Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase 3 trial

Abstract

BACKGROUND

Surrogate endpoints in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase 3 trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase 3 trial.

PATIENTS AND METHODS

Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS.

RESULTS

After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS (75.9% [95% CI 72.30-79.50] vs 71.3% [95% CI 67.60-74.90]; P = 0.034; PC 1) and resulted in a shift towards lower NAR groups (P = 0.034, PC 2) compared to fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI, 88.2 95.2), 81.8% (95% CI, 78.4-85.1) and 58.1 (95% CI 52.4-63.9) for low, intermediate and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS (low vs high NAR: HR 4.670; 95% CI 3.106-7.020; P < 0.001; low vs intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001) in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC4.

CONCLUSION

Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase 3 trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase 3 trial datasets should aim to confirm trial-level surrogacy.

Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer

Abstract

Background

The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer. Here we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study.

Patients and methods

A total of 668 postmenopausal women with HR+, HER2– recurrent/metastatic breast cancer were randomized (1:1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3-weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary endpoint was locally assessed PFS. The key secondary endpoint was overall survival (OS). Other secondary endpoints included overall response rate (ORR) and safety. Biomarker analysis was an exploratory endpoint.

Results

At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months (95% confidence interval [CI], 23.0–30.3) for ribociclib plus letrozole and 16.0 months (95% CI, 13.4–18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI, 0.457–0.704; log-rank P=9.63 × 10⁻⁸). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio: 0.746; 95% CI, 0.517–1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity.

Conclusions

The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy.

Clinical trials number

NCT01958021

Litter breakdown as a tool for assessment of the efficiency of afforestation and ash-aided phytostabilization on metal-contaminated soils functioning in Northern France

Abstract

The main objective of the study was to assess the efficiency of phytoremediation methods implemented for 14 years on highly metal-contaminated soils. The different experimental strategies were plots planted with a tree mix or with a single tree species coupled or not with the use of fly-ashes as an amendment to limit metals mobility in soil. The breakdown of poplar litter on the four plots was monitored during 10 months. In parallel, colonization of litter bags by functional groups of mesofauna (Collembola and Acari) was followed. Two mesh-sized litter bags were used to allow distinguishing microbial and mesofaunal actions on the litter breakdown. We observed the breakdown of litter in four studied plots. Litter breakdown occurred faster in 3-mm litter bags than 250 μm ones during summer demonstrating the importance of mesofauna. Mixed plantation allowed faster litter breakdown than mono-specific plantation. A higher abundance of mesofauna and/or better abiotic conditions (moisture, shading…) could explain this result. Regarding litter breakdown and mesofauna, no significant difference was observed between the amended plots and those subjected to soil phytomanagement. However, communities of the studied area are disturbed since a low abundance of detritivores was observed. This could explain also the slower litter breakdown than expected in our study. To conclude, among the phytomanagement methods tested, mixed plantations could provide a benefit for the restoration of degraded soils. By contrast, the use of fly-ashes does not seem to have any effect on the functionality of ecosystem neither on the litter breakdown process nor on the abundance of mesofauna.

Gender differences in the fluorescence of human skin in young healthy adults

Skin Research and Technology, EarlyView.

Structure-based working model of SecDF, a proton-driven bacterial protein translocation factor

Abstract

The bacterial membrane protein SecDF enhances protein translocation across the membrane driven by the complex of SecA ATPase and SecYEG. Many newly synthesized proteins in the cytoplasm are programmed to be translocated to the periplasm via the narrow channel that is formed in the center of SecYEG. During the protein translocation process, SecDF is proposed to undergo repeated conformational transitions to pull out the precursor protein from the SecYEG channel into the periplasm. Once SecDF captures the precursor protein on the periplasmic surface, SecDF can complete protein translocation even if SecA function is inactivated by ATP depletion, implying that SecDF is a protein translocation motor that works independent of SecA. Structural and functional analyses of SecDF in 2011 suggested that SecDF utilizes the proton gradient and interacts with precursor protein in the flexible periplasmic region. The crystal structures of SecDF in different states at more than 3Å resolution were reported in 2017 and 2018, which further improved our understanding of the dynamic molecular mechanisms of SecDF. This review summarizes recent structural studies of SecDF.

Ask not what your technician can do for you—ask what you can do for your technician

Abstract

Historically, the vital roles played by technicians in Higher Education have had little recognition. Job opportunities are often overlooked by those who have no working knowledge of such organisations and poorly defined career pathways mean that it may not be a first choice for well-qualified, ambitious individuals. With just over a third of all Higher Education technicians in the UK now due to retire in the next 10 to 15 years, fundamental changes are needed, both to attract large numbers of people into vacant roles and to retain current technical staff.National initiatives, founded and driven by charitable and professional bodies, are currently working to address the issues of technicians within Higher Education. Organisations have been urged to take action or face potential recruitment difficulties and skills gaps over the coming years. In light of these national campaigns, institutions across the UK are beginning to develop proper structured career pathways, provide professional development and improve recognition for the work of their technical workforce. Whilst these are encouraging signs, only time will tell if enough has been done to raise both the profile and appeal of a technical career in Higher Education.

Hyponatremia in patients with esophageal cancer treated with chemotherapy including cisplatin

Abstract

Background

Little is known about hyponatremia in patients with esophageal cancer treated with cisplatin-based chemotherapy. The aim of this study was to analyze the risk factors for hyponatremia and its effect on outcomes in patients with esophageal cancer treated with chemotherapy including cisplatin.

Methods

We retrospectively analyzed the records of 137 patients with esophageal cancer who received chemotherapy including cisplatin for the first time between January 2011 and December 2014.

Results

Hyponatremia (Na < 135 mEq/L) was seen in 77 patients (59%), of whom 29 had Grade 3 (120 ≤ Na < 130 mEq/L) or Grade 4 (Na < 120 mEq/L) hyponatremia. We divided patients into the hyponatremia group (patients with Na < 130 mEq/L) and the control group (patients with Na ≥ 130 mEq/L), and compared the results between the two groups. Three patients (2%) were diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone. The serum sodium level before starting chemotherapy was significantly lower and white blood cell count was significantly higher in the hyponatremia group. Appetite loss was seen significantly more often in the hyponatremia group as the chemotherapy-related adverse effect. There was no significant difference in overall survival between the two groups.

Conclusions

Hyponatremia is a common adverse effect induced by cisplatin. Caution should be exercised with patients with a low sodium level before starting chemotherapy. Hyponatremia can be associated with other chemotherapy-related adverse effects, and it should therefore be treated correctly.

Editorial: Synthesizing the Evidence on Prisoner Health—Taking Stock and Moving Forward

Biochemical responses of the Protaetia brevitarsis Lewis larvae to subchronic copper exposure

Abstract

Copper (Cu) is one of the most commonly detected heavy metals in livestock manure pollution. Protaetia brevitarsis Lewis larvae are widely used in the decomposition of livestock manure. During decomposition, heavy metals in livestock manure can accumulate in P. brevitarsis larvae and affect normal growth and reproduction. Therefore, this research focused on characterizing the toxic effects of Cu to P. brevitarsis Lewis larvae. Larvae were exposed to Cu concentrations of 0, 100, 200, 400, and 800 mg kg⁻¹ in edible fungi residue for 7, 14, 21, and 28 days. Results showed that the soluble protein content was markedly increased in 200 and 400 mg kg⁻¹ treatment groups on day 28. Compared to the control group, superoxide dismutase (SOD) and glutathione S-transferase (GST) activities were significantly stimulated on day 7 and then decreased as exposure length was increased (e.g., after 14, 21, and 28 days). Catalase (CAT) activity was also significantly increased after 7 days of exposure. Malondialdehyde (MDA) levels were markedly increased in the 100, 200, and 400 mg kg⁻¹ treatment groups on day 7. However, as time and Cu concentration were increased, MDA levels gradually decreased. These results indicate that Cu has biochemical effects on P. brevitarsis Lewis larvae, and both time and dose affect this biochemical response.

Quantification of Carbon Nanotubes by Raman Analysis

Abstract

The increasing prevalence of carbon nanotubes (CNTs) in manufacturing and research environments, together with the potential exposure risks, necessitates development of reliable and accurate monitoring methods for these materials. We examined quantification of CNTs by two distinct methods based on Raman spectroscopy. First, as measured by the Raman peak intensity of aqueous CNT suspensions, and second, by Raman mapping of air filter surfaces onto which CNTs were collected as aerosols or applied as small-area (0.05 cm²) deposits. Correlation (R² = 0.97) between CNT concentration and Raman scattering intensity for suspensions in cuvettes was found over a concentration range from about 2 to 10 µg/ml, but measurement variance precludes practical determination of a calibration curve. Raman mapping of aerosol sample filter surfaces shows correlation with CNT mass when the surface density is relatively high (R² = 0.83 and 0.95 above about 5 µg total mass on filter), while heterogeneity of CNT deposition makes obtaining representative maps of lower density samples difficult. This difficulty can be mitigated by increasing the area mapped relative to the total sample area, improving both precision and the limit of detection (LOD). For small-area deposits, detection of low masses relevant to occupational monitoring can be achieved, with an estimated LOD of about 50 ng.

Development of Fe/Nb-based solar photocatalysts for water treatment: impact of different synthesis routes on materials properties

Abstract

Semiconductors based on Fe/Nb oxides can present both solar sensitivity and high catalytic activity. However, there is still a lack regarding the comparison between different routes to produce Fe/Nb-based solar photocatalysts and the evaluation of the impact of the synthesis operating conditions on the material properties. In this work, Fe/Nb₂O₅ ratio, type of precipitating agent, presence/absence of washing stage, and temperature of calcination were verified to be the most relevant parameters in the synthesis by the co-precipitation method. These factors led to remarkable differences in the properties and performance of the photocatalysts produced by each distinct synthesis route. Composition, iron species present in the materials, crystallinity characteristics, and pH of the catalysts were affected, leading to different photocatalytic activities under UV-Vis light. Due to their characteristics, the synthesized materials are potential photocatalysts for application in solar processes.

Graphical abstract

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A case series: Association of anaphylaxis with a significant decrease in platelet levels and possible secondary risk of thrombosis

Immunity, Inflammation and Disease, EarlyView.

Cluster analysis of microclimate data to optimize the number of sensors for the assessment of indoor environment within museums

Abstract

For the first time, the cluster analysis (k-means) has been applied on long time series of temperature and relative humidity measurements to identify the thermo-hygrometric features in a museum. Based on ASHRAE (2011) classification, 84% of time all rooms in the Napoleonic Museum in Rome (case study) were found in the class of control B. This result was obtained by analyzing all recorded data in 10 rooms of the museum as well as using the cluster aggregation. The use of objective-oriented methodology allows to achieve an acceptable knowledge of the microclimate in case of multi-room buildings, reducing computations with large amounts of collected data and time-consuming in redundant elaborations. The cluster analysis enables to reduce the number of the sensors in microclimate monitoring programs within museums, provided that the representativeness of the instrument location is known, and professional conservators have assessed that the artifacts are well preserved.

Is Gd-DTPA Necessary in Clinical Practice for Peripheral Nerve Injury? [LETTERS]

REPLY: [LETTERS]

Common Origin of Brachiocephalic and Left Common Carotid Arteries: Proposal of New Terminology [LETTERS]

Multicentric Experience in Distal-to-Proximal Revascularization of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection [INTERVENTIONAL]

BACKGROUND AND PURPOSE:

Internal carotid dissection is a frequent cause of ischemic stroke in young adults. It may cause tandem occlusions in which cervical carotid obstruction is associated with intracranial proximal vessel occlusion. To date, no consensus has emerged concerning endovascular treatment strategy. Our aim was to evaluate our endovascular "distal-to-proximal" strategy in the treatment of this stroke subtype in the first large multicentric cohort.

MATERIALS AND METHODS:

Prospectively managed stroke data bases from 2 separate centers were retrospectively studied between 2009 and 2014 for records of tandem occlusions related to internal carotid dissection. Atheromatous tandem occlusions were excluded. The first step in the revascularization procedure was intracranial thrombectomy. Then, cervical carotid stent placement was performed depending on the functionality of the circle of Willis and the persistence of residual cervical ICA occlusion, severe stenosis, or thrombus apposition. Efficiency, complications, and radiologic and clinical outcomes were recorded.

RESULTS:

Thirty-four patients presenting with tandem occlusion stroke secondary to internal carotid dissection were treated during the study period. The mean age was 52.5 years, the mean initial NIHSS score was 17.29 ± 6.23, and the mean delay between onset and groin puncture was 3.58 ± 1.1 hours. Recanalization TICI 2b/3 was obtained in 21 cases (62%). Fifteen patients underwent cervical carotid stent placement. There was no recurrence of ipsilateral stroke in the nonstented subgroup. Twenty-one patients (67.65%) had a favorable clinical outcome after 3 months.

CONCLUSIONS:

Endovascular treatment of internal carotid dissection–related tandem occlusion stroke using the distal-to-proximal recanalization strategy appears to be feasible, with low complication rates and considerable rates of successful recanalization.

Diffusion-Weighted Zonal Oblique Multislice-EPI Enhances the Detection of Small Lesions with Diffusion Restriction in the Brain Stem and Hippocampus: A Clinical Report of Selected Cases [ADULT BRAIN]

SUMMARY:

Diffusion restriction is the morphologic hallmark of acute ischemic infarcts and excitotoxic brain injury in various cerebral pathologies. Diffusion restriction is visible as hyperintensity on DWI and as hypointensity on ADC maps. Due to the vicinity of multiple anatomic structures in the brain stem and hippocampus, very small lesions with diffusion restriction may result in severe clinical symptomatology, but these small lesions easily go undetected on standard cerebral DWI due to insufficient spatial resolution, T2* blurring, and image artifacts caused by susceptibility-related image distortions. Diffusion-weighted zonal oblique multislice–EPI with reduced FOV acquisition permits a considerable increase in spatial resolution and enhances the visualization of very small pathologic lesions in the brain stem and hippocampus. Improved performance in the depiction of different pathologic lesions with diffusion restriction in the brain stem and hippocampus using this sequence compared with standard DWI in selected cases is presented.

Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease [FUNCTIONAL]

BACKGROUND AND PURPOSE:

Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods.

MATERIALS AND METHODS:

Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment.

RESULTS:

Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15).

CONCLUSIONS:

In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings.

Consensus Needed for Noncontrast CT Markers in Intracerebral Hemorrhage [LETTERS]