[The pathology of adverse events with immune checkpoint inhibitors]. / Pathologie der Nebenwirkungen von Immune-Checkpoint-Inhibitoren.

BACKGROUND: Immunotherapy has gained importance with the development of new effective cancer treatments. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that promote T­cell mediated tumor immune rejection. Checkpoint blockade also carries the risk of inducing autoimmune reactions ("immune related adverse events", irAEs). The diagnosis and classification of irAEs constitute a new and important field in pathology. AIM: Practice-oriented review of the diagnosis and classification of irAEs. MATERIALS AND METHODS: Structured, selective literature review based on PubMed und UpToDate ® online. RESULTS: The most common irAEs affect the skin, the gastrointestinal tract, the liver, and the respiratory system. The correct diagnosis and classification of irAEs by an interdisciplinary care team is essential for appropriate therapy and the prevention of long-term sequelae. Other important irAEs affect the endocrine organs, the heart, the joints, the kidneys and the nervous system. Because of their rarity and/or limited options for bioptic diagnosis, only limited data on the morphology and pathophysiology of these irAEs are currently available. Autopsies carried out after ICI therapy constitute an important element of quality control and allow better documentation of the incidence and pathogenesis of irAEs. DISCUSSION: Pathology plays a central role in the diagnosis and treatment of irAEs. Future studies may contribute to a better mechanistic understanding of irAEs for individualized knowledge-based risk assessment.

[PSAP expression in a primary presacral neuroendocrine tumor. Potential for confusion with prostate cancer]. / PSAP-Expression in einem primären präsakralen neuroendokrinen Tumor. Verwechslungsmöglichkeit mit einem Prostatakarzinom.

Primary presacral neuroendocrine tumors are a rare entity with less than 30 cases described in the literature so far. Here we report of a primary presacral neuroendocrine tumor diagnosed at autopsy which was wrongly diagnosed as metastasized prostate cancer before. Misdiagnosis was due to the localization of the tumor, its morphology and its positivity for prostate-specific acid phosphatase (PSAP) when the patient was alive. This is the first report of PSAP and somatostatin receptor expression in this type of tumor.

[Embolization of hydrophilic guide wire coating]. / Embolisation von Katheterbeschichtung in das Myokard.

The number of interventional cardiovascular procedures has been rising steadily. Such procedures include the intravascular insertion of catheters and guide wires. These devices consist of a metallic core and coil that may be covered by hydrophilic coating to ease crossability and control for challenging lesions. We report two cases where insertion of a ChoICE® PT guide wire into the coronary artery led to embolization of the hydrophilic coating material with occlusion of small intramyocardial arteries.

Acute toxoplasmosis mimicking melanoma metastases: review of conditions causing false-positive results on (18)F-FDG PET/CT.

Invasive malignant melanoma is the most common fatal form of skin cancer. Fluorine-18-fluorodeoxyglucose positron emission tomography-computed tomography demonstrates a very high sensitivity and specificity for the detection of melanoma metastases. Here, we report an unusual case of toxoplasma lymphadenitis in a male adult patient mimicking a malignant cervical lymphadenopathy. Toxoplasmosis is a zoonosis caused by the intracellular parasite Toxoplasma gondii, which is usually asymptomatic in immunocompetent hosts.

Giant cell arteritis--a changing entity.

Giant cell arteritis (GCA) is the most common of the vasculitis syndromes and, being a disease of the elderly, its incidence is increasing with the general ageing of the population. GCA is most feared for its early complications, namely blindness and stroke, resulting from inflammation and subsequent occlusion of ocular and extra cranial arteries, respectively. More recently, however, GCA has been recognised to also affect limb arteries and the aorta with a high prevalence. These newly recognised features of GCA pose diagnostic, therapeutic and prognostic challenges to treating physicians. Here, recent developments in the field of GCA are summarised and discussed.

[Ectomesenchymal chondromyxoid tumor of the anterior tongue]. / Ektomesenchymaler chondromyxoider Tumor des vorderen Zungenabschnitts.

Ectomesenchymal chondromyxoid tumor of the anterior tongue is a rare entity. To date, 37 cases have been reported in the literature. We present the case of a 52-year-old male patient with an ectomesenchymal chondromyxoid tumor at the typical location with a characteristic lobular proliferation of ovoid and fusiform uniform tumor cells on a chondromyxoid background and showing expression of typical immunohistochemical markers GFAP and S-100. Despite its rarity, this special tumor should be considered in the differential diagnosis when dealing with localized swellings of the anterior tongue.

The cyclohexane tolerance and Phe-Arg-ß-naphtylamide susceptibility of multidrug-resistant Enterobacter cloacae clinical isolates, and the predominance of one PFGE clone in Hungary.

The report concerns the molecular epidemiology, cyclohexane tolerance and Phe-Arg-ß-naphtylamide (PAßN) susceptibility of multidrug-resistant Enterobacter cloacae isolates, with high-level fluoroquinolone resistance collected from healthcare facilities in a nationwide survey. A total of 113 multidrug-resistant E. cloacae isolates (recovered in 1997-2005) were subjected to disc diffusion tests, ERIC-PCR and XbaI PFGE. Representatives of the ERIC-types (n = 67) were tested further with cyclohexane and PAßN, using ciprofloxacin as the substrate. Forty-four per cent of the isolates were derived from the urinary tract, 19% from the bloodstream, 17% from the respiratory tract, and 15% from wound infections. Four ERIC-types (A, B, C and D) were distinguished, but 109 isolates were found to belong to a single, epidemic ERIC type: A. PFGE results suggested that the epidemic-type isolates were of monoclonal origin. Forty-two patients were involved in four outbreaks caused by the epidemic-type strains. Eighty-one cases were found to be nosocomial. At least fourfold reduction in ciprofloxacin MICs was found in the presence of PAßN in 79% of representative isolates (representing types A, C and D); an eightfold or greater reduction in ciprofloxacin MICs in the presence of PAßN (PAßN+) was found in 37% of representative isolates, representing types A and C. Eighty-five per cent of the representative isolates were found to be cyclohexane-tolerant, representing types A, C and D. This is the first report of a wide distribution of cyclohexane-tolerant or PAßN+ strains of E. cloacae. These feature-indicators of adaptive mechanisms that help bacteria to survive in hospital wards may have contributed to the nationwide spread of type A strains.

Human trichinellosis in Hungary from 1965 to 2009.

Human trichinellosis was first documented in Hungary in 1891 and then there were an increased number of reports up to 1964 when the most severe outbreak occurred. After that, no information was available on the international literature on human trichinellosis which occurred from 1965 up to the present years. The aim of this study was to collect all the data available in Hungarian official data-sources on human trichinellosis which occurred from 1965 up to 2009 in Hungary. Furthermore, a comparative analysis was performed on the different serological tests used along the 45 years of investigation. In the period in question, 573 infections were documented in Hungary. Of them, 57 occurred in the years 1965-69, 130 in 1970-79, 302 in 1980-89, 27 in 1990-99, and 57 in 200009. The most common sources of infection were pork from backyard pigs and hunted wild boars. Sporadic cases and small family outbreaks marked the last ten years. The comparison of serological tests shows that the ELISA is a good test for the first screening, but ELISA-positive serum samples should be confirmed by western blot except for clinically clear-cut cases.

[Molecular heterogeneity of malignant melanomas]. / Molekulare Heterogenität maligner Melanome.

Malignant melanomas make up a heterogeneous group of tumors characterized by particular genetic aberrations depending on their anatomic localization and UV exposure. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway is found in the majority of melanomas, with either somatic missense mutations of BRAF or, considerably more rarely, mutations of N-RAS. The loss of both products of the CDKN2A gene, proteins p16(ARF) and p14(INK4a), or amplification of microphthalmia-associated transcriptional factor (MITF) are also predisposing factors in the development of melanoma. BRAF mutations are observed mainly in melanomas on skin liable to intermittent UV exposure. Acral and mucosal melanomas, and also melanomas on skin damaged by chronic exposure to the sun are characterized by distinct patterns of chromosomal aberrations with frequent amplifications and alterations of the KIT gene, while BRAF mutations are rarely found in these sites. Uveal melanomas show recurrent chromosomal losses (1p, 3, 6q) and gains (6p, 8q), but mutations of BRAF are hardly ever found. So far, ancillary molecular studies are not regularly applied in the routine diagnostic procedures performed when malignant melanoma is suspected. In the future, however, the development of targeted molecular therapies will require that molecular pathological techniques are used to identify the melanoma patients who will most probably benefit from a particular therapy.

[Cytology in the internet]. / Zytologie im Internet.

Computer-based learning (E-learning) is of increasing importance for the education of students and professionals. Various publicly accessible online courses for cytologists now exist and some of these are presented in this paper. For the learning platform Patho-Basiliensis (http://www.unibas.ch/patho/) we have developed several learning materials: a database of 726 cytology images, a cytopathology course to teach the basics of cytopathology, and a game testing histologic-cytologic correlation. Tests on lung and urinary cytology were attended by 383 international participants. The virtual microscopy technology will revolutionize telecytology and cytology education.

[Management and causes of pneumocephalus. Case report and review of the literature]. / Ursachen und Management des Pneumenzephalus. Fallbericht und Ubersicht.

Pneumocephalus is commonly seen after head and facial trauma, tumors of the skull base, after neurosurgery or otorhinolaryngology, and rarely spontaneously. Venous air embolism can result from right-to-left shunting or pneumocephalus. We report two cases of pneumocephalus, one after surgery of the paranasal sinus and the other after transabdominal prostatectomy. Clinical signs of the pneumocephalus were headache followed by epileptic seizures and, respectively, severely impaired consciousness after the operation. Treatment was either revision of the skull base with craniotomy or conservative therapy of the brain edema. Based on these case reports and the medical literature on pneumocephalus, we review the causes and treatment of this rare condition.

Glucocorticoid-regulated human serotonin transporter (5-HTT) expression is modulated by the 5-HTT gene-promotor-linked polymorphic region.

Mood, emotion and cognition are modulated by serotonergic neurotransmission, while the physiological function of serotonergic synapses depends on serotonin reuptake, which is mediated by the serotonin transporter (5-HTT). Allelic variation of 5-HTT expression in humans is caused by a functional gene-promoter polymorphism with two predominant variant alleles, which are associated with variations in anxiety measures as previously reported. Here we report that administration of dexamethasone, a potent glucocorticosteroid hormone, results in an increase in 5-HTT expression in immortalized human B-lymphoblastoid cells, which express the human 5-HTT. Functional reporter gene assays as well as 5-HT uptake and inhibitor binding measures revealed a genotype-dependent dose-response to glucocorticosteroid administration, which was antagonized by RU 38486, a non-specific glucocorticosteroid hormone antagonist. The allele-specific differences after administration of dexamethasone depended on the repetitive GC-rich sequence located approximately 1.4 kb upstream of the 5-HTT gene transcription site because of absence of a significant steroid effect after transfecting a deletional mutant reporter gene construct, which lacks this repetitive promoter sequence. Our findings may contribute to explain the vulnerability to stress-related disorders in susceptible individuals, in whom further clinical studies should follow up on these in vitro findings.

Emergence of extremely high penicillin and cefotaxime resistance and high-level levofloxacin resistance in clinical isolates of Streptococcus pneumoniae in Hungary.

Oxacillin disc diffusion tests revealed that 36.7% of 327 Hungarian Streptococcus pneumoniae strains from clinical specimens were not penicillin susceptible. Determination of the MICs of penicillin, cefotaxime and levofloxacin for these strains by Etest confirmed that 30 (9.2%), 19 (5.8%) and four to 11 (1.2-3.4%) were fully penicillin-, cefotaxime- and levofloxacin-resistant, respectively. Most had extremely high MICs. Lower respiratory tract strains were more resistant than those from the upper respiratory tract. Levofloxacin-resistant strains were either penicillin intermediate or resistant, but their MICs did not correlate strongly.

Functional characterization of the murine serotonin transporter gene promoter in serotonergic raphe neurons.

We have isolated and characterized the 5'-flanking regulatory region of the murine serotonin 5-HT transporter (5-HTT) gene. A TATA-like motif and several potential binding sites for transcription factors, including two AP1, several AP2 and AP4 binding sites, CCAAT and GC boxes (SP1 binding sites), a nuclear factor-kappaB, and a cyclic AMP response element-like motif, are present in the 5'-flanking region. A approximately 2.2-kb fragment (-2,143 to +51 with respect to the transcription start site), which had been fused to the luciferase reporter gene and transiently expressed in a 5-HTT-expressing cell line and in serotonergic raphe neurons derived from embryonic rat brainstem, displayed both constitutive and inducible promoter activity. Functional promoter mapping revealed two clusters of activating elements from bp -82 to -527 and bp -1,001 to -1,937. A cell/neuron-selective silencer element(s) is contained between bp -294 and -527. Our findings suggest that (1) the murine 5-HTT gene promoter is active in serotonergic raphe neurons but significantly repressed in neuronal cells from frontal cortex that do not express 5-HTT, (2) the information contained within approximately 0.5 kb of the 5'-flanking sequence is sufficient to confer its cell-selective expression, (3) the promoter responds to cyclic AMP- and protein kinase C-dependent induction, and (4) the expression of the 5-HTT is regulated by a combination of positive and negative cis-acting elements operating through a basal promoter unit defined by a TATA-like motif. Fusion of the 5-HTT gene promoter unit to a gene of choice may aid its cell-selective expression in transgenic strategies.

Gene structure and 5'-flanking regulatory region of the murine serotonin transporter.

By modulating the magnitude and duration of postsynaptic responses, carrier-facilitated serotonin (5-HT) transport into and release from the presynaptic neuron is central to the fine tuning of serotonergic neurotransmission. The 5-HT transporter (5-HTT) is the prime target for widely used antidepressants, psychostimulants, drugs of abuse and neurotoxins. We have isolated the gene encoding the murine 5-HTT and determined the sequence of all exons including adjacent intronic regions and approximately 3.6 kb of the 5'-flanking regulatory region. The murine 5-HTT gene is composed of 14 exons spanning approximately 34 kb. The single gene transcript after splicing is 2744 bp in length and it contains 186 bp of 5' untranslated region (5'-UTR) and 668 bp of 3'-UTR. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, AP4, SP1 as well as CRE- and GRE-like motifs are present in the GC-rich 5'-flanking region. The characterization of murine 5-HTT cDNA and genomic organization will facilitate studies of 5-HT uptake function with molecular pharmacologic and transgenic strategies as well as investigations of its role in quantitative traits and psychiatric disorders.

The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication.

By conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter gene's 5'-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio, years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and non-human primate populations.