[Opicapone for the treatment of Parkinson's disease: real-life data in Spain]. / Opicapona para el tratamiento de la enfermedad de Parkinson: datos de vida real en España.

Opicapone is a catechol-O-methyl-transferase (iCOMT) inhibitor authorized in Europe in 2016 and indicated as adjunctive therapy to preparations of levodopa/ DOPA decarboxylase inhibitors in adult patients with Parkinson's disease and end-of-dose motor fluctuations who cannot be stabilised on those combinations. The efficacy of opicapone in these patients has been demonstrated in two pivotal randomized clinical trials, BIPARK I and BIPARK II, in which it has demonstrated its superiority versus placebo and non-inferiority versus entacapone. Although they constitute the gold standard for the evaluation of interventions, randomized clinical trials present limitations of external validity due to the use of strict eligibility criteria. Therefore, it is considered necessary to have a more comprehensive evaluation of the efficacy of the drug, complementing the information obtained from randomized clinical trials with that of "real world or real clinical practice" studies. The objective of this review has been to collect and put into perspective the information available on opicapone coming from real clinical practice studies in Spain. The data from Spain with opicapone in 18 series with more than 1,000 patients in total, confirm the safety and efficacy previously reported with this iCOMT. Furthermore, they show that opicapone is especially useful in patients with a less advanced stage of the disease and mild motor fluctuations, which would suggest that the earlier its introduction in the therapeutic scheme for the management of motor fluctuations, the better is the benefit-risk ratio for the drug.

TITLE: Opicapona para el tratamiento de la enfermedad de Parkinson: datos de vida real en España.Resumen. La opicapona es un inhibidor de la catecol-O-metiltransferasa (iCOMT) autorizado en Europa en 2016 como terapia adyuvante a las preparaciones de levodopa/inhibidores de la dopa descarboxilasa en pacientes adultos con enfermedad de Parkinson y fluctuaciones motoras de final de dosis que no puedan ser estabilizados con esas combinaciones. La eficacia de la opicapona en estos pacientes ha sido demostrada en dos ensayos clínicos pivotales, BIPARK I y BIPARK II, en los que se ha demostrado la superioridad frente al placebo y la no inferioridad frente a la entacapona. A pesar de que constituyen el estándar para la evaluación de intervenciones, los ensayos clínicos aleatorizados presentan limitaciones de validez externa debidas a la utilización de criterios estrictos de elegibilidad. Por tanto, se considera necesario disponer de una evaluación más amplia de la eficacia general del fármaco, complementando la información de los ensayos clínicos aleatorizados con estudios de 'vida real o práctica clínica real'. El objetivo de esta revisión ha sido recopilar y poner en perspectiva la información disponible sobre los resultados de la opicapona en estudios de práctica clínica real en España. Los datos acumulados en España con opicapona en 18 series con más de 1.000 pacientes confirman la seguridad y la eficacia de este iCOMT comunicadas previamente. Además, muestran que la opicapona es especialmente útil en pacientes en un estadio de la enfermedad menos avanzado y fluctuaciones motores leves, lo que sugeriría una mejor relación beneficio-riesgo cuanto más temprana sea su introducción en el esquema terapéutico para el tratamiento de las fluctuaciones motoras.

Maintenance treatment in metastatic colorectal cancer: in search of the best strategy.

Over the last 2 decades, the standard fluoropyrimidine-based chemotherapy backbone for metastatic colorectal cancer has been complemented by the addition of novel biological agents, achieving impressive increases in 5-year survival rates. Nonetheless, these new combinations have also entailed increases in toxicity, leading to evaluation of de-escalated chemotherapy regimens and "drug holiday" periods in attempts to reduce side effects and optimise quality of life without impairing efficacy. Here, we review the current and emerging evidence for maintenance schedules with chemotherapy and targeted agents, versus continuous treatment after induction treatment, in metastatic colorectal cancer patients.

Fossil-calibrated molecular phylogenies reveal that leaf-mining moths radiated millions of years after their host plants.

Coevolution has been hypothesized as the main driving force for the remarkable diversity of insect-plant associations. Dating of insect and plant phylogenies allows us to test coevolutionary hypotheses and distinguish between the contemporaneous radiation of interacting lineages vs. insect 'host tracking' of previously diversified plants. Here, we used nuclear DNA to reconstruct a molecular phylogeny for 100 species of Phyllonorycter leaf-mining moths and 36 outgroup taxa. Ages for nodes in the moth phylogeny were estimated using a combination of a penalized likelihood method and a Bayesian approach, which takes into account phylogenetic uncertainty. To convert the relative ages of the moths into dates, we used an absolute calibration point from the fossil record. The age estimates of (a selection of) moth clades were then compared with fossil-based age estimates of their host plants. Our results show that the principal radiation of Phyllonorycter leaf-mining moths occurred well after the main radiation of their host plants and may represent the dominant associational mode in the fossil record.

Insect herbivory, plant defense, and early Cenozoic climate change.

Insect damage on fossil leaves from the Central Rocky Mountains, United States, documents the response of herbivores to changing regional climates and vegetation during the late Paleocene (humid, warm temperate to subtropical, predominantly deciduous), early Eocene (humid subtropical, mixed deciduous and evergreen), and middle Eocene (seasonally dry, subtropical, mixed deciduous and thick-leaved evergreen). During all three time periods, greater herbivory occurred on taxa considered to have short rather than long leaf life spans, consistent with studies in living forests that demonstrate the insect resistance of long-lived, thick leaves. Variance in herbivory frequency and diversity was highest during the middle Eocene, indicating the increased representation of two distinct herbivory syndromes: one for taxa with deciduous, palatable foliage, and the other for hosts with evergreen, thick-textured, small leaves characterized by elevated insect resistance. Leaf galling, which is negatively correlated with moisture today, apparently increased during the middle Eocene, whereas leaf mining decreased.

A Dendroctonus bark engraving (Coleoptera: Scolytidae) from a middle Eocene Larix (Coniferales: Pinaceae): early or delayed colonization?

An engraving made by a scolytid bark beetle, assigned to the genus Dendroctonus of the tribe Tomicini, has been identified on a mummified, middle Eocene (45 Ma) specimen of Larix altoborealis wood from the Canadian High Arctic. Larix altoborealis is the earliest known species of Larix, a distinctive lineage of pinaceous conifers that is taxonomically identifiable by the middle Eocene and achieved a broad continental distribution in northern North America and Eurasia during the late Cenozoic. Dendroctonus currently consists of three highly host-specific lineages that have pinaceous hosts: a basal monospecific clade on Pinoideae (Pinus) and two sister clades that consist of a speciose clade associated exclusively with Pinoideae and six species that breed overwhelmingly in Piceoideae (Picea) and Laricoideae (Pseudotsuga and Larix). The middle Eocene engraving in L. altoborealis represents an early member of Dendroctonus that is ancestral to other congeneric species that colonized a short-bracted species of Larix. This fossil occurrence, buttressed by recent data on the phylogeny of Pinaceae subfamilies and Dendroctonus species, indicates that there was phylogenetically congruent colonization by these bark-beetle lineages of a Pinoideae + (Piceoideae + Laricoideae) host-plant sequence. Based on all available evidence, an hypothesis of a geochronologically early invasion during the Early Cretaceous is supported over an alternative view of late Cenozoic cladogenesis by bark beetles onto the Pinaceae. These data also suggest that host-plant chemistry may be an effective species barrier to colonization by some bark-beetle taxa over geologically long time scales.

Timing the radiations of leaf beetles: hispines on gingers from latest cretaceous to recent.

Stereotyped feeding damage attributable solely to rolled-leaf hispine beetles is documented on latest Cretaceous and early Eocene ginger leaves from North Dakota and Wyoming. Hispine beetles (6000 extant species) therefore evolved at least 20 million years earlier than suggested by insect body fossils, and their specialized associations with gingers and ginger relatives are ancient and phylogenetically conservative. The latest Cretaceous presence of these relatively derived members of the hyperdiverse leaf-beetle clade (Chrysomelidae, more than 38,000 species) implies that many of the adaptive radiations that account for the present diversity of leaf beetles occurred during the Late Cretaceous, contemporaneously with the ongoing rapid evolution of their angiosperm hosts.

A Carboniferous insect gall: insight into early ecologic history of the Holometabola.

Although the prevalence or even occurrence of insect herbivory during the Late Carboniferous (Pennsylvanian) has been questioned, we present the earliest-known ecologic evidence showing that by Late Pennsylvanian times (302 million years ago) a larva of the Holometabola was galling the internal tissue of Psaronius tree-fern fronds. Several diagnostic cellular and histological features of these petiole galls have been preserved in exquisite detail, including an excavated axial lumen filled with fecal pellets and comminuted frass, plant-produced response tissue surrounding the lumen, and specificity by the larval herbivore for a particular host species and tissue type. Whereas most suggestions over-whelmingly support the evolution of such intimate and reciprocal plant-insect interactions 175 million years later, we provide documentation that before the demise of Pennsylvanian age coal-swamp forests, a highly stereotyped life cycle was already established between an insect that was consuming internal plant tissue and a vascular plant host responding to that herbivory. This and related discoveries of insect herbivore consumption of Psaronius tissues indicate that modern-style herbivores were established in Late Pennsylvanian coal-swamp forests.

Ninety-seven million years of angiosperm-insect association: paleobiological insights into the meaning of coevolution.

From well preserved leaf damage of the mid-Cretaceous Dakota Flora (97 million years ago), three distinctive, insect-mediated feeding traces have been identified and assigned to two extant genera and one subfamily. These taxa are the leaf miners Stigmella and Ectoedemia of the Nepticulidae and Phyllocnistinae of the Gracillariidae. These fossils indicate that within 25 million years of early angiosperm radiation, the organs of woody dicots already were exploited in intricate and modern ways by insect herbivores. For Ectoedemia and its platanoid host, we document 97 million years of continuity for a plant-insect interaction. The early occurrence during the mid-Cretaceous of diverse and extensive herbivory on woody angiosperms may be associated with the innovation of deciduousness, in which a broadleafed angiosperm provided an efficient, but disposable, photosynthetic organ that with-stood the increased cost of additional insect herbivory. Moreover, the group represented in this study, the leaf-mining Lepidoptera, exhibits a wide range of subordinal taxonomic differentiation and includes the Gracillariidae, a member of the most derived lepidopteran suborder, the Ditrysia. Ditrysian presence during the mid-Cretaceous, in addition to lepidopteran body-fossil evidence from Early Cretaceous and Late Jurassic deposits, suggests that the radiation of major lepidopteran lineages probably occurred during the Late Jurassic on a gymnosperm-dominated flora.

Insect diversity in the fossil record.

Insects possess a surprisingly extensive fossil record. Compilation of the geochronologic ranges of insect families demonstrates that their diversity exceeds that of preserved vertebrate tetrapods through 91 percent of their evolutionary history. The great diversity of insects was achieved not by high origination rates but rather by low extinction rates comparable to the low rates of slowly evolving marine invertebrate groups. The great radiation of modern insects began 245 million years ago and was not accelerated by the expansion of angiosperms during the Cretaceous period. The basic trophic machinery of insects was in place nearly 100 million years before angiosperms appeared in the fossil record.