Lights and Shadows in Immuno-Oncology Drug Development

The rapidly evolving landscape of immuno-oncology (IO) is redefining the treatment of a number of cancer types. IO treatments are becoming increasingly complex, with different types of drugs emerging beyond checkpoint inhibitors. However, many of the new drugs either do not progress from phase I-II clinical trials or even fail in late-phase trials. We have identified at least five areas in the development of promising IO treatments that should be redefined for more efficient designs and accelerated approvals. Here we review those critical aspects of IO drug development that could be optimized for more successful outcome rates in all cancer types. It is important to focus our efforts on the mechanisms of action, types of response and adverse events of these novel agents. The use of appropriate clinical trial designs with robust biomarkers of response and surrogate endpoints will undoubtedly facilitate the development and subsequent approval of these drugs. Further research is also needed to establish biomarker-driven strategies to select which patients may benefit from immunotherapy and identify potential mechanisms of resistance

Free water imaging of the cholinergic system in dementia with Lewy bodies and Alzheimer's disease

INTRODUCTION: Degeneration of cortical cholinergic projections from the nucleus basalis of Meynert (NBM) is characteristic of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), whereas involvement of cholinergic projections from the pedunculopontine nucleus (PPN) to the thalamus is less clear. METHODS: We studied both cholinergic projection systems using a free water-corrected diffusion tensor imaging (DTI) model in the following cases: 46 AD, 48 DLB, 35 mild cognitive impairment (MCI) with AD, 38 MCI with Lewy bodies, and 71 controls. RESULTS: Free water in the NBM-cortical pathway was increased in both dementia and MCI groups compared to controls and associated with cognition. Free water along the PPN-thalamus tract was increased only in DLB and related to visual hallucinations. Results were largely replicated in an independent cohort. DISCUSSION: While NBM-cortical projections degenerate early in AD and DLB, the thalamic cholinergic input from the PPN appears to be more selectively affected in DLB and might associate with visual hallucinations. Highlights: Free water in the NBM-cortical cholinergic pathways is increased in AD and DLB. NBM-cortical pathway integrity is related to overall cognitive performance. Free water in the PPN-thalamus cholinergic pathway is only increased in DLB, not AD. PPN-thalamus pathway integrity might be related to visual hallucinations in DLB

Reliability of dynamic contrast-enhanced magnetic resonance imaging data in primary brain tumours: a comparison of Tofts and shutter speed models

Purpose To investigate the robustness of pharmacokinetic modelling of DCE-MRI brain tumour data and to ascertain reliable perfusion parameters through a model selection process and a stability test. Methods DCE-MRI data of 14 patients with primary brain tumours were analysed using the Tofts model (TM), the extended Tofts model (ETM), the shutter speed model (SSM) and the extended shutter speed model (ESSM). A no-effect model (NEM) was implemented to assess overfitting of data by the other models. For each lesion, the Akaike Information Criteria (AIC) was used to build a 3D model selection map. The variability of each pharmacokinetic parameter extracted from this map was assessed with a noise propagation procedure, resulting in voxel-wise distributions of the coefficient of variation (CV). Results The model selection map over all patients showed NEM had the best fit in 35.5% of voxels, followed by ETM (32%), TM (28.2%), SSM (4.3%) and ESSM (<0.1%). In analysing the reliability of Ktrans, when considering regions with a CV<20%, ≈25% of voxels were found to be stable across all patients. The remaining 75% of voxels were considered unreliable. Conclusions The majority of studies quantifying DCE-MRI data in brain tumours only consider a single model and whole-tumour statistics for the output parameters. Appropriate model selection, considering tissue biology and its effects on blood brain barrier permeability and exchange conditions, together with an analysis on the reliability and stability of the calculated parameters, is critical in processing robust brain tumour DCE-MRI data

Basin-Scale Control on the Phytoplankton Biomass in Lake Victoria, Africa

The relative bio-optical variability within Lake Victoria was analyzed through the spatio-temporal decomposition of a 1997–2004 dataset of remotely-sensed reflectance ratios in the visible spectral range. Results show a regular seasonal pattern with a phase shift (around 2 months) between the south and north parts of the lake. Interannual trends suggested a teleconnection between the lake dynamics and El-Niño phenomena. Both seasonal and interannual patterns were associated to conditions of light limitation for phytoplankton growth and basin-scale hydrodynamics on phytoplankton access to light. Phytoplankton blooms developed during the periods of lake surface warming and water column stability. The temporal shift apparent in the bio-optical seasonal cycles was related to the differential cooling of the lake surface by southeastern monsoon winds. North-south differences in the exposure to trade winds are supported by the orography of the Eastern Great Rift Valley. The result is that surface layer warming begins in the northern part of the lake while the formation of cool and dense water continues in the southern part. The resulting buoyancy field is sufficient to induce a lake-wide convective circulation and the tilting of the isotherms along the north-south axis. Once surface warming spreads over the whole lake, the phytoplankton bloom dynamics are subjected to the internal seiche derived from the relaxation of thermocline tilting. In 1997–98, El-Niño phenomenon weakened the monsoon wind flow which led to an increase in water column stability and a higher phytoplankton optical signal throughout the lake. This suggests that phytoplankton response to expected climate scenarios will be opposite to that proposed for nutrient-limited great lakes. The present analysis of remotely-sensed bio-optical properties in combination with environmental data provides a novel basin-scale framework for research and management strategies in Lake Victoria

Examining the dynamics of phytoplankton biomass in Lake Tanganyika using Empirical Orthogonal Functions

The spatial and seasonal variations in phytoplankton concentrations can be pronounced in large tropical lakes and can have a direct impact on the regional communities in developing nations. Given the complex hydrodynamics and ecology of the African Great Lakes, there is a clear need for spatial databases to address their inter-annual and seasonal variability. In the past, phytoplankton studies in these extensive ecosystems focused mostly on point stations or lake transects repeated over several years. In the present work, satellite based reflectanceswere used to determine anomalies in chlorophyll related reflectance bands over a 7-year period for the whole of Lake Tanganyika. Empirical Orthogonal Function analysis was used to define regions with similar temporal co-variation of phytoplankton biomass. Using AutoRegressive Integrated Moving Average modelling techniques, it was possible to determine differences in phytoplankton dynamics and link these to climate and lake basin characteristics. An important shift in the phytoplankton seasonalitywas observed at the end of 2000, in concomitance to changes in wind and air temperatures which favoured entrainment of nutrients present in the deeper lake waters. This shift confirms the high sensitivity of the lake to climate change. The combination of extensive satellite based measurements with modelling approaches that consider both spatial and temporal dynamics is an important contribution to the understanding of long term changes in this important freshwater ecosystem

Sonoelastography of canine patellar tendon: feasibility, repeatability and reproducibility.

INTRODUCTION Sonoelastography (EUS) is a recent ultrasound technique for the evaluation of tissue elasticity and the me- chanical properties of tissues by estimating their strain, defined as the fractional change in length of a tissue when an external force is applied. Nowadays in veterinary medicine, there are only few publications about the use of EUS for the assessment of abdominal tissues in cat and dogs and musculoskeletal system in horses. The aims of the present study were to describe the sonoelastographic characteristic of the patellar tendon in clinical healthy dogs, to in- vestigate if EUS is a feasible, repeatable and reproducible technique for the evaluation of the patellar ten- don and to establish the normal pattern at EUS of the patellar tendon in healthy dogs. MATERIALS AND METHODS Fourteen dogs were considered in this prospective study. Each dog enrolled, had a normal physical and or- thopaedic examination, a normal blood workup and a normal B-mode patellar tendon ultrasonographic ex- amination in both legs. EUS was performed without sedation by two different operators: a well-trained ultrasonographer and a sen- ior student. For EUS dogs were positioned in lateral recumbency with the knee in maximal passive flexion. EUS images were obtained by applying light rhythmic pressure with the probe. Only longitudinal sections were acquired, and the operators evaluated each patellar tendon twice. Investigation was made blindly and each operator was not aware about the results of the acquisition of the other operator. Ultrasonographic and sonoelastographic evaluation were carried out using an Esaote My LabTMClass C ul- trasound machine equipped with a 12-18 MHz linear transducer. For the EUS evaluation was used the ESAOTE ElaXto software. Only images without artifacts were evaluated. Subsequently ROIs were drawn in the central area of the ten- don, in order to measure the softness of the tissue (Elx-t%sft, the percentage of softness of the tissue in the ROI). Categorical, qualitative data analysis was performed using a weighted kappa statistic for repeated evalua- tions by the same (repeatability) and by a different observer (reproducibility). A categorical qualitative as- sessment was performed based on a grading scale of 1–5 (1 = soft; 2 = mostly soft; 3 = intermediate; 4 = mostly hard; 5 = hard), where tissue stiffness was depicted by a color scale (blue = hard, red = soft, green=intermediate). Values were assigned as follows; Elx-t%sft > 70% = 1, 50% < Elx-t%sft < 70% = 2, 30% < Elx-t%sft < 50% = 3, 20% < Elx-t%sft < 30% = 4, Elx-t%sft < 20% = 5. Percentages of concordant observations were given for comparison. RESULTS Qualitatively, all the 28 patellar tendons evaluated were predominantly red (soft), with a mean +/- SD Elx- t%sft of 94.9% +/-9.3, while the peritendinous tissue was mostly green (intermediate). The overlying dermal layer appeared mostly blue (hard), while the underlying fat pad was mostly green (intermediate) with red (soft) striations. Overall, 89.3% of the patellar tendons were graded as soft or mostly soft, whilst the re- maining 10.7% were classified as intermediate. Repeatability was 86.2%, with a weighted kappa of 0.64 (good), for the well-trained sonographer and 83.3%, with a weighted kappa of 0.53 (moderate), for the senior student. Reproducibility was 86.2%, with a weighed kappa of 0.65 (good). CONCLUSION The results of this study suggest that EUS is a feasible imaging modality to evaluate tissue strain and soft- ness/stiffness in the patellar tendon in dogs. Similarly to the patellar tendon in humans, the normal canine patellar tendon showed a highly soft and homogeneous elastogram. The semi-quantitative analysis demon- strated that EUS was moderately repeatable and reproducible. In conclusion, EUS could be useful in the evaluation of the canine patellar tendon in dogs. More studies are needed in dogs with patellar tendon anomalies, such as injuries, thickening and tendinosis. REFERENCES Porta F, Damjanov N, Galluccio F et al. (2014): Ultrasound elastography is a reproducible and feasible tool for the eval- uation of the patellar tendon in healthy subjects. International journal of Rheumatic diseases; 17:762-766. White J, Gay J, Farnsworth R et al. (2014): Ultrasound elastography of the liver, spleen, and kidneys in clinically normal cats. Veterinary Radiology & Ultrasound; 55:428-434. Lustgarten M, Redding WR, Labens R et al. (2014): Elastographic charateristics of the metacarpal tendon in horses with- out clinical evidence of tendon injury. Veterinary Radiology & Ultrasound; 55:92-101. Jeon S, Lee G, Lee SK et al. (2015): Ultrasonographic elastography of the liver, spleen, kidneys and prostate in clinical- ly nor-mal beagle dogs [corrected]. Veterinary Radiology & Ultrasound; 56:425-431

Sonoelastographic Features of the Patellar Ligament in Clinically Normal Dogs

Objective This article describes the sonoelastographic features of the patellar ligament of sound dogs and tests feasibility, reproducibility and repeatability. Methods Clinically healthy medium-to-large breed dogs were enrolled. Sonoelastographic images of the patellar ligaments were obtained in lateral recumbency with the stifle flexed by an experienced operator and by a senior veterinary student. The elasticity colour map included red (soft), green (intermediate) and blue (hard). Tissue elasticity was measured by calculating the percentage of softness with dedicated software. Categorical, qualitative data analysis was performed using a weighted kappa statistic for repeatability and reproducibility. A categorical qualitative assessment was performed based on a grading scale of 1 to 5 (soft, mostly soft, intermediate, mostly hard and hard). Results Fourteen clinically normal dogs were considered. A total of 28 patellar ligaments were examined. Overall, 25 of the patellar ligaments were graded as soft or mostly soft and the remaining 3 as intermediate. Repeatability was 86.2%, with a weighted kappa of 0.64 (good), for the well-trained sonographer and 83.3%, with a weighted kappa of 0.53 (moderate), for the senior student. Reproducibility was 86.2%, with a weighed kappa of 0.65 (good). Clinical Significance Sonoelastography of the canine patellar ligament is a feasible and reproducible technique. Patellar ligaments in clinically normal dogs showed highly elastic biomechanical properties. Copyright © 2018, Schattauer GmbH. All rights reserved