unpredictable for the individual patient. Amongst other variables, genetic polymorphisms determine the interindividual heterogeneity in both toxicity and therapeutic efficacy. Due to the better molecular characterization of colorectal cancer and the development of new target-directed therapies, it should be possible to predict which therapeutic interventions will have a high likelihood of success for an individual patient

Nonreferral of possible soft tissue sarcomas in adults: a dangerous omission in policy

Introduction. The aim of this study is to compare outcomes in three groups of STS patients treated in our specialist centre: patients referred immediately after an inadequate initial treatment, patients referred after a local recurrence, and patients referred directly, prior to any treatment. Patients and methods. We reviewed all our nonmetastatic extremity-STS patients with a minimum follow-up of 2 years. We compared three patient groups: those referred directly to our centre (group A), those referred after an inadequate initial excision (group B), and patients with local recurrence (group C). Results. The study included 174 patients. Disease-free survival was 73%, 76%, and 28% in groups A, B, and C, respectively (P < .001). Depth, size, and histologic grade influenced the outcome in groups A and B, but not in C. Conclusion. Initial wide surgical treatment is the main factor that determines local control, being even more important than the known intrinsic prognostic factors of tumour size, depth, and histologic grade. The influence on outcome of initial wide local excision (WLE), which is made possible by referral to a specialist centre, is paramount