A phase I trial of LHC165 single agent and in combination with spartalizumab in patients with advanced solid malignancies.

BACKGROUND: LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors. MATERIALS AND METHODS: In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 µg biweekly through intratumoral (IT) injection and LHC165 600 µg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion. RESULTS: Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 µg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site. CONCLUSIONS: LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.

Efecto de inoculantes bacterianos edáficos mixtos en el desarrollo temprano de cultivares mejorados de cacao (Theobroma cacao L.) en un sistema agroforestal tradicional del norte de Oaxaca, México / Effect of mixed edaphic bacterial inoculants in the early development of improved cocoa cultivars (Theobroma cacao L.) in a traditional agroforestry system of Oaxaca, Mexico

El cacao (Theobroma cacao L.) es nativo de América del Sur y representa uno de los recursos «bioculturales¼ más significativos de Mesoamérica, ya que es una región donde se domesticó y tuvo relevancia como bebida ritual y como moneda en muchas culturas prehispánicas hasta la llegada de los españoles, quienes difundieron su uso en el mundo y lo convirtieron en una de las mercancías «commodity¼ más consumidas. Mediante este trabajo se propone una alternativa para atender la problemática de las plantaciones a través de la introducción de una diversidad amplia de cultivares de cacao en sistemas agroforestales tradicionales, en sinergia con la inoculación de bacterias edáficas fijadoras de nitrógeno y solubilizadoras de fósforo insoluble. En una parcela agroforestal tradicional se introdujeron plantas de cacao injertadas de cuatro cultivares y se dispusieron 3 tratamientos: aplicación de biofertilizante, aplicación de fertilizante químico y testigo. Se registraron la altura, el diámetro basal, el número de hojas y el número de ramas a los 2 y 12 meses, y se caracterizó la población de microorganismos asociada alrededor del tallo bajo la copa de las plantas. Los resultados de crecimiento muestran un buen potencial para los 4 cultivares estudiados y se observó que la biofertilización generó efectos significativos en algunos de los indicadores de crecimiento de las plantas de cacao. Así, las asociaciones vegetales en un sistema agroforestal podrían ser favorables para potenciar el desarrollo de frutos y resistencia a plagas y enfermedades.

Cocoa plant (Theobroma cacao L.) is native from South America and it represents one of the most significant "bio-cultural" resources of Mesoamerica, since it is a region where it was domesticated and had a relevance as ritual drink and as currency in many pre-hispanic cultures until the arrival of the Spaniards who spread its use worldwide, and became it one of the most consumed commodity goods. Through this research, an alternative is proposed to address the problem of cultivars through the introduction of a wide variety of cocoa plants in traditional agroforestry systems, in synergy with the inoculation of nitrogen-fixing and insoluble phosphor solubilizing edaphic bacterial consortia. Four cultivars of improved grafted cocoa plants were introduced in a traditional agroforestry plot and three fertilization treatments were applied: application of biofertilizer, application of chemical fertilizer and control. Measurements of height, stem diameter, number of leaves and branches were recorded at 2 and 12 months after planting and rhizosphere microbial populations were characterized. Growth results showed good potential for all studied cultivars and it was observed that biofertilization foresees significant effects in some of the growth indicators of cocoa plant. Thereby, plant associations in an agroforestry system could be favorable to promote fruit development and resistance to pests and diseases.

[Effect of mixed edaphic bacterial inoculants in the early development of improved cocoa cultivars (Theobroma cacao L.) in a traditional agroforestry system of Oaxaca, Mexico]. / Efecto de inoculantes bacterianos edáficos mixtos en el desarrollo temprano de cultivares mejorados de cacao (Theobroma cacao L.) en un sistema agroforestal tradicional del norte de Oaxaca, México.

Cocoa plant (Theobroma cacao L.) is native from South America and it represents one of the most significant "bio-cultural" resources of Mesoamerica, since it is a region where it was domesticated and had a relevance as ritual drink and as currency in many pre-hispanic cultures until the arrival of the Spaniards who spread its use worldwide, and became it one of the most consumed commodity goods. Through this research, an alternative is proposed to address the problem of cultivars through the introduction of a wide variety of cocoa plants in traditional agroforestry systems, in synergy with the inoculation of nitrogen-fixing and insoluble phosphor solubilizing edaphic bacterial consortia. Four cultivars of improved grafted cocoa plants were introduced in a traditional agroforestry plot and three fertilization treatments were applied: application of biofertilizer, application of chemical fertilizer and control. Measurements of height, stem diameter, number of leaves and branches were recorded at 2 and 12 months after planting and rhizosphere microbial populations were characterized. Growth results showed good potential for all studied cultivars and it was observed that biofertilization foresees significant effects in some of the growth indicators of cocoa plant. Thereby, plant associations in an agroforestry system could be favorable to promote fruit development and resistance to pests and diseases.

Tyrosine kinase inhibitors in treating soft tissue sarcomas: sunitinib in non-GIST sarcomas

Sarcomas are uncommon malignancies that represent more than 50 different tumor types. Surgery remains the mainstay of treating localised disease. Anthracycline and ifosfamide-based chemotherapy is an option for advanced disease; however, effective treatment of advanced soft tissue sarcoma remains a challenge. Advances in understanding the genetic nature of cancer have led to the development of new treatment options for sarcoma. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic properties and promising activity in the treatment of GIST refractory to imatinib, however in either soft tissue sarcoma, experience with sunitinib is under development in different clinical trials. In this review we offer the experience with this small molecular target in non-GIST sarcomas (AU)

Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma.

In myeloma, the prognostic impact of different strategies used to detect chromosome 13 deletion (Delta13) remains controversial. To address this, we compared conventional cytogenetics and interphase fluorescence in situ hybridization (iFISH) in a large multicenter study (n=794). The ability to obtain abnormal metaphases was associated with a poor prognosis, which was worse if Delta13, p53 deletion or t(4;14) was present, but only Delta13 remained significant on multivariate analysis. Patients with Delta13, by either cytogenetics or iFISH, had a poor prognosis. However, when cases with Delta13 detectable by both cytogenetics and iFISH were separated from those detected by iFISH only, the poor prognosis of iFISH-detectable Delta13 disappeared; their outcome matched that of patients with no detectable Delta13 (P=0.115). Addition of ploidy status to iFISH-Delta13 did not affect the prognostic value of the test. Indeed both cytogenetics and iFISH Delta13 divided both hyperdiploidy and nonhyperdiploidy into two groups with similar prognoses, indicating that the poor prognosis of ploidy is entirely due to its association with Delta13. We conclude that Delta13 detected by metaphase analysis is a critical prognostic factor in myeloma. Absence of Delta13, even in those patients yielding only normal or no metaphases, is associated with a relatively good prognosis.

The usefulness of computerized dynamic posturography for the study of equilibrium in patients with Meniere's disease: correlation with clinical and audiologic data.

The use of computerized dynamic posturogaphy (CDP) in the evaluation of patients with balance alterations not only allows quantification of the subject's capacity to maintain a stable centre of gravity, but also analysis of the degree to which the subject is able to use different types of sensory information. The present study investigated the possible use of CDP for clinical staging of vestibular diseases, specifically Meniere's disease (MD). We applied CDP sensory organization tests to 75 patients with definitive MD (AAO-HNS 1995 criteria). A total of 98 CDP sessions were included in the analysis, which focused on four CDP parameters specifically related to vestibular function (condition-5 score, condition-6 score, overall balance score, and VEST, a measure of the relative importance of vestibular information for maintenance of balance). We found a statistically significant relationship between audiometric hearing threshold and CDP scores, especially in patients with audiometrically advanced disease. In addition, CDP scores showed statistically significant variation with time elapsed since the last typical vertigo attack, suggesting that patients can be usefully grouped into three MD activity-level categories: recent post-attack (less than 1 week since last vertigo attack), late post-attack (1 week - 60 days since last attack), and inactive MD (more than 60 days since last attack). On the basis of these results, we propose expected ranges for each of the four CDP parameters in each of the three MD activity-level categories, allowing staging in terms of balance and posture. This staging system complements existing staging systems (based on audiometric criteria, and on subjective assessment of the severity of vertigo attacks and their implications for quality of life).

[Can we computerize our archive of clinical histories?]. / Podemos informatizar nuestro archivo de historias clínicas?

Case-histories have unquestionable legal importance, as it is shown by High Court Jurisprudence. This is due to the fact that it must report all the patient's process and disease, being thus the relationship doctor-patient completely transcribed (or at least all its relevant issues). So, in case of accusation, the most important evidence deciding doctor's sentence or acquittal will be within case-history. That is why the sentence "Case-history can be doctor's best allied, but also doctor's worst enemy" has been coined. In this setting one can understand perfectly how important the issue posed by this work is, since nowadays computers development offers to us a great number of advantages when collecting case-histories. This has made many health workers- and hospitals-think about keeping them in software. Actually, many of them have already been doing it for quite a long time. For this reason we are going to analyse this topic from a legal point of view, since legal standards provided by Law must be followed: preserve citizens' right to privacy and confidentiality. Security guidelines provided also by Law must be observed, which will allow to guarantee who the author of the document is (authentication) and that there has not been any later manipulation of data (integrity).

¿Podemos informatizar nuestro archivo de historias clínicas? / Can we computerize our case-histories archives?

La historia clínica tiene una trascendencia jurídica fuera de toda duda, como demuestra la jurisprudencia del Tribunal Supremo. Ello se debe a que en ella se debe recoger todo el proceso del paciente y de su enfermedad, transcribiéndose en su totalidad la relación médico-paciente (o al menos todos sus hechos relevantes). Así pues, en caso de denuncia las principales pruebas que determinarán la condena o absolución del médico estarán contenidas en la historia clínica. Y es por ello que se ha acuñado la frase: La historia clínica puede ser el mejor aliado, pero también el peorenemigo del médico. En este marco se comprende perfectamente la importancia de la duda planteada en este trabajo, pues en la actualidad el desarrollo de la informática nos ofrece un gran número de ventajas a la hora de recoger las historias clínicas, lo que ha llevado a que muchos profesionales y centros hospitalarios se estén planteando guardar las mismas en soporte informático, y de hecho, muchos ya lo están haciendo desde hace tiempo. Por esta razón, analizaremos este tema desde el punto de vista jurídico, ya que se deben cumplir las normas legales previstas por la Ley: preservar el derecho a la intimidad y confidencialidad de todos los ciudadanos; y observar las normas de seguridad previstas por la Ley, que permitirán acreditar quién es el autor del documento (autentificación) y que no ha existido ninguna manipulación posterior de los datos (integridad) (AU)

Case-histories have unquestionable legal importance, as it is shown by High Court Jurisprudence. This is due to the fact that it must report all the patient's process and disease, being thus the relationship doctor-patient completely transcribed (or at least all its relevant issues). So, in case of accusation, the most important evidence deciding doctor's sentence or acquittal will be within case-history. That is why the sentence "Case-history can be doctor's best allied, but also doctor's worst enemy" has been coined. In this setting one can understand perfectly how important the issue posed by this work is, since nowadays computers development offers to us a great number of advantages when collecting case-histories. This has made many health workers- and hospitals-think about keeping them in software. Actually, many of them have already been doing it for quite a long time. For this reason we are going to analyse this topic from a legal point of view, since legal standards provided by Law must be followed: preserve citizens' right to privacy and confidentiality. Security guidelines provided also by Law must be observed, which will allow to guarantee who the author of the document is (authentication) and that there has not been any later manipulation of data (integrity) (AU)

Contributions to and review of dicrocoeliosis, with special reference to the intermediate hosts of Dicrocoelium dendriticum.

An epidemiological study on dicrocoeliosis caused by Dicrocoelium dendriticum was carried out on sheep, molluscs and ants in the mountains of León province (NW Spain) between 1987-1991. The results concerning the intermediate hosts and a review of some aspects of dicrocoeliosis are summarized. Mollusc collection for the helminthological study was random throughout the study area at fortnightly intervals. Twenty-nine Gastropoda species were identified. D. dendriticum infection was only detected in 2.98%, of the 2084 Helicella itala examined and in 1.06% of 852 H. corderoi. The highest infection prevalence was detected in H. itala in September and in H. corderoi in February. Daughter sporocysts with well-developed cercariae predominated in spring and autumn. Infection prevalence increased with mollusc age and size. Ants were collected from anthills or plants to which they were attached. The behaviour of ants in tetania was followed. Twenty-one Formicidae species were identified, but only the following harboured D. dendriticum: Formica cunicularia (1158 examined specimens, 0.69% infection prevalence, 2-56 metacercariae per ant); F. sanguinea (234, 1.28%, 2-63); F. nigricans (1770, 4.97%, 1-186); F. rufibarbis (288, 6.59%, 2-107). In a flat area close to León town, 95.39% of the 2085 F. rufibarbis specimens collected in tetania contained metacercariae (1-240) in the abdomen. These were used for parasite characterization by isoelectric focusing and to infect lambs and hamsters. Only one brainworm per ant was found.

Maturity-onset diabetes of the young: recent findings indicate insulin resistance/obesity are not factors.

Maturity-onset diabetes of the young (MODY) is a relatively rare subtype of type 2 diabetes characterized by an early age of onset and autosomal dominant inheritance. Unlike type 2 diabetes, which is often associated with insulin resistance, MODY is caused by a primary defect in pancreatic beta-cell function resulting in a decrease in insulin secretion. Obesity is not a feature of MODY. However, environmental stressors that increase the demand for insulin, such as illness or puberty, may unmask the genetically limited insulin secretory reserve of the undiagnosed MODY patient. Euglycemia is the primary goal of therapy, and diet is the cornerstone of glycemic control. Sulfonylureas and/or exogenous insulin may also be required depending on the degree of dysfunction of the beta cells.