First-line single-agent regorafenib in frail patients with metastatic colorectal cancer: a pilot phase II study of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)

BackgroundTreatment of frail patients with advanced colorectal cancer (CRC) is controversial. This pilot phase II trial aimed to assess the efficacy and safety of regorafenib when administered in first-line to frail patients with advanced CRC.MethodsFrail patients without prior advanced colorectal cancer treatment were included in the study. Definition of frailty was defined per protocol based on dependency criteria, presence of chronic comorbid pathologies and/or geriatric features. Main objective: to assess progression-free survival (PFS) rate at 6months. Treatment consisted of 28-daycycles of orally administered regorafenib 160mg/day (3 weeks followed by 1 week rest).ResultsForty-seven patients were included in the study. Median age was 81years (range 63-89). Frailty criteria: dependency was observed in 26 patients (55%), comorbidities in 27 (57%) and geriatric features in 18 (38%). PFS rate at 6months was 45% (95% confidence interval [CI] 30-60]. Median PFS was 5.6months (95%CI 2.7-8.4). Median overall survival (OS) was 16months (95%CI 7.8-24). Complete response, partial response and stable disease were observed in one, two and 21 patients respectively (objective response rate 6.4%; disease control rate 51%). Thirty-nine patients (83%) experienced grade 3-4 adverse events (AEs). The most common grade 3-4 AEs were hypertension (15 patients; 32%), asthenia (14; 30%), hypophosphatemia (6; 13%); diarrhea (4; 8%), hand-foot-skin reaction (4; 8%). There were two toxic deaths (4.2%) (grade 5 rectal bleeding and death not further specified). Dose reduction was required in 26 patients (55%) and dose-delays in 13 patients (28%).ConclusionsThe study did not meet the pre-specified boundary of 55% PFS rate at 6months. Toxicity observed (83% patients experienced grade 3 and 4 AEs) preclude its current use in clinical practice on this setting. Disease control rate and overall survival results are interesting and might warrant further investigation to identify those who benefit from this approach.Trial registrationThis trial was prospectively registered at EudraCT (2013-000236-94). Date of trial registration: April 9th, 2013

Shell structure at N=28 near the dripline: spectroscopy of 42^{42}Si, 43^{43}P and 44^{44}S

Measurements of the N=28 isotones 42Si, 43P and 44S using one- and two-proton knockout reactions from the radioactive beam nuclei 44S and 46Ar are reported. The knockout reaction cross sections for populating 42Si and 43P and a 184 keV gamma-ray observed in 43P establish that the d_{3/2} and s_{1/2} proton orbits are nearly degenerate in these nuclei and that there is a substantial Z=14 subshell closure separating these two orbits from the d_{5/2} orbit. The increase in the inclusive two-proton knockout cross section from 42Si to 44S demonstrates the importance of the availability of valence protons for determining the cross section. New calculations of the two-proton knockout reactions that include diffractive effects are presented. In addition, it is proposed that a search for the d_{5/2} proton strength in 43P via a higher statistics one-proton knockout experiment could help determine the size of the Z=14 closure.Comment: Phys. Rev. C, in pres

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid

Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology. 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models. We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants. The combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer's Disease-related episodic memory decline, suggesting utility in clinical trials

Absolute and Relative Surrogate Measurements of the \u3csup\u3e236\u3c/sup\u3eU(\u3cem\u3en,f\u3c/em\u3e) Cross Section as a Probe of Angular Momentum Effects

Using both the absolute and relative surrogate techniques, the 236U(n,f) cross section was deduced over an equivalent neutron energy range of 0 to 20 MeV. A 42 MeV 3He beam from the 88 Inch Cyclotron at Lawrence Berkeley National Laboratory was used to perform a (3He,α) pickup reaction on targets of 235U (Jπ=7/2−) and 238U (Jπ = 0+) and the fission decay probabilities were determined. The 235U(3He,αf) and 238U(3He,αf) were surrogates for 233U(n,f) and 236U(n,f), respectively. The cross sections extracted using the surrogate method were compared to directly measured cross sections. The sensitivity of these cross sections to the Jπ -population distributions was explored

Deducing the \u3csup\u3e237\u3c/sup\u3eU(\u3cem\u3en,f\u3c/em\u3e) Cross Section Using the Surrogate Ratio Method

We have deduced the cross section for 237U(n, f) over an equivalent neutron energy range from 0 to 20 MeV using the surrogate ratio method. A 55 MeV4He beam from the 88 inch cyclotron at Lawrence Berkeley National Laboratory was used to induce fission in the following reactions: 238U(α, αf) and 236U(α, αf). The 238U reaction was a surrogate for 237U(n, f), and the 236U reaction was used as a surrogate for 235U(n, f). Scattered α particles were detected in a fully depleted segmented silicon telescope array over an angle range of 35° to 60° with respect to the beam axis. The fission fragments were detected in a third independent silicon detector located at backward angles between 106° and 131°

Statistical \u3cem\u3eγ\u3c/em\u3e Rays in the Analysis of Surrogate Nuclear Reactions

The surrogate nuclear reaction method is being applied in many efforts to indirectly determine neutron-induced reaction cross sections on short-lived isotopes. This technique aims to extract accurate (n,γ) cross sections from measured decay properties of the compound nucleus of interest (created using a different reaction). The advantages and limitations of a method that identifies the γ-ray decay channel by detecting any high-energy (“statistical”) γ ray emitted during the relaxation of the compound nucleus were investigated. Data collected using the Silicon Telescope Array for Reaction Studies and Livermore-Berkeley Array for Collaborative Experiments silicon and germanium detector arrays were used to study the decay of excited gadolinium nuclei following inelastic proton scattering. In many cases, this method of identifying the γ-ray decay channel can simplify the experimental data collection and greatly improve the detection efficiency for γ-ray cascades. The results show sensitivity to angular-momentum differences between the surrogate reaction and the desired (n,γ) reaction similar to an analysis performed using low-lying discrete transitions even when ratios of cross sections are considered

Surrogate Ratio Method in the Actinide Region Using the (\u3cem\u3eα,α\u27f\u3c/em\u3e) Reaction

In the Surrogate Method, the measured decay probability of a compound nucleus formed via a direct reaction is used to extract the cross section for a reaction with a different entrance channel that proceeds through the same compound nucleus. An extension of the Surrogate Method, the Surrogate Ratio Method (SRM), uses a ratio of measured decay probabilities to infer an unknown cross section relative to a known one. To test the SRM we compare the direct-reaction-induced fission probability ratio of 234U(α, α’ f ) to 236U(α, α’f ) with the ratio of cross sections of 233U(n, f ) to 235U(n, f ). These ratios were found to be in agreement over an equivalent neutron energy range of 0.4–18 MeV

Studying neutron-rich 18 N in fusion-evaporation reactions

Light neutron-rich nuclei provide an excellent opportunity to study the changes in nuclear shell structure that occur with increasing neutron number and are an important testing ground for shell model theories. Probably one of the most striking examples of shell modification is the occurrence of intruder ground states, which signal an inversion of the normal shell ordering. Intruder ground states are observed around {sup 32}Mg (Z=10-12), ''the island of inversion'', and in {sup 11}Be. An analogous situation appears in the Z=2 He isotopes, where the intrusion of sd excitations in p-shell configurations becomes important in the heavy helium isotopes. Finally, for Z=8, recent data on {sup 20}O [1] show a reduction in the p-sd shell gap with increasing neutron number. It remains an open question whether the observed diminishing of the p-sd shell gap is restricted to O and F isotopes or extends also to neighboring nuclei. Here, we report preliminary results on {sup 18}N (Z=7), which is sufficiently far from stability to exhibit modified shell structure and yet still within the reach of stable beam facilities utilizing state-of-the art detector systems. {sup 18}N was produced in the {sup 9}Be({sup 11}B,2p){sup 18}N reaction at the 88'' Cyclotron at LBNL and studied using the LIBERACE-STARS detector array--an array of large area segmented silicon detectors (E-{Delta}E) and six HPGe Clover detectors. This experiment was the first to use a fusion-evaporation reaction to populate {sup 18}N. Previous information on the excited states of 18N came from {sup 18}C beta-decay [2] and charge-exchange reactions [3]. These are highly selective reactions and the fusion-evaporation reaction used here can provide a more comprehensive picture of the excitation spectrum. The beam energy of 50 MeV was chosen to optimize the cross section for the evaporation of 2 protons while simultaneously suppressing the evaporation of additional neutrons in conjunction with the 2p channel. The two proton tag cleanly selects the weak (sub milli-barn) {sup 18}N products. A natural lead catcher foil was mounted between the target and Silicon detectors (3 cm distance) to detect gamma-rays emitted from long lived (t{sub 1/2} &lt; 1 {micro}s) states. The {sup 18}N {gamma}-ray spectrum is shown in figure 1 and a preliminary level scheme in figure 2. New transitions were observed at 628 and 155 keV. The 628 and 114 keV transitions are shown to be in coincidence. The origin of the 298 keV line is currently being investigated. In ref. [2] a lifetime of &gt; 600 ns was assigned to the first excited state at 114 keV. However, from our measurement we estimate a lifetime value of &lt; 30 ns for this state; far shorter than the value of &gt; 600 ns given from the beta decay experiment

Altered perivascular fibroblast activity precedes ALS disease onset

Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology

Benchmarking the External Surrogate Ratio Method using the (alpha,alpha' f) reaction at STARS

We measured the ratio of the fission probabilities of {sup 234}U* relative to {sup 236}U* formed via an ({alpha},{alpha}{prime}) direct reactions using the STARS array at the 88-inch cyclotron at the Lawrence Berkeley National Laboratory. This ratio has a shape similar to the ratio of neutron capture probabilities from {sup 233}U(n; f) and {sup 235}U(n; f), indicating the alpha reactions likely formed a compound nucleus. This result indicates that the ratios of fission exit channel probabilities for two actinide nuclei populated via ({alpha}, {alpha}{prime}) can be used to determine an unknown fission cross section relative to a known one. The validity of the External Surrogate Ratio Method (ESRM) is tested and the results support the conclusions of Burke et al. [1]