Pathology of immune checkpoint inhibitor-induced injury of the gastrointestinal tract and hepatobiliary system

Immune checkpoint inhibitors (ICIs) are becoming the standard of care treatment for many malignancies. ICIs are associated with a unique spectrum of immune-related adverse events (irAEs) due to the blockade of inhibitory signals of immune activation. The main objective of this study is to review the characteristic histological features and pathologic differential diagnosis of ICI-related injury of the gastrointestinal (GI) tract and hepatobiliary system. Diarrhea and hepatitis are some of the more common irAEs. The pathology of ICI-related injury is both diverse and largely non-specific, with various site-specific findings to become familiar with. Early and accurate recognition of an irAE is important in order to initiate proper management. This generally includes withdrawal of ICI therapy, and possibly the administration of a corticosteroid or other immunosuppressives depending on the severity of injury.     

Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more

After many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo.     

Preparation and identification of multifunctional mesoporous silica nanoparticles for in vitro and in vivo dual-mode imaging,theranostics, and targeted tracking

Mesoporous silica nanoparticles (MSNs) can provide a structural foundation for a new generation of nanocarriers with a broad range of functionalities. Multifunctional MSNs can serve as all-in-one diagnostic and therapeutic tools that can be used to simultaneously visualize and treat various diseases, such as cancer. This research study is the first time that two lanthanide-based imaging systems have been combined to incorporate controlled drug release and targeted tracing into a single MSN-based nano-platform for a novel theranostic drug delivery system. Doping lanthanide ions, i.e., europium (Eu) and gadolinium (Gd) ions, into an MSN structure (EuGd-MSNs) imparts fluorescence and magnetism to the nanostructure that can be used to develop magnetic resonance imaging (MRI) and biological fluorescence tools. Current cancer research has revealed that most human cancer cells express a large number of folate receptors on their surface. Grafting folic acid (FA) onto the EuGd-MSN surface (EuGd-FA-MSNs) imparts a targeting function to the MSN because of the specificity of the binding of FA to cell surface receptors. Furthermore, grafting anticancer drugs, such as camptothecin (CPT), onto the surface of these MSNs by forming disulfide bonds (EuGd-SS-CPT-FA-MSNs) enables intracellular controlled drug release. A high concentration of intracellular glutathione cleaves the disulfide bond to release the drug and treat the disease. The results of in vitro and in vivo studies show that the functionalized MSNs can be successfully used as a platform to integrate dual-imaging, targeting, and therapeutic treatment in multifunctional diagnosis drug delivery systems.     

电流密度成像及其在生物电阻抗成像中的应用

本文首先介绍了生物电阻抗成像(electrical impedance tomography,EIT)的数学模型、系统设计、算法分类及其存在的问题。然后介绍了由加拿大Toronto大学的Joy、Scott等人提出的电流密度成像(current density imaging,CDI)的基本原理及发展现状,提出将CDI应用到EIT可以得到精确度与分辨率都较高的阻抗图像及实现的基本思路。最后讨论了将CDI应用到EIT的发展前景及需要解决的问题。     

大鼠三叉神经解剖和MR成像

目的探讨大鼠三叉神经大体解剖形态及其磁共振成像(magnetic resonance imaging,MRI)方法和MRI表现。方法6只体质量为200～300 g的SD大鼠,使用头部固定头盔在临床1.5 TMRI成像系统上进行常规T1、T2加权自旋回波(spin echo,SE)和三维破坏性稳态梯度回聚(three-dimensional spoiled gradient-recalled,3D-SPGR)序列MR成像,在多平面重建图像上测量大鼠三叉神经各段长度与直径;对大鼠三叉神经进行解剖和测量,与MR图像对照。结果使用大鼠头部固定头盔有效地减少了MRI移动伪影;10.16 cm(4英寸)腕线圈和7.62 cm(3英寸)动物体部线圈均获得了较清晰的大鼠头部MR解剖图像;3D-SPGR T1WI清楚地显示了三叉神经,多平面重建可显示三叉神经主干的全程,并可测量各段的长度和直径。结论大鼠的三叉神经解剖结构与人类相似,主要不同是大鼠三叉神经眼支与上颌神经合为一个神经干,达眶尖处分开;大鼠的三叉神经较粗大,在1.5 TMR成像系统可以被清楚地显示。     

Measurement of Signal-to-Noise and Contrast-to-Noise in the fBIRN Multicenter Imaging Study

The ability to analyze and merge data across sites, vendors, and field strengths depends on one's ability to acquire images with the same image quality including image smoothness, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). SNR can be used to compare different magnetic resonance scanners as a measure of comparability between the systems. This study looks at the SNR and CNR ratios in structural fast spin-echo T₂-weighted scans acquired in five individuals across ten sites that are part of Functional Imaging Research of Schizophrenia Testbed Biomedical Informatics Research Network (fBIRN). Different manufacturers, field strengths, gradient coils, and RF coils were used at these sites. The SNR of gray matter was fairly uniform (41.3–43.3) across scanners at 1.5 T. The higher field scanners produced images with significantly higher SNR values (44.5–108.7 at 3 T and 50.8 at 4 T). Similar results were obtained for CNR measurements between gray/white matter at 1.5 T (9.5–10.2), again increasing at higher fields (10.1–28.9 at 3 T and 10.9 at 4 T).     

Nosologic imaging of the brain: segmentation and classification using MRI and MRSI

A new technique is presented to create nosologic images of the brain based on magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI). A nosologic image summarizes the presence of different tissues and lesions in a single image by color coding each voxel or pixel according to the histopathological class it is assigned to. The proposed technique applies advanced methods from image processing as well as pattern recognition to segment and classify brain tumors. First, a registered brain atlas and a subject‐specific abnormal tissue prior, obtained from MRSI data, are used for the segmentation. Next, the detected abnormal tissue is classified based on supervised pattern recognition methods. Class probabilities are also calculated for the segmented abnormal region. Compared to previous approaches, the new framework is more flexible and able to better exploit spatial information leading to improved nosologic images. The combined scheme offers a new way to produce high‐resolution nosologic images, representing tumor heterogeneity and class probabilities, which may help clinicians in decision making. Copyright © 2008 John Wiley & Sons, Ltd.     

Diagnostic performance of contrast-enhanced ultrasound and enhanced magnetic resonance for breast nodules

In the current study, we sought to evaluate the diagnostic efficacies of conventional ultrasound (US), contrastenhanced US (CEUS), combined US and CEUS and magnetic resonance imaging (MRI) in detecting focal solid breast lesions. Totally 117 patients with 120 BI-RADS category 4A-5 breast lesions were evaluated by conventional US and CEUS, and MRI, respectively. SonoVue was used as contrast agent in CEUS and injected as an intravenous bolus; nodule scan was performed 4 minutes after bolus injection. A specific sonographic quantification software was used to obtain color-coded maps of perfusion parameters for the investigated lesion, namely the time-intensity curve. The pattern of contrast enhancement and related indexes regarding the time-intensity curve were used to describe the lesions, comparatively with pathological results. Histopathologic examination revealed 46 benign and 74 malignant lesions. Sensitivity, specificity, and accuracy of US in detecting malignant breast lesions were 90.14%, 95.92%, and 92.52%, respectively. Meanwhile, CE-MRI showed sensitivity, specificity, and accuracy of 88.73%, 95.92%, and 91.67%, respectively. The area under the ROC curve for combined US and CEUS in discriminating benign from malignant breast lesions was 0.936, while that of MRI was 0.923, with no significant difference between them, as well as among groups. The time-intensity curve of malignant hypervascular fibroadenoma and papillary lesions mostly showed a fast-in/fast-out pattern, with no good correlation between them (kappa < 0.20). In conclusion, the combined use of conventional US and CEUS displays good agreement with MRI in differentiating benign from malignant breast lesions.     

Clinical characteristics and treatment of angiomatous meningiomas: a report of 27 cases

Angiomatous meningioma (AM) is a rare histological variant of meningioma. Twenty seven patients (14 male and 13 female) with angiomatous meningioma were treated in our institution. Their clinical presentation, neuroimaging studies, treatment and follow-up were investigated. The age of patients ranged from 24 to 72 years with a mean of 51.8 years. The clinical presentation was non-specific and depended on the location of the tumor and was mainly due to the mass effect. On computed tomography (CT) scanning, AMs showed slightly hyperintensity. On magnetic resonance imaging (MRI), AMs demonstrated hypointensity on T1-weighted images (T1WI), hyperintensity on T2-weighted images (T2WI), slight hypointensity on diffusion-weighted images (DWI), enhancement on postcontrast T1WI, peritumoral edema, and rich signal voids of vessels in the tumor. On histology, all tumors exhibited abundant blood vessels with at least focal classic meningothelial differentiation. Thirteen, eight, and six cases were achieved Simpson grade I, II and III-IV resection respectively. Nineteen cases were followed for 8 to 125 months with a mean of 47.9 months. Four patients with residual tumor were treated with postoperative radiation therapy and all of them had stable disease. One patient with Simpson grade II resection was not treated with radiation therapy and developed recurrent tumor in 5 years. In conclusion, angiomatous meningiomas have relative high male to female ratio, more frequent peritumoral edema, and rich blood vessels. Gross total resection is still the treatment of choice. These patients with residual tumor after surgery can benefit from radiation therapy. Overall, the prognosis of AMs are as good as other benign meningiomas.     

pH‐ and Temperature‐Sensitive Chitosan Hydrogels: Swelling and MRI Studies

MRI and swelling experiments are used to probe the state of water and infer the microstructure of chitosan hydrogels. SEM reveals a porous open scaffold‐type structure for hydrogels that were equilibrated at 2 °C before freezing as compared to those equilibrated at 37 °C. ADC MRI measurements reveal an anisotropy in the microstructure of these gels. T₁ relaxation MRI values were larger as the pH increased from 7.6 to 12.0, the result of a lower rate of exchange between protons of the hydration sphere of the polymer and bulk water. The thermosensitive and pH‐sensitive properties of these hydrogels can be utilized in the development of innovative materials for biotechnological and biomedical applications, including criobiocatalysis and bioremediation as well as in programmed drug delivery.

     

A theranostic agent to enhance osteogenic and magnetic resonance imaging properties of calcium phosphate cements

With biomimetic biomaterials, like calcium phosphate cements (CPCs), non-invasive assessment of tissue regeneration is challenging. This study describes a theranostic agent (TA) to simultaneously enhance both imaging and osteogenic properties of such a bone substitute material. For this purpose, mesoporous silica beads were produced containing an iron oxide core to enhance bone magnetic resonance (MR) contrast. The same beads were functionalized with silane linkers to immobilize the osteoinductive protein BMP-2, and finally received a calcium phosphate coating, before being embedded in the CPC. Both in vitro and in vivo tests were performed. In vitro testing showed that the TA beads did not interfere with essential material properties like cement setting. Furthermore, bioactive BMP-2 could be efficiently released from the carrier-beads. In vivo testing in a femoral condyle defect rat model showed long-term MR contrast enhancement, as well as improved osteogenic capacity. Moreover, the TA was released during CPC degradation and was not incorporated into the newly formed bone. In conclusion, the described TA was shown to be suitable for longitudinal material degradation and bone healing studies.     

Kinetic Modeling of Contrast-Enhanced MRI: An Automated Technique for Assessing Inflammation in the Rheumatoid Arthritis Wrist

In recent years, development of rheumatoid arthritis (RA) drug therapy has been more directly targeted to counteract specific mechanisms of inflammation, and it is now believed that early aggressive treatment with disease modifying drugs is important to inhibit future structural joint damage. The development of these new treatments has increased the need for methodologies to assess disease activity in RA and monitor the effectiveness of drug therapy. Unlike X-ray, which shows only structural bone damage, magnetic resonance imaging (MRI) can depict soft tissue damage and synovitis, the primary pathology of RA. Recent studies have also indicated that MRI is sensitive to pathophysiologic changes that may predate radiographic erosions and may predict future joint damage. In this study, we have developed a computer automated analysis technique for MR wrist images that provides an objective measure of RA synovitis. This method applies a two-compartment pharmacokinetic model to every voxel of a dynamic contrast-enhanced MRI (DCE-MRI) dataset and outputs resulting parametric images. The aim of this technique is to not only objectively quantify the severity of rheumatoid synovitis, but to also locally determine where areas of serious disease activity are situated through kinetic modeling of blood-tissue exchange. Preliminary results show good correlation to early enhancement rate, which has previously been shown to be a useful clinical marker of RA activity. However, the use of tracer kinetic modeling methods potentially provides more specific information regarding underlying RA physiology. This approach could provide a useful new tool in RA patient management and could substantially improve RA therapeutic studies by calculating objective biomarkers of the disease state.     

Noninvasive investigation of asymmetrically conjoined tripus twins with features of rachipagus, parapagus dicephalus, and cephalopagus

A hypothetical mechanism for conjoined twinning postulated by Spencer ([2003] Developmental Malformations and Clinical Implications, Baltimore: Johns Hopkins University Press, p 1–476) suggests that, after separation, monovular twins fuse in one of eight predictable homologous sites. The tripus fetal specimen under study embodies characteristics of three types therefore preventing it from classification into a simple variant of any one of the eight twin types described by Spencer. The aim of this study was to reveal internal structural anomalies of the fetal specimen by using magnetic resonance imaging and computerized tomography. Dorsally appended to the primary twin is a secondary head mass (brain tissue and ocular globe) and two spinal columns converging at T4/T5, suggesting rachipagus twinning. The ventral orientation of the secondary twin's (right lateral) lower limb suggests parapagus twinning. The caudal divergence of the spinal columns and the presence of a secondary hemipelvis, separate from the primary pelvis, suggest cephalopagus twinning. Measurements of the long bones indicate a gestational age of ～20–23 weeks. Secondary malformations of the primary fetal body include anencephaly, cleft palate, renal agenesis, decreased left ventricular outflow, and a prematurely terminating descending aorta. This study demonstrates the possibility of using current imaging techniques to study very old, formalin‐preserved human material for documentation and scientific discussion without destroying the specimen, thus keeping it intact for posterity. Clin. Anat. 25:1023–1029, 2012. © 2012 Wiley Periodicals, Inc.     

Reliability and precision of pseudo‐continuous arterial spin labeling perfusion MRI on 3.0 T and comparison with 15O‐water PET in elderly subjects at risk for Alzheimer's disease

Arterial spin labeling (ASL) offers MRI measurement of cerebral blood flow (CBF) in vivo, and may offer clinical diagnostic utility in populations such as those with early Alzheimer's disease (AD). In the current study, we investigated the reliability and precision of a pseudo‐continuous ASL (pcASL) sequence that was performed two or three times within one hour on eight young normal control subjects, and 14 elderly subjects including 11 with normal cognition, one with AD and two with Mild Cognitive Impairment (MCI). Six of these elderly subjects including one AD, two MCIs and three controls also received ¹⁵O‐water positron emission tomography (PET) scans 2 h before their pcASL MR scan. The instrumental reliability of pcASL was evaluated with the intraclass correlation coefficient (ICC). The ICCs were greater than 0.90 in pcASL global perfusion measurements for both the young and the elderly groups. The cross‐modality perfusion imaging comparison yielded very good global and regional agreement in global gray matter and the posterior cingulate cortex. Significant negative correlation was found between age and the gray/white matter perfusion ratio (r = –0.62, p < 0.002). The AD and MCI patients showed the lowest gray/white matter perfusion ratio among all the subjects. The data suggest that pcASL provides a reliable whole brain CBF measurement in young and elderly adults whose results converge with those obtained with the traditional ¹⁵O‐water PET perfusion imaging method. pcASL perfusion MRI offers an alternative method for non‐invasive in vivo examination of early pathophysiological changes in AD. Copyright © 2009 John Wiley & Sons, Ltd.     

Neurometabolic and structural alterations in rat brain due to acute hypobaric hypoxia: in vivo 1H MRS at 7 T

In response to hypobaric hypoxia (HH), which occurs at high altitude, the brain undergoes deleterious changes at the structural and metabolite level. In vivo T₂ weighted imaging (T2WI) and ¹H‐MRS was performed to understand the structural and metabolic changes in the hippocampus region of rat brain. Data were acquired pre‐exposure (baseline controls), immediately after exposure and subsequently at the first, fourth, seventh and 14th days post exposure at normoxia. T₂ weighted images of rat brain showed hyperintensity in the CA2/CA3 region of the hippocampus 7 d after acute HH, which persisted till 14 d, probably indicating structural changes in the hippocampus. ¹H‐MRS results showed no change in metabolite level immediately after acute HH exposure, but on the first day of normoxia the myo‐inositol level was significantly decreased, possibly due to altered astrocyte metabolism. Metabolic alterations showing an increase in choline and decrease in glutamate on the fourth day of normoxia may be seen as a process of demyelination and loss of glutamate pool respectively. On the seventh and 14th days of normoxia, decreases in N‐acetylaspartate, creatine and glutamine + glutamate were observed, which might be due to decreased viability of glutamatergic neurons. In vivo ¹H‐MRS demonstrated early neurometabolic changes prior to probable structural changes post acute HH exposure. The extension of these studies will help in early risk assessment, developing intervention and strategies for combating HH related changes. Copyright © 2014 John Wiley & Sons, Ltd.     

Fabry disease revisited: Management and treatment recommendations for adult patients

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the “classic” phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit. However, much of the current literature reports outcomes after late initiation of ERT, once substantial organ damage has already occurred. Updated monitoring and treatment guidelines for pediatric patients with Fabry disease have recently been published. Expert physician panels were convened to develop updated, specific guidelines for adult patients. Management of adult patients depends on 1) a personalized approach to care, reflecting the natural history of the specific disease phenotype; 2) comprehensive evaluation of disease involvement prior to ERT initiation; 3) early ERT initiation; 4) thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients and response to therapy in treated patients; 5) use of adjuvant treatments for specific disease manifestations; and 6) management by an experienced multidisciplinary team.     

Modulation of cortical excitability induced by repetitive transcranial magnetic stimulation: influence of timing and geometrical parameters and underlying mechanisms

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that activates neurons via generation of brief pulses of high-intensity magnetic field. If these pulses are applied in a repetitive fashion (rTMS), persistent modulation of neural excitability can be achieved. The technique has proved beneficial in the treatment of a number of neurological and psychiatric conditions. However, the effect of rTMS on excitability and the other performance indicators shows a considerable degree of variability across different sessions and subjects. The frequency of stimulation has always been considered as the main determinant of the direction of excitability modulation. However, interactions exist between frequency and several other stimulation parameters that also influence the degree of modulation. In addition, the spatial interaction of the transient electric field induced by the TMS pulse with the cortical neurons is another contributor to variability. Consideration of all of these factors is necessary in order to improve the consistency of the conditioning effect and to better understand the outcomes of investigations with rTMS. These user-controlled sources of variability are discussed against the background of the mechanisms that are believed to drive the excitability changes. The mechanism behind synaptic plasticity is commonly accepted as the driver of sustained excitability modulation for rTMS and indeed, plasticity and rTMS share many characteristics, but definitive evidence is lacking for this. It is more likely that there is a multiplicity of mechanisms behind the action of rTMS. The different mechanisms interact with each other and this will contribute to the variability of rTMS-induced excitability changes. This review investigates the links between rTMS and synaptic plasticity, describes their similarities and differences, and highlights a neglected contribution of the membrane potential. In summary, the principal aims of this review are (i) to discuss the different experimental and subject-related factors that contribute to the variability of excitability modulation induced by rTMS, and (ii) to discuss a generalized underlying mechanism for the excitability modulation.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.