Background
Delirium is common in elderly patients after surgery and is associated with poor outcomes. This study aimed to investigate the impact of intraoperative dexmedetomidine on the incidence of ...delirium in elderly patients undergoing major surgery.
Methods
This was a randomized double‐blind placebo‐controlled trial. Elderly patients (aged 60 years or more) scheduled to undergo major non‐cardiac surgery were randomized into two groups. Patients in the intervention group received a loading dose of dexmedetomidine 0·6 μg/kg 10 min before induction of anaesthesia followed by a continuous infusion (0·5 μg per kg per h) until 1 h before the end of surgery. Patients in the control group received volume‐matched normal saline in the same schedule. The primary outcome was the incidence of delirium during the first 5 days after surgery. Delirium was assessed with the Confusion Assessment Method (CAM) for non‐ventilated patients and CAM for the Intensive Care Unit for ventilated patients.
Results
In total, 309 patients who received dexmedetomidine and 310 control patients were included in the intention‐to‐treat analysis. The incidence of delirium within 5 days of surgery was lower with dexmedetomidine treatment: 5·5 per cent (17 of 309) versus 10·3 per cent (32 of 310) in the control group (relative risk (RR) 0·53, 95 per cent c.i. 0·30 to 0·94; P = 0·026). The overall incidence of complications at 30 days was also lower after dexmedetomidine (19·4 per cent (60 of 309) versus 26·1 per cent (81 of 310) for controls; RR 0·74, 0·55 to 0·99, P = 0·047).
Conclusion
Intraoperative dexmedetomidine halved the risk of delirium in the elderly after major non‐cardiac surgery. Registration number: ChiCTR‐IPR‐15007654 (
www.chictr.org.cn).
Antecedentes
El delirio después de la cirugía es frecuente en los pacientes de edad avanzada y se asocia con malos resultados. El objetivo de este estudio fue investigar el impacto de la administración intraoperatoria de dexmedetomidina en la incidencia de delirio en pacientes mayores sometidos a operaciones de cirugía mayor.
Métodos
Se trataba de un ensayo aleatorizado, doble ciego y controlado con placebo. Un total de 620 pacientes mayores (60 años o más) fueron programados para ser sometidos a intervenciones (no cardiacas) de cirugía mayor y se aleatorizaron a dos grupos. Los pacientes en el grupo de intervención recibieron una dosis de carga de dexmedetomidina (0,6 μg/kg, 10 minutos antes de la inducción anestésica) seguida de una infusión continua (0,5 μg/kg/h) hasta 1 h antes de la finalización de la cirugía. Los pacientes del grupo control recibieron el mismo volumen de suero salino siguiendo la misma pauta. El resultado principal era la incidencia de delirio durante los primeros 5 días postoperatorios. Para la valoración del delirio se utilizó el método para la evaluación de la confusión (Confusion Assessment Method, CAM) en pacientes no intubados y el CAM‐UCI para los pacientes intubados.
Resultados
En total, 309 pacientes que recibieron dexmedetomidina y 310 del grupo control se incluyeron en el análisis por intención de tratar. La incidencia de delirio durante los primeros 5 días tras la cirugía fue inferior en presencia de tratamiento con dexmedetomidina que en ausencia del mismo: 5,5% (17/309) versus 10,3% (32/310); riesgo relativo (RR) 0,53, i.c. del 95% 0,30‐0,94, P = 0,026. La incidencia global de complicaciones a los 30 días excluyendo el delirio también fue inferior en presencia que en ausencia de tratamiento con dexmedetomidina (19,4% (60/309) versus 26,1% (81/301), RR 0,74, i.c. del 95% 0,55‐0,99, P = 0,047).
Conclusión
La administración intraoperatoria de dexmedetomidina reduce la presencia de delirio en los pacientes mayores tras cirugía mayor no cardiaca.
In this RCT, intraoperative infusion of dexmedetomidine was found to reduce the rate of postoperative delirium and surgery‐related complications. The shortcomings of previous studies, such as study design and sample size, were amended, providing more robust evidence for clinical practice.
Halved the rate of delirium
Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. ...Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.
IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.
Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05) with atezolizumab, and 8·51 months (6·41–10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 11% of 179), anaemia (ten 6%), increased blood creatine phosphokinase (12 7%), and fatigue (eight 4%). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).
IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.
F Hoffmann-La Roche Ltd/Genentech Inc.
Recent analysis of satellite data obtained during the 9 October 2012 geomagnetic storm identified the development of peaks in electron phase space density, which are compelling evidence for local ...electron acceleration in the heart of the outer radiation belt, but are inconsistent with acceleration by inward radial diffusive transport. However, the precise physical mechanism responsible for the acceleration on 9 October was not identified. Previous modelling has indicated that a magnetospheric electromagnetic emission known as chorus could be a potential candidate for local electron acceleration, but a definitive resolution of the importance of chorus for radiation-belt acceleration was not possible because of limitations in the energy range and resolution of previous electron observations and the lack of a dynamic global wave model. Here we report high-resolution electron observations obtained during the 9 October storm and demonstrate, using a two-dimensional simulation performed with a recently developed time-varying data-driven model, that chorus scattering explains the temporal evolution of both the energy and angular distribution of the observed relativistic electron flux increase. Our detailed modelling demonstrates the remarkable efficiency of wave acceleration in the Earth's outer radiation belt, and the results presented have potential application to Jupiter, Saturn and other magnetized astrophysical objects.
In megabar shock waves, materials compress and undergo a phase transition to a dense charged-particle system that is dominated by strong correlations and quantum effects. This complex state, known as ...warm dense matter, exists in planetary interiors and many laboratory experiments (for example, during high-power laser interactions with solids or the compression phase of inertial confinement fusion implosions). Here, we apply record peak brightness X-rays at the Linac Coherent Light Source to resolve ionic interactions at atomic (ångström) scale lengths and to determine their physical properties. Our in situ measurements characterize the compressed lattice and resolve the transition to warm dense matter, demonstrating that short-range repulsion between ions must be accounted for to obtain accurate structure factor and equation of state data. In addition, the unique properties of the X-ray laser provide plasmon spectra that yield the temperature and density with unprecedented precision at micrometre-scale resolution in dynamic compression experiments.
Background
Primary tumour location is emerging as an important prognostic factor in localized and metastatic colorectal cancers. However, its prognostic role in colorectal liver metastasis (CRLM) ...after hepatectomy remains controversial. A systematic review and meta‐analysis was undertaken to evaluate its prognostic value.
Methods
References were identified through searches of PubMed, Embase, Web of Science and the Cochrane Library comparing overall or disease‐free survival after hepatic resection between patients with CRLM originating from right‐ or left‐sided colorectal cancers. Data were pooled using hazard ratios (HRs) and 95 per cent confidence intervals according to a random‐effects model. Meta‐regression and subgroup analyses were conducted to assess the effect of underlying confounding factors on HR estimates and to adjust for this.
Results
The final analysis included 21 953 patients from 45 study cohorts. Compared with left‐sided primary tumour location, right‐sided location was associated with worse overall survival (HR 1·39, 95 per cent c.i. 1·28 to 1·51; P < 0·001; prediction interval 1·00 to 1·93), and also tended to have a negative impact on disease‐free survival (HR 1·18, 1·06 to 1·32; P = 0·004; prediction interval 0·79 to 1·75). Subgroup analysis showed that the negative effect of right‐sided primary tumour location on overall survival was more prominent in the non‐Asian population (HR 1·47, 1·33 to 1·62) than the Asian population (HR 1·18, 1·05 to 1·32) (P for interaction <0·01).
Conclusion
This study demonstrated a prognostic role for primary tumour location in patients with CRLM receiving hepatectomy, especially regarding overall survival. Adding primary tumour location may provide important optimization of prognosis prediction models for CRLM in current use.
Antecedentes
La ubicación del tumor primario (primary tumor location, PTL) ha surgido como un factor pronóstico importante en los cánceres colorrectales (colorectal cancers, CRCs) localizados y metastásicos. Sin embargo, todavía se discute su relevancia como factor pronóstico tras la resección de metástasis hepáticas de cáncer colorrectal (colorectal liver metastases, CRLM). Se realizó una revisión sistemática y un metaanálisis para determinar su valor pronóstico.
Métodos
En PubMed, EMBASE, Web of Science y la Biblioteca Cochrane se identificaron los trabajos que compararon la supervivencia global (overall survival, OS) y la supervivencia libre de enfermedad (disease‐free survival, DFS) tras la resección hepática de CRLM cuyo CRCs estuviese situado en el lado derecho o izquierdo. Los datos se expresaron en forma del cociente de riesgos instantáneos (hazard ratio, HR) e intervalos de confianza del 95% (i.c. del 95%) de acuerdo con un modelo de efectos aleatorios. Se efectuaron análisis de metarregresión y de subgrupos para evaluar el efecto de los factors de confusión existentes en las estimaciones de HR, ajustando por los mismos.
Resultados
El análisis final incluyó 21.953 pacientes de cohortes de 45 estudios. La PTL en el lado derecho en comparación con el lado izquierdo se asoció con una peor supervivencia global (HR 1,39; i.c. del 95% 1,28‐1,51; P < 0,001; intervalo de predicción 1,00‐1,93) y una tendencia a un impacto negativo en la DFS (HR 1,18; i.c. del 95% 1,06‐1,32; P = 0,004; intervalo de predicción 0,79‐1,75). El análisis de subgrupos mostró que el efecto negativo de la PTL del lado derecho en la OS fue más prominente en la población no asiática (HR 1,47; i.c. del 95% 1,33‐1,62) que en la asiática (HR 1,18; i.c. del 95% 1,05‐1,32; Pinteracción < 0,01).
Conclusión
Este estudio demostró que la PTL tiene un papel pronóstico tras la hepatectomía de las CRLM, especialmente respecto a la OS. La adición de la PTL proporcionaría una optimización importante en los modelos actuales de predicción pronóstica de CRLM.
The prognostic role of primary tumour location in colorectal liver metastases (CRLM) after hepatectomy remains controversial. This meta‐analysis demonstrated a prognostic role of primary tumour location in CRLM receiving hepatectomy, especially regarding overall survival.
Primary tumor location has prognostic value
Various physical processes are known to cause acceleration, loss, and transport of energetic electrons in the Earth's radiation belts, but their quantitative roles in different time and space need ...further investigation. During the largest storm over the past decade (17 March 2015), relativistic electrons experienced fairly rapid acceleration up to ~7 MeV within 2 days after an initial substantial dropout, as observed by Van Allen Probes. In the present paper, we evaluate the relative roles of various physical processes during the recovery phase of this large storm using a 3‐D diffusion simulation. By quantitatively comparing the observed and simulated electron evolution, we found that chorus plays a critical role in accelerating electrons up to several MeV near the developing peak location and produces characteristic flat‐top pitch angle distributions. By only including radial diffusion, the simulation underestimates the observed electron acceleration, while radial diffusion plays an important role in redistributing electrons and potentially accelerates them to even higher energies. Moreover, plasmaspheric hiss is found to provide efficient pitch angle scattering losses for hundreds of keV electrons, while its scattering effect on > 1 MeV electrons is relatively slow. Although an additional loss process is required to fully explain the overestimated electron fluxes at multi‐MeV, the combined physical processes of radial diffusion and pitch angle and energy diffusion by chorus and hiss reproduce the observed electron dynamics remarkably well, suggesting that quasi‐linear diffusion theory is reasonable to evaluate radiation belt electron dynamics during this big storm.
Key Points
Radiation belt electrons experienced rapid acceleration up to multi‐MeV during 17 March 2015 storm
Chorus plays an important role in accelerating electrons to multi‐MeV near PSD peak location
Radial diffusion is critical in redistributing electrons and could provide further acceleration
Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, ...collaborating with the Pharmacogenomics Research Network, began eMERGE‐PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE‐PGx data release includes sequence‐derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation‐Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.
Local acceleration driven by whistler‐mode chorus waves is fundamentally important for accelerating seed electron populations to highly relativistic energies in the outer radiation belt. In this ...study, we quantitatively evaluate chorus‐driven electron acceleration during the 17 March 2013 storm, when the Van Allen Probes observed very rapid electron acceleration up to several MeV within ~12 hours. A clear radial peak in electron phase space density (PSD) observed near L* ~4 indicates that an internal local acceleration process was operating. We construct the global distribution of chorus wave intensity from the low‐altitude electron measurements made by multiple Polar Orbiting Environmental Satellites (POES) satellites over a broad region, which is ultimately used to simulate the radiation belt electron dynamics driven by chorus waves. Our simulation results show remarkable agreement in magnitude, timing, energy dependence, and pitch angle distribution with the observed electron PSD near its peak location. However, radial diffusion and other loss processes may be required to explain the differences between the observation and simulation at other locations away from the PSD peak. Our simulation results, together with previous studies, suggest that local acceleration by chorus waves is a robust and ubiquitous process and plays a critical role in accelerating injected seed electrons with convective energies (~100 keV) to highly relativistic energies (several MeV).
Key Points
Rapid electron acceleration with a radial PSD peak is observed during a storm
Chorus driven electron acceleration reproduces observed electron evolution
Local acceleration by chorus waves is a robust and ubiquitous process
The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery ...with surgery alone in this patient population.
We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery.
From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003).
Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation KWF Kankerbestrijding; Netherlands Trial Register number, NTR487.).
PDF
