Karim Burkhardt

Imaging of the larynx and hypopharynx

The purpose of this article is to review currently used imaging protocols for the evaluation of pathologic conditions of the larynx and hypopharynx, to describe key anatomic structures in the larynx and hypopharynx that are relevant to tumor spread and to discuss the clinical role of Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and PET CT in the pretherapeutic workup and posttherapeutic follow-up of patients with squamous cell carcinoma of this region. A detailed discussion of the characteristic neoplastic submucosal invasion patterns, including extension to the preepiglottic space, paraglottic space and laryngeal cartilages and the implications of imaging for tumor staging and treatment planning is provided. The present article also reviews less common tumors of this region, such as chondrosarcoma, lymphoma, minor salivary gland tumors and lipoma. As the majority of non-neoplastic conditions do not require imaging the role of CT and MRI is discussed in some particular situations, such as to delineate cysts and laryngoceles, abscess formation in inflammatory conditions, to evaluate laryngeal and hypopharyngeal involvement in granulomatous and autoimmune diseases, and to evaluate the extent of laryngeal fractures due to severe blunt trauma.

Pathology Findings With Acrylic Implants

We report the pathological findings in cases of acrylic implants obtained by direct intratumoral injection of polymethyl-methacrylate (PMMA) and N-butyl-cyano-acrylate (NBCA). Direct intratumoral injection of acrylic implants was performed for a variety of primary and secondary bone lesions. These types of treatments have been used at our institution in the last 4 years for 40 vertebroplasty (PMMA) procedures and for nine bone lesions of other locations (PMMA, NBCA). Postmortem histology became available for 1 case of PMMA and for 5 cases with NBCA intratumoral acrylic implants. The pathological findings associated with PMMA and NBCA were evaluated and compared. PMMA exhibited a macroscopic and microscopic rim of tumor necrosis, 6 months after implantation. NBCA exhibited compressive effects on the nearby tumor tissue, however, without signs of significant necrosis outside the acrylic tumor cast. Tumor captured inside the acrylic cast showed extensive to near complete necrosis. Acrylic implants may lead to necrosis when injected directly in tumors. The necrotizing effect may extend beyond the limits of an implant in the case of PMMA. Such an extended effect of PMMA, when compared with NBCA, may be due to the variable toxicity of acrylic implants, including the different degrees of the exothermic reaction during polymerization.

Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures.

In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of endothelial cells lining brain microvessels and forming the blood-brain barrier. Many lipophilic drugs, including antiepileptic drugs, are potential substrates for Pgp. Overexpression of Pgp in endothelial cells of the blood-brain barrier has been determined in patients with drug resistant forms of epilepsy such as temporal lobe epilepsy and rodent models of temporal lobe epilepsy and suggested to lead to reduced penetration of antiepileptic drugs into the brain. Expression of Pgp after seizures has also been described in astrocytes, whereas it is not clear whether neurons can express Pgp. In the present study, Pgp expression was studied by immunohistochemistry in rats 24 h after a status epilepticus induced by either pilocarpine or kainate, widely used models of temporal lobe epilepsy. Unexpectedly, in addition to endothelial Pgp staining, intense Pgp staining was found in neurons in the CA3c/CA4 sectors and hilus of the hippocampus formation, but not in other brain regions examined. The neuronal Pgp staining was confirmed by two different Pgp antibodies. Double immunolabeling and confocal microscopy showed that Pgp was colocalized with the neuronal marker neuronal nuclear antigen, but not with the glial marker glial fibrillary acidic protein. No neuronal Pgp staining was seen in control rats. The expression of Pgp in neurons after limbic seizures was substantiated by determining Pgp encoding genes (mdr1a, mdr1b) in neurons by real time quantitative RT-PCR. Increased Pgp expression in hippocampal neurons is likely to affect the action of drugs with intraneuronal targets and, in view of recent evidence from other cell types, could be associated with prevention of apoptosis which is involved in neuronal damage developing after seizures such as produced by pilocarpine.

Plant-induced seizures: reappearance of an old problem.

Abstract Several plant-derived essential oils have been known for over a century to have epileptogenic properties. We report three healthy patients, two adults and one child, who suffered from an isolated generalized tonic-clonic seizure and a generalized tonic status, respectively, related to the absorption of several of these oils for therapeutic purposes. No other cause of epilepsy was found, and outcome was good in the two adult cases, but the course has been less favorable in the child. A survey of the literature shows essential oils of 11 plants to be powerful convulsants (eucalyptus, fennel, hyssop, pennyroyal, rosemary, sage, savin, tansy, thuja, turpentine, and wormwood) due to their content of highly reactive monoterpene ketones, such as camphor, pinocamphone, thujone, cineole, pulegone, sabinylacetate, and fenchone. Our three cases strongly support the concept of plant-related toxic seizure. Nowadays the wide use of these compounds in certain unconventional medicines makes this severe complication again possible.

Expression and localization of VEGF‐C and VEGFR‐3 in glioblastomas and haemangioblastomas

Primary human brain tumours account for approximately 2% of all cancers. High levels of expression of vascular endothelial growth factor‐A (VEGF‐A), a potent angiogenic factor, are linked to poor prognosis. In contrast, the potential role in human brain tumour biology of newer VEGF family members, VEGF‐C and VEGF‐D, both of which are lymphangiogenic factors, is poorly understood. In the present study, the expression of all VEGFs (VEGF‐A, ‐B, ‐C, and ‐D) and their receptors (VEGFR‐1, ‐2, and ‐3) has been assessed in 39 primary human brain tumours. The well‐established findings were confirmed with VEGF‐A. Surprisingly, however, VEGF‐C and VEGF‐D, as well as VEGFR‐3, were expressed in some tumour types such as haemangioblastomas and glioblastomas, despite their lack of lymphatic vessels. VEGF‐C and VEGFR‐3 transcripts were localized to the tumour palisade around necrotic areas in glioblastomas and were evenly distributed throughout haemangioblastomas. VEGF‐C protein was localized by immunohistochemistry to the palisade layer in glioblastomas. More than 50% of VEGF‐C‐positive cells also expressed the intermediate‐stage inflammatory macrophage marker CD163; however, a significant proportion of VEGF‐C‐positive cells were CD163‐negative. These data demonstrate the presence of molecules, primarily described as regulators of lymphangiogenesis, in normal human brain and brain tumours that are devoid of lymphatics. Their localization in macrophages points to a role in tumour‐associated inflammation. Copyright

Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development

Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies.

Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson's disease pathogenesis.

Parkinsons disease (PD) pathology spreads throughout the brain following a region‐specific process predominantly affecting the substantia nigra (SN) pars compacta. SN exhibits a progressive loss of dopaminergic neurons responsible for the major cardinal motor symptoms, along with the occurrence of Lewy bodies in the surviving neurons. To gain new insights into the underlying pathogenic mechanisms in PD, we studied postmortem nigral tissues dissected from pathologically confirmed PD cases (n = 5) and neurologically intact controls (n = 8). Using a high‐throughput shotgun proteomic strategy, we simultaneously identified 1795 proteins with concomitant quantitative data. To date, this represents the most extensive catalog of nigral proteins. Of them, 204 proteins displayed significant expression level changes in PD patients versus controls. These were involved in novel or known pathogenic processes including mitochondrial dysfunction, oxidative stress, or cytoskeleton impairment. We further characterized four candidates that might be relevant to PD pathogenesis. We confirmed the differential expression of ferritin‐L and seipin by Western blot and demonstrated the neuronal localization of gamma glutamyl hydrolase and nebulette by immunohistochemistry. Our preliminary findings suggest a role for nebulette overexpression in PD neurodegeneration, through mechanisms that may involve cytoskeleton dynamics disruption. All MS data have been deposited in the ProteomeXchange with identifier PXD000427 (http://proteomecentral.proteomexchange.org/dataset/PXD000427).

Cerebral vasculitis during FK 506 treatment in a liver transplant patient

The immunosuppressive agent FK 506 is widely used in liver transplant patients. Neurotoxicity is a major complication of its use. We report progressive and irreversible neurologic complications occurring in a 39-year-old women who underwent liver transplantation and was treated with FK 506. Neuropathologic examination revealed multiple vasculitic lesions. The possibility of an FK 506-mediated toxic effect on the cerebral vessels is suggested.

Diffusion-weighted and PET/MR Imaging after Radiation Therapy for Malignant Head and Neck Tumors.

Interpreting imaging studies of the irradiated neck constitutes a challenge because of radiation therapy-induced tissue alterations, the variable appearances of recurrent tumors, and functional and metabolic phenomena that mimic disease. Therefore, morphologic magnetic resonance (MR) imaging, diffusion-weighted (DW) imaging, positron emission tomography with computed tomography (PET/CT), and software fusion of PET and MR imaging data sets are increasingly used to facilitate diagnosis in clinical practice. Because MR imaging and PET often yield complementary information, PET/MR imaging holds promise to facilitate differentiation of tumor recurrence from radiation therapy-induced changes and complications. This review focuses on clinical applications of DW and PET/MR imaging in the irradiated neck and discusses the added value of multiparametric imaging to solve diagnostic dilemmas. Radiologists should understand key features of radiation therapy-induced tissue alterations and potential complications seen at DW and PET/MR imaging, including edema, fibrosis, scar tissue, soft-tissue necrosis, bone and cartilage necrosis, cranial nerve palsy, and radiation therapy-induced arteriosclerosis, brain necrosis, and thyroid disorders. DW and PET/MR imaging also play a complementary role in detection of residual and recurrent disease. Interpretation pitfalls due to technical, functional, and metabolic phenomena should be recognized and avoided. Familiarity with DW and PET/MR imaging features of expected findings, potential complications, and treatment failure after radiation therapy increases diagnostic confidence when interpreting images of the irradiated neck. Online supplemental material is available for this article.

Orbital tumours and tumour-like lesions: exploring the armamentarium of multiparametric imaging

AbstractAlthough the orbit is a small anatomical space, the wide range of structures present within it are often the site of origin of various tumours and tumour-like conditions, both in adults and children. Cross-sectional imaging is mandatory for the detection, characterization, and mapping of these lesions. This review focuses on multiparametric imaging of orbital tumours. Each tumour is reviewed in relation to its clinical presentation, compartmental location, imaging characteristics, and its histological features. We herein describe orbital tumours as lesions of the globe (retinoblastoma, uveal melanoma), optic nerve sheath complex (meningioma, optic nerve glioma), conal-intraconal compartment (hemangioma), extraconal compartment (dermoid/epidermoid, lacrimal gland tumours, lymphoma, rhabdomysarcoma), and bone and sinus compartment (fibrous dysplasia). Lesions without any typical compartmental localization and those with multi-compartment involvement (veno-lymphatic malformation, plexiform neurofibroma, idiopathic orbital pseudotumour, IgG4 related disease, metastases) are also reviewed. We discuss the role of advanced imaging techniques, such as MR diffusion-weighted imaging (DWI), diffusion tensor imaging, fluoro-2-deoxy-D-glucose positron emission tomography CT (FDG-PET CT), and positron emission tomography MRI (MRI PET) as problem-solving tools in the evaluation of those orbital masses that present with non-specific morphologic imaging findings. Main messages/Teaching points • A compartment-based approach is essential for the diagnosis of orbital tumours. • CT and MRI play a key role in the work-up of orbital tumours. • DWI, PET CT, and MRI PET are complementary tools to solve diagnostic dilemmas. • Awareness of salient imaging pearls and diagnostic pitfalls avoids interpretation errors.