Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

Interobserver agreement on landmark and flexure identification in colon capsule endoscopy.

PURPOSE: When an optical colonoscopy is carried out, Scope Guide can assist the endoscopist in determining the localization. In colon capsule endoscopy (CCE), this support is not available. To our knowledge, the interobserver agreement on landmark identification has never been studied. This study aims to investigate the interobserver agreement on landmark identification in CCE. METHODS: An interobserver study was carried out comparing the landmark identification (the ileocecal valve, hepatic flexure, splenic flexure, and anus) in CCE investigations between an external private contractor and three in-house CCE readers with different levels of experience. All CCE investigations analyzed in this study were carried out as a part of the Danish screening program for colorectal cancer. Patients were between 50 and 74 years old with a positive fecal immunochemical test (FIT). A random sample of 20 CCE investigations was taken from the total sample of more than 800 videos. RESULTS: Overall interobserver agreement on all landmarks was 51%. Interobserver agreement on the first cecal image (ileocecal valve), hepatic flexure, splenic flexure, and last rectal image (anus) was 72%, 29%, 22%, and 83%, respectively. The overall interobserver agreement, including only examinations with adequate bowel preparation (n = 16), was 54%, and for individual landmarks, 73%, 32%, 24%, and 85%. CONCLUSION: Overall interobserver agreement on all four landmarks from CCE was poor. Measures are needed to improve landmark identification in CCE investigations. Artificial intelligence could be a possible solution to this problem.

Off-ball behavior in association football: A data-driven model to measure changes in individual defensive pressure.

This study describes an approach to evaluate the off-ball behaviour of attacking players in association football. The aim was to implement a defensive pressure model to examine an offensive player's ability to create separation from a defender using 1411 high-intensity off-ball actions including 988 Deep Runs (DRs) DRs and 423 Change of Directions (CODs). Twenty-two official matches (14 competitive matches and 8 friendlies) of the German National Team were included in the research. To validate the effectiveness of the pressure model, each pass (n = 25,418) was evaluated for defensive pressure on the receiver at the moment of the pass and for the pass completion rate (R = -.34, p < .001). Next, after assessing the inter-rater reliability (Fleiss Kappa of 80 for DRs and 78 for CODs), three expert raters annotated all DRs and CODs that met the pre-set criteria. A time-series analysis of each DR and COD was calculated to the nearest 0.1 second, finding a slight increase in pressure from the start to the end of the off-ball actions as defenders re-established proximity to the attacker after separation was created. A linear mixed model using run type (DR or COD) as a fixed effect with the local maximum as a fixed effect on a continuous scale resulted in p < 0.001, d = 4.81, CI = 0.63 to 0.67 for the greatest decrease in pressure, p < 0.001, d = 0.143, CI = 9.18 to 10.61 for length of the longest decrease in pressure, and p < 0.001, d = 1.13, CI = 0.90 to 1.11 for the fastest rate of decrease in pressure. As these values pertain to the local maximum, situations with greater starting pressure on the attacker often led to greater subsequent decreases. Furthermore, there was a significant (p < .0001) difference between offensive and defensive positions and the number of off-ball actions. Results suggest the model can be applied to quantify and visualise the pressure exerted on non-ball-possessing players. This approach can be combined with other methods of match analysis, providing practitioners with new opportunities to measure tactical performance in football.

Chitin in Strawberry Cultivation: Foliar Growth and Defense Response Promotion, but Reduced Fruit Yield and Disease Resistance by Nutrient Imbalances.

Strawberry cultivation is associated with high mineral fertilizer doses and extensive use of chemical plant protection products. Based on previous research, we expected that chitin application to peat substrate would increase the nutrient availability and activate the plant systemic defense response, resulting in higher strawberry yields and fewer disease symptoms. We set up two experiments in which the temporal variability and differences in initial nutrient concentrations of the growing media were taken into account. Chitin treatment resulted in the attraction of plant growth-promoting fungi toward the plant root, such as species from genera Mortierella and Umbelopsis. In addition, by the end of the experiments 87 mg of mineral nitrogen (N) per liter of substrate was mineralized, which can be related to the observed increase in plant shoot biomass. This, however, led to nutrient imbalances in plant shoots and fruit; N concentration in the leaves increased over 30%, exceeding the optimal range, while phosphorous (P) and potassium (K) deficiencies occurred, with concentrations lower than 50% of the optimal range. This may explain the decreased fruit yield and disease resistance of the fruit toward Botrytis cinerea. In contrast, chitin caused a clear defense priming effect in the strawberry leaves, with a strong induction of the jasmonic acid response, resulting in fewer foliar disease symptoms. Chitin causes positive effects on shoot growth and foliar disease resistance, but caution needs to be taken for nutrient imbalances leading to negative influences on root growth, fruit production, and disease susceptibility toward B. cinerea.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Improved cancer detection in Waldeyer's tonsillar ring by 68Ga-FAPI PET/CT imaging.

PURPOSE: In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [18F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [18F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [68Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. METHODS: Eight patients with suspicion of a malignant tumor in Waldeyer's tonsillar ring or a CUP syndrome were examined. PET/CT scans with [18F]-FDG and [68Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. RESULTS: Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [18F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [68Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for 18F-FDG and 16.06 ± 6.29 for 68Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [18F]FDG and 3.55 ± 0.47 for [68Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [18F] FDG (p = 0.03). Mean TBRmax for the [68Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [18F]FDG (10.90 vs. 4.11). CONCLUSION: Non-invasive imaging of FAP expression by [68Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [18F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [68Ga]FAPI PET/CT imaging.

Nanotechnology for catalysis and solar energy conversion.

This roadmap on Nanotechnology for Catalysis and Solar Energy Conversion focuses on the application of nanotechnology in addressing the current challenges of energy conversion: 'high efficiency, stability, safety, and the potential for low-cost/scalable manufacturing' to quote from the contributed article by Nathan Lewis. This roadmap focuses on solar-to-fuel conversion, solar water splitting, solar photovoltaics and bio-catalysis. It includes dye-sensitized solar cells (DSSCs), perovskite solar cells, and organic photovoltaics. Smart engineering of colloidal quantum materials and nanostructured electrodes will improve solar-to-fuel conversion efficiency, as described in the articles by Waiskopf and Banin and Meyer. Semiconductor nanoparticles will also improve solar energy conversion efficiency, as discussed by Boschloo et al in their article on DSSCs. Perovskite solar cells have advanced rapidly in recent years, including new ideas on 2D and 3D hybrid halide perovskites, as described by Spanopoulos et al 'Next generation' solar cells using multiple exciton generation (MEG) from hot carriers, described in the article by Nozik and Beard, could lead to remarkable improvement in photovoltaic efficiency by using quantization effects in semiconductor nanostructures (quantum dots, wires or wells). These challenges will not be met without simultaneous improvement in nanoscale characterization methods. Terahertz spectroscopy, discussed in the article by Milot et al is one example of a method that is overcoming the difficulties associated with nanoscale materials characterization by avoiding electrical contacts to nanoparticles, allowing characterization during device operation, and enabling characterization of a single nanoparticle. Besides experimental advances, computational science is also meeting the challenges of nanomaterials synthesis. The article by Kohlstedt and Schatz discusses the computational frameworks being used to predict structure-property relationships in materials and devices, including machine learning methods, with an emphasis on organic photovoltaics. The contribution by Megarity and Armstrong presents the 'electrochemical leaf' for improvements in electrochemistry and beyond. In addition, biohybrid approaches can take advantage of efficient and specific enzyme catalysts. These articles present the nanoscience and technology at the forefront of renewable energy development that will have significant benefits to society.

Evaluation of liquid-phase thermometry in impinging jet sprays using synchrotron x-ray scattering.

Liquid thermometry during primary and secondary breakup of liquid sprays is challenging due to the presence of highly dynamic, optically complex flow features. This work evaluates the use of x-ray scattering from a focused, monochromatic beam of the Advanced Photon Source at Argonne National Laboratory for the measurement of liquid temperatures within the mixing zone of an impinging jet spray. The measured scattering profiles are converted to temperature through a previously developed two-component partial least squares (PLS) regression model. Transmitive mixing during jet merging is inferred through spatial mapping of temperatures within the impingement region. The technique exhibits uncertainties of ±2K in temperature and 2% in capturing the correct scattering profile, showing its potential utility for probing liquid temperature distributions in multiphase flows.

Increased expression profile of NCSTN, Notch and PI3K/AKT3 in hidradenitis suppurativa.

BACKGROUND: In a small number of kindreds with familial hidradenitis suppurativa (HS) different mutations of NCSTN (nicastrin) have been identified. Blocking of NCSTN leads to impairment of the Notch and PI3K/AKT signalling pathway, which is assumed to play a pathogenic role in HS. However, very limited data are available concerning expression levels of these pathway components in HS skin. OBJECTIVES: To analyse the mRNA and protein expression of NCSTN, Notch1-3, PIK3R3 and AKT3 in HS. METHODS: Skin samples from healthy controls, lesional and perilesional skin of HS patients with and without a positive family history were analysed by quantitative real-time RT-PCR and immunohistochemistry. Univariate statistical analyses were conducted regarding association between expression levels and patient's characteristics. RESULTS: Expression levels of all investigated genes showed significantly higher levels in lesional HS skin compared with healthy controls. Univariate analysis showed no association between a positive family history and mRNA expression levels. Perilesional HS skin of patients with mild disease severity (Hurley I) showed significant higher mRNA expression levels of the investigated pathway components compared to moderate (Hurley II) and severe disease (Hurley III). CONCLUSION: We found no evidence for diminished expression levels of the Notch signalling. In contrast, the NCSTN, Notch and PI3K/AKT signalling components are overexpressed in HS. Future research is needed to investigate a possible pathogenetic role or to reveal a coactivation of these overexpressed components during inflammatory response in HS.

Frequency of circulating subpopulations of T-regulatory cells in patients with hidradenitis suppurativa.

BACKGROUND: Decreased number of T-regulatory cells (Tregs) and/or their loss of function potentially lead to uncontrolled immune-mediated inflammatory responses. There are only few data available on Tregs in hidradenitis suppurativa (HS) - a disease in which it has been suggested that host immune factors and an overactive immune system of the follicular epithelium play a pathogenetic role. OBJECTIVES: To analyse frequencies of Tregs subpopulations in blood of HS patients in comparison with a healthy control group. MATERIALS & METHODS: Blood samples obtained from HS patients and healthy controls were evaluated by flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The frequency of natural Tregs among CD4+ T lymphocytes were significantly reduced in the HS group compared to the healthy controls. The proportion of activated Tregs, non-suppressive Tregs and proliferating Tregs showed no significant difference when compared to controls. Regarding Tregs frequencies, there was no significant difference between the three Hurley stages. Serum concentrations of IL-10, TGF-ß1 and IL-17A did not show significant differences between the HS and control group. CONCLUSION: The reduction of natural Tregs observed in blood of HS patients could be the result of Tregs homing to sites of inflammatory hot spots in HS skin. Further studies are justified evaluating the role of circulating Tregs during the evolution of HS lesions and as a biomarker for treatment response.

Acetyl zingerone: An efficacious multifunctional ingredient for continued protection against ongoing DNA damage in melanocytes after sun exposure ends.

OBJECTIVE: Recent research has shown that significant levels of cyclobutane pyrimidine dimers (CPDs) in DNA continue to form in melanocytes for several hours in the dark after exposure to ultraviolet radiation (UVR) ends. We document the utility of a new multifunctional ingredient, 3-(4-hydroxy, 3-methoxybenzyl)-pentane-2,4-dione (INCI acetyl zingerone (AZ)), to protect melanocytes against CPD formation after UVR exposure ends. METHODS: The use of AZ as an intervention to reduce CPD formation after irradiation was assessed in vitro by comparing kinetic profiles of CPD formation for several hours after irradiation in cells that were untreated or treated with AZ immediately after irradiation. Multifunctional performance of AZ as an antioxidant, quencher and scavenger was established using industry-standard in vitro chemical assays, and then, its efficacy in a more biological assay was confirmed by its in vitro ability to reduce intracellular levels of reactive oxygen species (ROS) in keratinocytes exposed to UVA radiation. Molecular photostability was assessed in solution during exposure to solar-simulated UVR and compared with the conventional antioxidant α-tocopherol. RESULTS: Even when added immediately after irradiation, AZ significantly inhibited ongoing formation of CPDs in melanocytes after exposure to UVA. Incubation with AZ before irradiation decreased intracellular levels of UVA-induced ROS formation in keratinocytes. Compared with α-tocopherol, the molecular structure of AZ endows it with significantly better photostability and efficacy to neutralize free radicals (∙OH, ∙OOH), physically quench singlet oxygen (1 O2 ) and scavenge peroxynitrite (ONOO- ). CONCLUSION: These results designate AZ as a new type of multifunctional ingredient with strong potential to extend photoprotection of traditional sunscreens and daily skincare products over the first few hours after sun exposure ends.

OBJECTIF: Une étude récente a montré que des taux significatifs de dimères cyclobutyliques de pyrimidine (Cyclobutane Pyrimidine Dimers, CPD) dans l'ADN continuaient à se former dans les mélanocytes pendant plusieurs heures, dans l'obscurité, après que leur exposition aux radiations ultraviolettes (UV) ait pris fin. Nous documentons l'utilité d'un nouvel ingrédient multifonctionnel, le 3-(4-hydroxy, 3- méthoxybenzyle)-pentane-2,4-dione (INCI acétyle zingérone (AZ)), pour protéger les mélanocytes contre la formation de CPD une fois l'exposition aux rayonnements UV terminée. MÉTHODES: L'utilisation d'AZ en tant qu'intervention pour réduire la formation de CPD après exposition aux ultraviolets a été évaluée in vitro en comparant les profils cinétiques de la formation de CPD pendant plusieurs heures après irradiation dans des cellules non traitées et dans des cellules traitées à l'AZ immédiatement après exposition. La performance multifonctionnelle de l'AZ comme agent antioxydant, absorbant et éliminateur a été établie à l'aide de dosages chimiques in vitro standard pour l'industrie, après quoi son efficacité à un dosage plus biologique a été confirmée par sa capacité in vitro à réduire les taux intracellulaires d'espèces réactives de l'oxygène (ROS) dans les kératinocytes exposés au rayonnement UV. La photostabilité moléculaire a été évaluée en solution pendant l'exposition UV simulée de rayonnements solaire et par rapport au traitement antioxydant conventionnel α-tocophérol. RÉSULTATS: Même lorsqu'il a été ajouté immédiatement après exposition, l'AZ a inhibé la formation continue de CPD dans les mélanocytes après l'exposition aux UV et ce de façon significative. Une incubation avec de l'AZ avant exposition a entraîné une diminution des taux intracellulaires de formation des ROS, induits par le rayonnement UV, dans les kératinocytes. Par rapport au α-tocophérol, la structure moléculaire de l'AZ lui confère une photostabilité significativement meilleure ainsi qu'une plus grande efficacité pour neutraliser les radicaux libres (∙OH, ∙OOH), absorber physiquement l'oxygène singulet (1 O2 ) et éliminer le peroxynitrite (ONOO- ). CONCLUSION: Ces résultats montrent que l'AZ, considéré comme un ingrédient multifonctionnel d'un type nouveau, jouit d'un fort potentiel de prolongation de l'effet photoprotecteur des écrans solaires traditionnels et des produits de soins de la peau pendant quelques heures après la fin de l'exposition au soleil.

[A review of the update of the German S3-guideline on diagnostics and therapy of bipolar disorders 2019]. / Überblick über Neuerungen der überarbeiteten und aktualisierten Leitlinie zur Diagnostik und Therapie bipolarer Störungen 2019.

Since the first publication of the guideline in 2012, which included critically reviewed evidence up to 2010, several hundred articles with new evidence were published and some topics of the clinical consensus needed to be reconsidered. Therefore, it was urgently necessary to revise the guideline to bring them up to date. In this article important revisions and updates are presented and the chances and limitations of the development of the guidelines and their implementation are discussed.

4D spatiotemporal evolution of liquid spray using kilohertz-rate x-ray computed tomography.

Four-dimensional (x,y,z,t) x-ray computed tomography was demonstrated in an optically complex spray using an imaging system consisting of three x-ray sources and three high-speed detectors. The x-ray sources consisted of high-flux rotating anode x-ray tube sources that illuminated the spray from three lines of sight. The absorption, along each absorption path, was collected using a CsI phosphor plate and imaged by a high-speed intensified CMOS camera at 20 kHz. The radiographs were converted to a quantitative equivalent path length (EPL) of liquid using a variable attenuation coefficient to account for beam hardening. The EPL data were then reconstructed using the algebraic reconstruction technique into high-speed time sequences of the three-dimensional liquid mass distribution.

Spin Pinning and Spin-Wave Dispersion in Nanoscopic Ferromagnetic Waveguides.

Spin waves are investigated in yttrium iron garnet waveguides with a thickness of 39 nm and widths ranging down to 50 nm, i.e., with an aspect ratio thickness over width approaching unity, using Brillouin light scattering spectroscopy. The experimental results are verified by a semianalytical theory and micromagnetic simulations. A critical width is found, below which the exchange interaction suppresses the dipolar pinning phenomenon. This changes the quantization criterion for the spin-wave eigenmodes and results in a pronounced modification of the spin-wave characteristics. The presented semianalytical theory allows for the calculation of spin-wave mode profiles and dispersion relations in nanostructures.

High SNP diversity in the non-toxic indigenous Jatropha curcas germplasm widens the potential of this upcoming major biofuel crop species.

BACKGROUND AND AIMS: Jatropha curcas (jatropha) is an oil crop cultivated in (sub)tropical regions around the world, and holds great promise as a renewable energy source. However, efforts to fully commercialize jatropha are currently hampered by the lack of genetic diversity in the extant breeding germplasm, and by the toxicity of its seeds meaning that its seed cake cannot be used as a protein source in animal feed, among other constraints. In Mexico, the species' native range, there are jatropha plants whose seeds are used to prepare traditional meals. This non-toxic jatropha 'type' is considered to harbour low genetic variation due to a presumed domestication bottleneck and therefore to be of limited breeding value; yet, very little is known regarding its origin and genetic diversity. METHODS: Using genotyping-by-sequencing (GBS), we extensively genotyped both indigenous toxic and non-toxic jatropha collected along roads and home gardens throughout southern Mexico. KEY RESULTS: Single nucleotide polymorphism diversity in non-toxic jatropha is relatively high, particularly in northern Veracruz state, the probable origin of this germplasm. Genetic differences between toxic and non-toxic indigenous genotypes are overall quite small. A a genome-wide association study supported a genomic region (on LG 8, scaffold NW_012130064), probably involved in the suppression of seed toxicity. CONCLUSIONS: Conservation actions are urgently needed to preserve this non-toxic indigenous, relatively wild germplasm, having potential as a fuel feedstock, animal feed and food source among other uses. More generally, this work demonstrates the value of conservation genomic research on the indigenous gene pool of economically important plant species.

The actinic dysplasia syndrome - diagnostic approaches defining a new concept in field carcinogenesis with multiple cSCC.

Usually, SCC lesions are surrounded by a number of clinically visible and non-visible (subclinical) areas of actinically damaged skin containing cells with dysplasia, and thus may be designated actinic dysplasia syndrome. The epithelial damage is caused mainly by UV radiation, inducing mutations in keratinocytes that may confer growth advantages resulting in preneoplastic fields. The development of visible dysplastic lesions (actinic keratosis - AK) and subsequent progression to invasive SCC requires further mutations in cancer-associated genes, like tumour suppressor genes and cell cycle regulators. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) represent a considerable advantage for the investigation of field cancerization. In addition, imaging allows the non-invasive monitoring of topical treatments for AKs. RCM provides in vivo horizontal skin sections with a high, 1-µm lateral resolution (similar to histopathology) but with a limited penetration (about 200 µm), which can hamper the visualization of important areas such as the dermal-epidermal junction. Conventional OCT has better penetration (1-2 mm) at the expense of a more limited resolution (much lower than histopathology). Line-field confocal OCT (LC-OCT) combines the high precision of RCM and the good penetration of OCT in a single device and therefore appears to be very useful in diagnosing/managing AKs.

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

BACKGROUND: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS: Nintedanib may have similar efficacy to sorafenib in aHCC.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Two-color volumetric laser-induced fluorescence for 3D OH and temperature fields in turbulent reacting flows.

Single-shot, two-color, volumetric laser-induced fluorescence was demonstrated for three-dimensional (3D), tomographic imaging of the structural properties of the OH radical and temperature field in a turbulent hydrogen-air flame. Two narrowband laser sources were tuned to the Q1(5) and Q1(14) transitions of the (1,0) band in the A2Σ←X2Π system and illuminated a volumetric region of the flame. Images from eight unique perspectives collected simultaneously from each of the two transitions were used to reconstruct overlapping OH fields with different Boltzmann fractions and map the 3D temperature distribution with nanosecond precision. Key strategies for minimizing sources of error, such as detector sensitivity and spatial overlap of the two fields, are discussed.

HIV prevention strategies and risk of infection: a model-based analysis.

Risk populations for HIV infections tend to neglect condom use, making alternative preventive approaches necessary. Accordingly, we modelled the risk of sexual HIV transmission for condom use vs. use of rapid diagnostic test (RDT) systems with subsequent exclusion of potential sexual partners with a correctly or falsely positive test from unprotected sex with and without the use of HIV pre-exposure prophylaxis (PrEP) in a bio-statistical approach. We combined a previously described model of transmission risk for HIV-exposed individuals with a newly suggested model of risk of HIV exposure for sexually active HIV-negative individuals. The model was adapted for several stages of infection and different strategies of HIV infection prevention.HIV prevention with RDTs can reduce the transmission risk by up to 97% compared with having sex without any prevention and up to 80% compared with condom use. Nevertheless, RDT-based prevention strategies demonstrate a lack of protection in several stages of infection; in particular, RNA-based RDT systems may fail under treatment. RDT-based pre-screening of potential sex partners prior to unprotected sexual contacts substantially reduces HIV transmission risk. Combination of different prevention strategies is advisable for high-risk groups.

PCR-based rapid diagnostic tests as a strategy for preventing infections with sexually transmitted diseases-a 'diagnostics-as-prevention' modelling approach.

The potential was modelled of molecular rapid diagnostic tests (RDTs) that target agents of sexually transmitted diseases (STDs) to contribute to a reduction in the exposure risk for sexually active populations who prefer condom-free high-risk contacts. The biostatistical approach is exemplified by considering the use of a PCR-based RDT for Chlamydia trachomatis and Neisseria gonorrhoeae in a population of German men having sex with men. We modelled the exposure risk as risk of sexual contact with individuals infected by a STD in spite of multiple RDTs having been conducted to identify STDs that could lead to avoidance of an infectious sexual contact. The risk for a given specific disease is influenced by the diagnostic accuracy of all diagnostic tests conducted. The simulation showed a reduction in exposure risk through conducting the selected PCR-based RDT as a strategy to prevent infections with C. trachomatis and N. gonorrhoeae in comparison with unprotected sexual contact of >97% for C. trachomatis and ≥96% for N. gonorrhoeae. Reliable knowledge of the performance characteristics of the diagnostic tests applied is essential for a thorough risk assessment based on such diagnostic approaches. SIGNIFICANCE AND IMPACT OF THE STUDY: A low-threshold use of molecular rapid diagnostic tests in settings where risky sexual activity is undertaken with deliberate non-use of condoms is modelled. Such an approach might contribute to a considerable reduction in the exposure risk if positively tested individuals are excluded from unprotected sexual intercourse. Protective effects are influenced by the prevalence of the disease and the performance characteristics of the applied tests. Precise knowledge of the performance characteristics of the test assays employed are prerequisites of a reliable risk assessment. The modelling approach is of particular use for preventive health experts.