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How targeted therapies and immunotherapies shape tumors, and thereby influence subsequent therapeutic responses, is poorly understood. In the present study, we show, in melanoma patients and mouse models, that when tumors relapse after targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies. We find that cross-resistance is mediated by a cancer cell–instructed, immunosuppressive tumor microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response. Restoring the numbers and functionality of CD103+ dendritic cells can re-sensitize cross-resistant tumors to immunotherapy. Cross-resistance does not arise from selective pressure of an immune response during evolution of resistance, but from the MAPK pathway, which not only is reactivated, but also exhibits an increased transcriptional output that drives immune evasion. Our work provides mechanistic evidence for cross-resistance between two unrelated therapies, and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy. Obenauf and colleagues report that acquired resistance to BRAF and MEK inhibitors in melanoma confers cross-resistance to immune checkpoint blockade by fostering a cancer cell–instructed, immune-evasive tumor microenvironment.

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy., The regulation of tumor inflammation is incompletely understood and the role of B cells is unclear. Here, the authors show that a specific subtype of B cells is induced in melanoma and required to recruit T lymphocytes and elicit inflammation.

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer’s proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer’s model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged

Background Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established. Objectives To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue. Methods We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one. Results Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. Conclusions Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.

Specific history-taking, drawing a family tree and thorough clinical examination are explained in detail. Standards and calibration in audiometry are presented. Pure-tone audiometry (PTA) and principles of masking, loudness tests and dead-region testing are outlined. Different test methods of behavioural measurements in children are provided.

The prognosis of childhood hearing impairment depends upon the type of hearing disorder diagnosed, its severity and time of onset, the time points at which the hearing impairment was detected and treatment begun, the nature and quality of the treatment and of professional and family support and the presence of associated disorders.

A number of common driver mutations have been identified in melanoma, but other genetic or epigenetic aberrations are also likely to play a role in the pathogenesis of melanoma and present potential therapeutic targets. Translocations of the anaplastic lymphoma kinase (ALK), for example, have been reported in spitzoid melanocytic neoplasms leading to kinase-fusion proteins that result in immunohistochemically detectable ALK expression. In this study, we sought to determine whether ALK was also expressed in non-spitzoid primary and metastatic cutaneous melanomas. ALK immunohistochemistry (IHC) was performed on 603 melanomas (303 primary and 300 metastatic tumors) from 600 patients. ALK IHC expression was identified in 7 primary and 9 metastatic tumors. In 5 of 7 primary tumors and in 6 of 9 metastatic lesions, the majority of tumor cells were immunoreactive for ALK. In the other two primary and three metastatic lesions, positive staining was identified in less than half of the tumor cells. ALK-positivity was found in the presence or absence of BRAF or NRAS mutations. In contrast to prior observations with ALK-positive Spitz tumors, none of the ALK-positive melanomas harbored a translocation. Instead, the ALK-positive melanomas predominantly expressed the recently described ALK isoform, ALKATI, which lacks the extracellular and transmembrane domains of wild-type ALK, consists primarily of the intracellular tyrosine kinase domain, and originates from an alternative transcriptional initiation (ATI) site within the ALK gene. The findings are clinically relevant as patients with metastatic melanoma who have ALK expression may potentially benefit from treatment with ALK kinase inhibitors.

Objectives It is essential to monitor hearing status in children not only as a mandatory requirement during universal newborn hearing screening (UNHS), but also later during preschool and school-age development. The present study considers the appropriateness of the Frequency-specific Animal Sound Test (FAST4) for use in children between the ages of 2.5 and 10 years; the comparability of hearing thresholds determined using FAST4 and those measured by pure tone audiometry (PTA); and the clinical and diagnostic utility of FAST4 in a variety of pediatric settings. Methods 322 children aged 2.6–14.1 years and 41 adults were tested with FAST4. Four animal sounds were presented via headphones and a hearing threshold was determined for the high and low frequency range. In addition, the hearing threshold of each child was measured by PTA. Results Results were analyzed from 156 normal-hearing and hearing-impaired children, mostly above the age of 4 years. In general, FAST4 yielded hearing levels comparable with those from PTA in children and in adults. FAST4 frequently had to be halted prematurely in children under 4 years old. Conclusions FAST4 is a strong candidate for use as an instrument for preschool hearing screening and offers several advantages over other hearing tests. FAST4 permits simple, swift and efficient determination of the hearing threshold and the test can be administered by staff without specialist training. A number of improvements have already been integrated into the successor model known as mFAST.

Angiosarcomas are rare malignant mesenchymal tumors of endothelial differentiation. The clinical behavior is usually aggressive and the prognosis for patients with advanced disease is poor with no effective therapies. The genetic bases of these tumors have been partially revealed in recent studies reporting genetic alterations such as amplifications of MYC (primarily in radiation-associated angiosarcomas), inactivating mutations in PTPRB and R707Q hotspot mutations of PLCG1. Here, we performed a comprehensive genomic analysis of 34 angiosarcomas using a clinically-approved, hybridization-based targeted next-generation sequencing assay for 341 well-established oncogenes and tumor suppressor genes. Over half of the angiosarcomas (n = 18, 53%) harbored genetic alterations affecting the MAPK pathway, involving mutations in KRAS, HRAS, NRAS, BRAF, MAPK1 and NF1, or amplifications in MAPK1/CRKL, CRAF or BRAF. The most frequently detected genetic aberrations were mutations in TP53 in 12 tumors (35%) and losses of CDKN2A in 9 tumors (26%). MYC amplifications were generally mutually exclusive of TP53 alterations and CDKN2A loss and were identified in 8 tumors (24%), most of which (n = 7, 88%) arose post-irradiation. Previously reported mutations in PTPRB (n = 10, 29%) and one (3%) PLCG1 R707Q mutation were also identified. Our results demonstrate that angiosarcomas are a genetically heterogeneous group of tumors, harboring a wide range of genetic alterations. The high frequency of genetic events affecting the MAPK pathway suggests that targeted therapies inhibiting MAPK signaling may be promising therapeutic avenues in patients with advanced angiosarcomas. OA gold

Hintergrund Spitzoide melanozytare Neoplasien (Spitz-Navi, atypische Spitz-Tumoren, spitzoide Melanome) sind eine klinisch, histopathologisch und genetisch heterogene Gruppe melanozytarer Hauttumoren.

Spitz tumors are a group of melanocytic neoplasms with distinct morphological features that tend to affect young individuals. Distinguishing benign from malignant Spitz tumors can be challenging, but cytogenetic and molecular tests have contributed to improvements in diagnostic accuracy. Spitz tumors harbor diverse genetic alterations, including mutations in HRAS, loss of BAP1, or kinase fusions in ROS1, NTRK1, ALK, BRAF, and RET genes. Limited data exist on the correlation between histopathological features and kinase fusions. Here, we describe the histopathological features of 105 Spitz tumors (Spitz nevi and atypical Spitz tumors), comparing lesions according to their immunoreactivity for ALK or NTRK1. Intersecting fascicular growth of fusiform melanocytes was seen in all but one ALK-positive tumor (27 of 28 or 96.4%), whereas it was infrequent in NTRK1-positive tumors (5 of 20 or 25.0%) and tumors negative for both ALK and NTRK1 (96.4% vs 25.0% vs 8.7%, P < .0027). There was a trend toward ALK-positive tumors being amelanotic compared with NTRK1-positive tumors and combined ALK-/NTRK1-negative tumors (89.3% vs 45% vs 47.4%, respectively, P = .1023) and lacking epithelioid cell morphology (0% vs 45.0% vs 41%, respectively, P = .6985). In conclusion, this study confirms that although not specific, the growth pattern of intersecting fascicles of amelanotic fusiform melanocytes is strongly associated with ALK expression.

Melanoma arising in the uveal tract (choroid, ciliary body and iris) is the most common intraocular malignant tumor [1]. The incidence of uveal melanoma (UM) in the US population is approximately f...

Summary Background Eruptive Spitz naevi have been reported rarely in the literature. In solitary Spitz naevi, BRAF and HRAS mutations, as well as increased copy numbers of chromosome 11p have been identified. Objectives To investigate the genetic changes underlying eruptive Spitz naevi. Methods We report on a 16-year-old boy who developed multiple disseminated eruptive Spitz naevi within a few months. We analysed BRAF, HRAS, KRAS and NRAS genes in 39 naevi from this patient for hotspot mutations. Furthermore, comparative genomic hybridization analysis was performed in three lesions. Results None of the Spitz naevi displayed a mutation in the analysed genes, and no chromosomal imbalances were observed. Conclusions Our results indicate that the typical genetic alterations described in solitary Spitz naevi appear to be absent in eruptive Spitz naevi. Yet unknown alternative genetic alterations must account for this rare syndrome.

BACKGROUND Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. METHODS We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. RESULTS We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. CONCLUSIONS Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).

Cutaneous lymphomas represent a heterogeneous group of malignant lymphoid diseases with particular tropism for the skin. Prognosis and treatment depend on the type of lymphoma, thus precise diagnosis and classification are of paramount importance. Classification of cutaneous lymphomas relies on a synthesis of all available information, including clinical history and presentation, histopathology, immunophenotype, and molecular data. Thanks to the efforts of the lymphoma groups of both the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC), a joint WHO-EORTC classification for primary cutaneous lymphomas has been proposed in 2005. The WHO-EORTC classification has been adsorbed with minor changes in the 2008 WHO classification of tumours of haematopoietic and lymphoid tissues, thus including for the first time primary cutaneous lymphomas as distinct subtypes of extranodal lymphomas in a general classification of lymphomas.

Despite the introduction of universal newborn hearing screening (UNHS), unilateral hearing loss (UHL) is sometimes recognized late. This diagnostic delay has adverse repercussions, given the importance of binaural hearing for the development of normal auditory processing. It is incorrect to maintain that unilateral hearing is the minimum requirement for adequate speech development and that hearing aid provision is consequently unnecessary. In our retrospective study, hearing aid provision resulted in improved directional and selective hearing (quiet and noisy environments) and, compared with their chronically ill counterparts, the children in our study displayed superior health-related quality of life (HRQoL) scores in all areas. On the basis of the results, the authors conclude that even mild hearing losses (from an auditory threshold of 30 to 40 dB) should have the opportunity for hearing aid provision. A selective literature review was conducted in PubMed and textbooks and with reference to national and international guidelines. Early diagnosis and treatment of UHL have a positive effect on verbal-cognitive, linguistic, communicative, and socio-emotional development, as demonstrated by neurophysiological studies. Among the treatment modalities with differing effects on the quality of binaural hearing, cochlear implants are now used increasingly in children with hearing loss bordering on deafness.Published evidence and clinical experience support early diagnosis and treatment. Wherever feasible, hearing aid provision before or at the end of the first year of life is recommended for children with UHL. What is Known: • Almost 30 years ago, poor academic performance was reported in children with unilateral hearing loss (UHL). • Despite improvements in treatment options, it is traditionally held that unilateral hearing is the minimum requirement for adequate speech development and hearing aid provision is unnecessary. What is New: • Academic and behavioral deficits in children with UHL may be mediated by deficiencies in the default mode network. • Published evidence supports the recommendation for hearing aid provision before or at the end of the first year of life in children with UHL.

Because of an expected increasing use of harmonic producing devices, the harmonic content in electrical distribution networks attracts more and more attention. Primarily, harmonics are caused by modern loads, which are connected to the electrical grid by power electronic interfaces. In order to analyze the effects of a widespread use of such nonlinear appliances, suitable nonlinear models have to be developed. This paper focusses on the practical implementation of an advanced mathematical approach, which is described theoretically in literature as the coupled Norton model. In order to consider the voltage dependency of current distortions, this approach describes the nonlinearity in time domain as a linear set of equations in frequency domain. This theoretical idea is analyzed and verified by suitable measurements. The model parameters are evaluated and validated for different groups of nonlinear devices. Because of a significant dependency of the model parameters on the underlying measurement set, special requirements are outlined. Furthermore, in order to apply the resulting nonlinear models in harmonic studies, an iterative harmonic load flow is proposed.

Cutaneous lesions of lupus erythematosus (LE) show a broad spectrum of clinicopathologic features. Histopathologically, besides typical patterns such as interface dermatitis, perivascular lymphocytic infiltrate and dermal mucin deposits, an involvement of the eccrine structures, especially the acrosyringium, may be observed. We describe the case of a 21-year-old woman with a 4-year history of systemic LE, who presented with a 'butterfly' rash over the cheeks as well as erythematous macules on the arms and décolleté. Biopsy from one lesion on the arm revealed interface changes, necrotic keratinocytes and exocytosis of lymphocytes restricted only to the regions of the acrosyringia. The epidermis between affected acrosyringia was normal with no hints of interface dermatitis. The eccrine glands and coils were not affected. In the dermis there were only sparse inflammatory infiltrates. Differential diagnoses such as erythema multiforme, drug eruption and lichen planus could be ruled out because of histopathologic features and clinical presentation. This is an example of a peculiar histopathological variant of cutaneous LE, characterized by exclusive involvement of the acrosyringia. The histopathologic features represent a pitfall in the diagnosis and can be correctly interpreted only upon correlation with clinical data.

Background Extranodal natural killer–/T-cell lymphoma, nasal type (ENKTCL-NT) is a highly aggressive lymphoma and prognosis is usually poor. The genetic background of primary cutaneous cases is poorly understood. Objective We sought to evaluate the clinicopathologic features of cutaneous ENKTCL-NT, and the prognostic significance of genomic copy number alterations. Methods Eight cases of cutaneous ENKTCL-NT (5 primary, 2 secondary, 1 no staging performed), including 2 patients with an unusually prolonged course of 5 and 23 years, were investigated using array comparative genomic hybridization. Results All patients presented with typical clinicopathologic features. Epstein-Barr virus was found in neoplastic cells in all specimens. Copy number alterations were detected in all 8 cases with losses on 6q (37.5% of cases) and 7p (37.5% of cases), and gains on 7q (37.5% of cases) being the most frequent. Complexity of array comparative genomic hybridization profile did not correlate with the course of the disease. However, an increase of copy number alterations was detected in sequential biopsy specimens of 1 long-term survivor. Limitations This was a small case series retrospective study. Conclusion Clinicopathologic features of cutaneous ENKTCL-NT are distinctive. Lower number of copy number alterations cannot be used as predictor for prolonged survival in cutaneous ENKTCL-NT.

For the evaluation of data generated by multicolor fluorescence in situ hybridization (FISH), we present here a synergistic approach that integrates the 3 most commonly used numerical algorithms in conjunction with 2 newly devised graphic tools for data visualization, namely "signal curves" and "rhombic heat maps." These two graphic tools provide information additional to the currently used numerical algorithms and thus facilitate the recognition and compensation of inherent errors that occur with the numerical method.

Dermatofibroma (cutaneous fibrous histiocytoma) represents a common benign mesenchymal tumor, and numerous morphological variants have been described. Some variants of dermatofibroma are characterized by an increased risk of local recurrences, and there are a few reported metastasizing cases. Unfortunately, an aggressive behavior cannot be predicted reliably by morphology at the moment, and we evaluated the value of array-comparative genomic hybridization (CGH) in this setting. Seven cases of clinically aggressive dermatofibromas were identified, and pathological and molecular features were evaluated. The neoplasms occurred in four female and in three male patients (mean age was 33 years, range 2–65 years), and arose on the shoulder, buttock, temple, lateral neck, thigh, ankle, and cheek. The size of the neoplasms ranged from 1 to 9 cm (mean: 3 cm). An infiltration of the subcutis was seen in five cases. Two neoplasms were completely excised, whereas an incomplete or marginal excision was reported in the remaining cases. Local recurrences were seen in six cases (time to the first recurrence ranged from 8 months to 9 years). Metastases were noted between 3 months and 8 years after diagnosis in six patients. Two patients died of disease, and two patients are alive with disease. Histologically, the primary tumors showed features of cellular dermatofibroma (four cases), cellular/aneurysmal dermatofibroma (one case), atypical/cellular dermatofibroma (one case), and classical dermatofibroma (one case). Mitotic figures ranged from 3 to 25 per 10 high-power fields, and focal necrosis was present in five cases. Interestingly, malignant transformation from cellular dermatofibroma to an obvious spindle cell/pleomorphic sarcoma was seen in one primary and in one recurrent neoplasm. Five neoplasms showed chromosomal aberrations by array-CGH, suggesting that these changes may represent an additional diagnostic tool in the recognition of cases of dermatofibroma with a metastatic potential.

Electronic components used in high power applications must be able to deal with rough operating conditions, like frequent changes of temperature, mechanical stress and short-term electrical overload. An important factor in this context is the electronic packaging, especially the electrical interconnection between the die and the output pins. In order to evaluate the effects of thermo-mechanical stress on the electrical interconnections during the lifetime (which can be up to 25 years), a simulation using the finite-element method is the mainly used approach. Another possibility is to simulate stress cycles through applying an equivalent mechanical or electrical load with regards to the expected operating conditions. To evaluate the results of the stress simulation on the electrical interconnections, the chip package must be cut open and this implies mechanical stress. This paper presents a preliminary investigation for a non destructive evaluation of electrical interconnections in integrated circuits via magnetic imaging.

Fluorescence in situ hybridization (FISH) for the diagnosis of melanoma makes use of specific fluorescent probes to detect selected chromosomal alterations on paraffin-embedded tissue samples. To date, interpretation of FISH data has been based on numerical values generated by 2 different computational algorithms that of Abbott and that of Gerami. To further evaluate the value of FISH in the diagnosis of malignant melanoma, we selected 163 clinically and histologically unequivocal cases of malignant melanoma in a cohort of 575 melanocytic tumors and analyzed FISH data using the criteria of Abbott, Gerami, and new combined criteria. Depending on the used criteria, FISH was positive in the unequivocal malignant melanoma in 69.3% (113/163) of cases using the Abbott criteria, 74.2% (121/163) of cases using the Gerami criteria, and 82.2% (134/163) of cases using the combined criteria of Abbott and Gerami. Although use of all 3 criteria was associated with 100% FISH negativity in a cohort of 30 unequivocal benign melanocytic nevi, use of the combined criteria revealed more FISH-positive cases in ambiguous benign melanocytic lesions than the criteria of Abbott or Gerami alone: Abbott, 125 of 367; Gerami, 146 of 367; combined, 161 of 367. Furthermore, we show that 66% (8/12) of FISH-negative cases of unequivocal melanoma are positive when analyzed by array comparative genomic hybridization (aCGH), demonstrating that false-negative results remain despite the usage of the combined criteria for evaluation of FISH data. In these 8 FISH-negative aCGH-positive cases, copy number alterations were often located on chromosomes 9p, a chromosomal locus that is not targeted by the FISH probes currently used. In conclusion, the existing criteria for the evaluation of multicolor melanocytic FISH are limited by a nonnegligeable rate of false negativity that can be reduced by using newly proposed combined criteria but at the cost of increased detection of FISH positivity in ambiguous benign melanocytic lesions.

Background Data on early lesions of primary cutaneous follicle center lymphoma (PCFCL), diffuse type are very limited. Objective We sought to elucidate the early clinicopathologic features of PCFCL, diffuse type. Methods Clinical, histologic, immunohistologic, molecular, and fluorescence in situ hybridization data from 24 patients with early lesions of PCFCL, diffuse type (male:female = 19:5; median age: 57 years) were determined. Results Lesions consisted mostly of solitary or clustered papules and small nodules located on the trunk (21 cases), arm (two cases), and scalp (one case). In 3 patients small papules were located at a distance from the main affected area. All biopsy specimens from early lesions showed aggregates of medium and large centrocytes admixed with small lymphocytes without formation of clear-cut lymph follicles. Staining for Bcl-2 was positive in only 7 cases, one revealing also a rearranged BCL2 signal by fluorescence in situ hybridization. Data on treatment and follow-up were available for 22 patients. At last examination 13 patients were in complete remission (median follow-up: 60 months), 6 were alive with skin disease alone (median follow-up: 60 months), two were alive with skin disease and bone-marrow or lymph node involvement, respectively, and one died of unrelated causes while in complete remission. Limitations The retrospective study and the fact that patients were treated at different institutions are limitations. Conclusions Early lesions of PCFCL, diffuse type present with characteristic clinicopathologic features. Dermatologists should be alert particularly to the early clinical manifestations of this lymphoma and to the presence of small, inconspicuous lesions at a distance from the main affected area in order to plan treatment properly.

Previously presented results of the newborn hearing screening in Hamburg and the perspectives are subsequently discussed. Minimum standards referring a participation of 95% of the neonates and a fail rate of less than 4% hearing-impaired children at the primary screening are fulfilled in Hamburg. Systematic screening of newborn hearing by an interdisciplinary approach provides early identification and intervention for children with permanent unilateral and bilateral hearing loss. But a newborn hearing screening on a voluntary basis alone cannot be maintained in the long run. Further, an anonymous data collection is not sufficient in regard to an uninterrupted tracking of conspicuous and unscreened neonates. A lost-to-follow-up rate of 31.3% at primary screening in Hamburg is much too high and emphasizes the need for a public health approach to a population-based newborn hearing screening with an elaborate and name-based tracking system. The legislation and implementation of a nationwide newborn hearing screening program in Germany and the association of German newborn hearing screening centers are highlighting long efforts of hearing professionals. But the implementation of a newborn hearing screening only makes sense if there exists an efficient tracking system. Sad to say, we are still a long way from the implementation of such a tracking system.

The actual, globally established, general digital procedures in basic architectural education,producing well-behaved, seemingly attractive up-to-date projects, spaces and first general-researchon all scale levels, apparently present a certain growing amount of deficiencies. These limitations surface only gradually, as the state of things on overall extents is generally deemed satisfactory. Some skills, such as "old-fashioned” analogue drawing are gradually eased-out ofundergraduate curricula and overall modus-operandi, due to their apparent slow inefficiencies in regard to various digital media's rapid readiness, malleability and unproblematic, quotidian availabilities. While this state of things is understandable, it nevertheless presents a definite challenge. The challenge of questioning how the assessment of conditions and especially their representation,is conducted, prior to contextual architectural action(s) of any kind.

9002 Background: Spitz tumors are melanocytic neoplasms with characteristic morphologic features that can overlap with melanoma. Predicting biologic behavior, which can range from an indolent disease to metastasis confined to regional lymph nodes and infrequent incidences of widespread metastatic disease with lethal outcome, is unreliable based on histopathological criteria and the genetic underpinnings of the disease as a whole are poorly understood. Methods: Genomic DNA and total RNA was isolated from 40 microns of FFPE sections from 20 benign Spitz nevi and 8 atypical Spitz tumors (with morphological features inconsistent with HRAS or BRAF/BAP1 mutations) in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3230 exons of 182 cancer-related genes plus 37 introns of 14 genes commonly fused on indexed hybridization-captured libraries to an average unique coverage of 997x, with 99.96% of exons being sequenced at ≥100x coverage. RNA sequencing was performed on indexed libraries captured using the cDNA Kinome hybridization kit (Agilent) generating >50,000,000 unique pairs per specimen. Results: Only a single case harbored a point mutation in a gene known to be recurrently mutated in melanocytic neoplasms, HRAS Q61L and no known alterations were found in BRAF, NRAS, KIT, GNAQ or GNA11. Remarkably, genomic rearrangements were observed in 19/28 (68%) of cases. The rearrangements fused the intact kinase domains of ROS1 (36%), ALK (14%), RET (7%), NTRK1 (7%) and BRAF (4%) to a wide range of predominantly novel 5’ partners including PWWP2A, PPFIBP1, ERC1, MYO5A, CLIP1, HLA-A, ZCCHC8, DCNT1, LMNA and CEP89. These gene rearrangements, which were all expressed, formed constitutively activated chimeric oncogenes. All fusions occurred in a mutually exclusive pattern and were more common in younger patients compared to patients whose tumors did not harbor fusions (median age 14 versus 24 years, p=0.02). Conclusions: Next generation sequencing identified gene fusions in two thirds of Spitz tumors which are likely to be useful as diagnostic markers that may also serve as therapeutic targets for the rare subset of these tumors that metastasize.

Background Transepidermal melanocytic migration (TEM) is an important diagnostic criterion for malignancy, especially in association with cytologic atypia. However, TEM may also be observed in benign melanocytic tumors, such as Spitz nevus, acral nevi, or nevi in infancy. We discuss the value of TEM for the diagnosis of melanocytic tumors in a young patient previously diagnosed as having 11 cutaneous melanomas. Observation A 17-year-old patient with a history of 11 cutaneous melanomas diagnosed in the past 3 years by different expert dermatopathologists presented in our department. The previous histological diagnoses of melanoma were mainly based on the presence of important TEM. A reevaluation of all histological specimens in light of the clinical context and the lack of genomic aberrations as detected by array-comparative genomic hybridization led to a revision of the previous diagnoses. The striking TEM observed represents, in our opinion, a constitutional element of the melanocytic nevi in this patient and not a marker of malignancy. Conclusion Awareness of this finding is important to avoid overdiagnosis of melanoma in cases of melanocytic nevi.

In January, 2007, a 36-year-old man presented to his derma tologist, with a 3-month history of constant itching of his head, neck, shoulders, and upper limbs. The itch had become so intense that it disturbed the patient’s sleep; it had a burning character, especially when the patient was wearing clothes. Treatment with topical cortico steroids and oral antihistamines produced no improve ment. The patient took no other regular medications, except occa sional nonsteroidal anti-infl ammatory drugs to relieve inter mittent neck pain: he had a 2-year history of neck pain and stiff ness. After 1 month, during which the itch contin ued to worsen, the patient was referred to us for further investigation. Physical examination showed slight redness of the aff ected skin, as well as excoriated fl at papules and erosions on the neck and forearms (fi gure). These signs were considered to be caused by rubbing and scratching. The results of blood tests, including a full blood count, plasma glucose, renal and liver function tests, and infl ammatory markers were all unremarkable. The association of neck pain, cervical stiff ness, and itch localised to areas supplied by the cervical spinal cord, pointed to a neurological cause for the itch. Neurological examination revealed abnormalities of both arms, particularly severe distally and in the right arm: hypoaesthesia, paraesthesia, muscle weakness, and reduced refl exes. Electromyography and nerve conduction tests showed an axonal injury, at the levels of the fi fth and sixth cervical roots. Further sensory testing revealed complete loss of heat sensation, and reduced vibration sense, in the index fi ngers of both hands, corresponding to the sixth cervical root. The symmetrical loss of motor and sensory function led us to suspect a lesion of the cervical spinal cord, aff ecting most or all of its width. Cervical MRI showed a lesion extending from the level of the fi rst to the seventh cervical vertebra, with prominent perifocal oedema. The lesion was excised by a decom pressive laminectomy, and was found to be an ependymoma on histopathological analysis. Irritation of the spinal cord, during the operation, caused weakness of all the patient’s limbs. This weakness decreased during residential rehabilitation; by April, 2007, the patient had regained most of his strength and coordination. The itch was no longer present. In May, 2007, the patient started to receive radiotherapy, to ensure that the tumour was eradicated. Sadly, he then developed a fi stula extending from the spinal cord to the skin—through which cerebrospinal fl uid leaked—and a subse quent infection of the fi stula and the surrounding tissue, though not of the spinal cord itself. The cord was seen on MRI to be oedematous. When last seen, in May, 2007, the patient had severe neurological defi cits—although, ironically, no itch. Itch can be classifi ed into four types: pruritoceptive, psychogenic, neurogenic, and neuropathic. 1