Artificial intelligence in digital pathology of cutaneous lymphomas: A review of the current state and future perspectives.

Primary cutaneous lymphomas (CLs) represent a heterogeneous group of T-cell lymphomas and B-cell lymphomas that present in the skin without evidence of extracutaneous involvement at time of diagnosis. CLs are largely distinct from their systemic counterparts in clinical presentation, histopathology, and biological behavior and, therefore, require different therapeutic management. Additional diagnostic burden is added by the fact that several benign inflammatory dermatoses mimic CL subtypes, requiring clinicopathological correlation for definitive diagnosis. Due to the heterogeneity and rarity of CL, adjunct diagnostic tools are welcomed, especially by pathologists without expertise in this field or with limited access to a centralized specialist panel. The transition into digital pathology workflows enables artificial intelligence (AI)-based analysis of patients' whole-slide pathology images (WSIs). AI can be used to automate manual processes in histopathology but, more importantly, can be applied to complex diagnostic tasks, especially suitable for rare disease like CL. To date, AI-based applications for CL have been minimally explored in literature. However, in other skin cancers and systemic lymphomas, disciplines that are recognized here as the building blocks for CLs, several studies demonstrated promising results using AI for disease diagnosis and subclassification, cancer detection, specimen triaging, and outcome prediction. Additionally, AI allows discovery of novel biomarkers or may help to quantify established biomarkers. This review summarizes and blends applications of AI in pathology of skin cancer and lymphoma and proposes how these findings can be applied to diagnostics of CL.

Getting it Right the First Time: Frozen Sections for Diagnosing Necrotizing Soft Tissue Infections.

BACKGROUND: The aim of this study was to investigate which histopathologic findings are most indicative for necrotizing soft tissue infections (NSTIs) in ambivalent cases. METHODS: Patients undergoing surgical exploration for suspected NSTIs with obtainment of incisional biopsies for histopathological assessment were included from January 2013 until August 2019. The frozen sections and formalin-fixed paraffin-embedded (FFPE) samples were retrospectively re-assessed. The primary outcome was the discharge diagnosis. RESULTS: Twenty-seven (69%) biopsies of the 39 included samples were from patients with NSTIs. Microscopic bullae (p = 0.043), severe fascial inflammation (p < 0.001) and fascial necrosis (p < 0.001) were significantly more often present in the NSTI group compared to the non-NSTI group. Muscle edema (n = 5), severe muscle inflammation (n = 5), muscle necrosis (n = 8), thrombosis (n = 10) and vasculitis (n = 5) were most frequently only seen in the NSTI group. In thirteen tissues samples, there were some discrepancies between the severity of findings in the frozen section and the FFPE samples. None of these discrepancies resulted in a different diagnosis or treatment strategy. CONCLUSION: Microscopic bullae, severe fascial or muscle inflammation, fascial or muscle necrosis, muscle edema, thrombosis and vasculitis upon histopathological evaluation all indicate a high probability of a NSTI. At our institution, diagnosing NSTIs is aided by using intra-operative frozen section as part of triple diagnostics in ambivalent cases. Based on the relation between histopathologic findings and final presence of NSTI, we recommend frozen section for diagnosing NSTIs in ambivalent cases.

Ethical considerations for modern molecular pathology.

Molecular pathology is becoming an increasingly important discipline in oncology as molecular tumor characteristics will increasingly determine targeted clinical cancer care. In recent years, many technological advances have taken place that contributed to the development of molecular pathology. However, attention to ethical aspects has been lagging behind as illustrated by the lack of publications or professional guidelines. Existing guidelines or publications on ethical aspects of DNA sequencing are mostly aimed at germline or tumor sequencing in clinical genetics or biomedical research settings. As a result, large differences have been demonstrated in the process of tumor sequencing analysis between laboratories. In this perspective we discuss the ethical issues to consider in molecular pathology by following the process of tumor DNA sequencing analysis from the preanalytical to postanalytical phase. For the successful and responsible use of DNA sequencing in clinical cancer care, several moral requirements must be met, for example, those related to the interpretation and returning of genetic results, informed consent, and the retrospective as well as future use of genetic data for biomedical research. Many ethical issues are new to pathology or more stringent than in current practice because DNA sequencing could yield sensitive and potentially relevant data, such as clinically significant unsolicited findings. The context of molecular pathology is unique and complex, but many issues are similar to those applicable to clinical genetics. As such, existing scholarship in this discipline may be translated to molecular pathology with some adaptations and could serve as a basis for guideline development. For responsible use and further development of clinical cancer care, we recommend that pathologists take responsibility for the adequate use of molecular analyses and be fully aware and capable of dealing with the diverse, complex, and challenging aspects of tumor DNA sequencing, including its ethical issues. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A 5-Year Evaluation of the Implementation of Triple Diagnostics for Early Detection of Severe Necrotizing Soft Tissue Disease: A Single-Center Cohort Study.

BACKGROUND: The standardized approach with triple diagnostics (surgical exploration with visual inspection, microbiological and histological examination) has been proposed as the golden standard for early diagnosis of severe necrotizing soft tissue disease (SNSTD, or necrotizing fasciitis) in ambivalent cases. This study's primary aim was to evaluate the protocolized approach after implementation for diagnosing (early) SNSTD and relate this to clinical outcome. METHODS: A cohort study analyzing a 5-year period was performed. All patients undergoing surgical exploration (with triple diagnostics) for suspected SNSTD since implementation were prospectively identified. Demographics, laboratory results and clinical outcomes were collected and analyzed. RESULT: Thirty-six patients underwent surgical exploration with eight (22%) negative explorations. The overall 30-day mortality rate was 25%, with an early, SNSTD-related mortality rate of 11% (n = 3). Of these, one patient (4%) underwent primary amputation, but died during surgery. No significant differences between baseline characteristics were found between patients diagnosed with SNSTD in early/indistinctive or late/obvious stage. Patient diagnosed at an early stage had a significantly shorter ICU stay (2 vs. 6 days, p = 0.031). Mortality did not differ between groups; patients who died were all ASA IV patients. CONCLUSION: Diagnosing SNSTD using the approach with triple diagnostics resulted in a low mortality rate and only a single amputation in a pre-terminal patient in the first 5 years after implementation. All deceased patients had multiple preexisting comorbidities consisting of severe systemic diseases, such as end-stage heart failure. Early detection proved to facilitate faster recovery with shorter ICU stay.

Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl.

The mechanism by which Wnt receptors transduce signals to activate downstream beta-catenin-mediated target gene transcription remains incompletely understood but involves Frizzled (Fz) receptor-mediated plasma membrane recruitment and activation of the cytoplasmic effector Dishevelled (Dvl). Here, we identify the deubiquitinating enzyme CYLD, the familial cylindromatosis tumor suppressor gene, as a negative regulator of proximal events in Wnt/beta-catenin signaling. Depletion of CYLD from cultured cells markedly enhances Wnt-induced accumulation of beta-catenin and target gene activation. Moreover, we demonstrate hyperactive Wnt signaling in human cylindroma skin tumors that arise from mutations in CYLD. At the molecular level, CYLD interacts with and regulates K63-linked ubiquitination of Dvl. Enhanced ubiquitination of the polymerization-prone DIX domain in CYLD-deficient cells positively links to the signaling activity of Dvl. Together, our results argue that loss of CYLD instigates tumor growth in human cylindromatosis through a mechanism in which hyperubiquitination of polymerized Dvl drives enhancement of Wnt responses.

Polyalkylimide: A Nonstable Filler Over Time.

BACKGROUND: Polyalkylimide hydrogel is supposed to be a permanent, biocompatible implant. However, years after subcutaneous implantation clinical complications are seen. OBJECTIVE: To increase the understanding of the changes that occur over time in this subdermal implanted filler. MATERIALS AND METHODS: The extruded filler material of 34 patients was evaluated by histologic examination. RESULTS: In most patients who had cosmetic disturbances but no complaints, histology showed no immune cells in or around the filler material. In patients with an acute inflammatory response, giant cell invasion was seen in and around the filler material. Patients with chronic complaints showed a neutrophilic cell influx in the extruded filler. In all patients, degeneration and calcification of the material was noted. The polyalkylimide hydrogel changed over time, both macroscopically and microscopically. As in most of the patients no immune response was seen around the filler material, this may indicate that the material is biocompatible. CONCLUSION: The authors conclude that a dermal filler should not be judged solely on its biocompatible characteristics but also on the degradation process over time in the human body.

The number of T cell allo-epitopes associates with CD4+ and CD8+ T-cell infiltration in pediatric cutaneous GVHD.

Risk factors for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HCST) include: HLA mismatches, sex-mismatch, and stem-cell source. We retrospectively analyzed if HLA- and sex-mismatching quantitatively affects the composition of GVHD-induced T-cell infiltrates. We quantified absolute numbers of CD4+ and CD8+ T cells present in tissue sections from skin biopsies of 23 pediatric HSCT-recipients with GVHD. HSCT with a sex-mismatched unrelated donor was associated with an increased number of CD4+ T cells when compared to a sex-matched unrelated donor (p=0.01). The absolute numbers of skin-infiltrating T cells were increased in patients expressing T-cell epitopes derived from the recipient's mismatched HLA, so called predicted indirectly recognizable HLA epitopes (PIRCHE). The combined expression of PIRCHE with a sex-mismatch resulted in the highest number of skin-infiltrating T cells. Our results indicate that an increased number of recipient-specific T-cell epitopes is associated with accumulation of CD4+ and CD8+ T cells in the skin.

Lack of concentration-dependent local toxicity of highly concentrated (5%) versus conventional 0.5% bupivacaine following musculoskeletal surgery in a rat model.

PURPOSE: Various sustained-release formulations incorporate high bupivacaine concentrations but data on local toxicity is lacking. This study explores local toxic effects of highly concentrated (5%) bupivacaine compared to clinically used concentrations in vivo following skeletal surgery, to assess the safety of sustained-release formulations with high bupivacaine concentrations. METHODS: Sixteen rats underwent surgery, in which screws with catheters affixed were implanted in the spine or femur in a factorial experimental design, allowing single-shot or continuous 72 h local administration of 0.5%, 2.5% or 5.0% bupivacaine hydrochloride. During the 30-day follow-up, animal weight was recorded and blood samples were obtained. Implantation sites underwent histopathological scoring for muscle damage, inflammation, necrosis, periosteal reaction/thickening and osteoblast activity. Effects of bupivacaine concentration, administration mode and implantation site on local toxicity scores were analyzed. RESULTS: Chi-squared tests for score frequencies revealed a concentration-dependent decrease in osteoblast count. Moreover, spinal screw implantation led to significantly more muscle fibrosis but less bone damage than femoral screw implantation, reflecting the more invasive muscle dissection and shorter drilling times related to the spinal procedure. No differences between bupivacaine administration modes regarding histological scoring or body weight changes were observed. Weight increased, while CK levels and leukocyte counts decreased significantly during follow-up, reflecting postoperative recovery. No significant differences in weight, leukocyte count and CK were found between interventional groups. CONCLUSION: This pilot study found limited concentration-dependent local tissue effects of bupivacaine solutions concentrated up to 5.0% following musculoskeletal surgery in the rat study population.

Dupilumab-Associated Lymphoid Reactions in Patients With Atopic Dermatitis.

Importance: Since the increased use of dupilumab for atopic dermatitis (AD) in daily practice, several cases have been reported on the development of cutaneous T-cell lymphomas (CTCL) and lymphoid infiltrates. Objective: To provide insight in the clinical and histopathologic features of patients with AD clinically suspected for CTCL during dupilumab treatment. Design, Setting, and Participants: This retrospective observational case series included adult (≥18 years) patients with AD treated with dupilumab between October 2017 and July 2022 at the University Medical Center Utrecht in the Netherlands. Main outcomes and measures: Relevant patient, disease, and treatment characteristics were evaluated. Skin biopsies before, during, and after treatment were collected and reassessed. Results: Fourteen patients (54.5% male) with a median (IQR) age of 56 (36-66) years suspected for CTCL with deterioration of symptoms during dupilumab treatment were included. Of 14 patients, 3 were retrospectively diagnosed with preexistent mycosis fungoides (MF). Eleven patients with AD were eventually diagnosed with a lymphoid reaction (LR). These patients showed MF-like symptoms; however, histopathologic findings were different, and included sprinkled distribution of small hyperchromatic lymphocytes in the upper epidermal section, a dysregulated CD4:CD8 ratio, and CD30 overexpression, without loss of CD2/CD3/CD5. The median time to clinical worsening was 4.0 months (IQR, 1.4-10.0). Posttreatment biopsies showed complete clearance of the LR in all patients. Conclusions and relevance: This study found that dupilumab treatment can cause a reversible and benign LR, which mimics a CTCL, though has distinctive histopathologic features.

Histological assessment of the sclerotic graft-versus-host response in the humanized RAG2-/-γc-/- mouse model.

Graft-versus-host disease (GVHD) remains a frequently occurring and difficult-to-treat complication in human allogeneic stem cell transplantation. Murine transplantation models are often used to study and understand the complex pathogenesis of GVHD and to explore new treatment strategies. Although GVHD kinetics may differ in murine and human models, adequate models are essential for identification of the crucial factors responsible for the major pathology in GVHD. We present a detailed description of the specific histological features of a graft-versus-host-induced fibrotic response in xenogeneic RAG2(-/-)γc(-/-) mice after total body irradiation and injection with human peripheral blood mononuclear cells. We describe the full morphological features of this reaction, including a detailed analysis of the specific tissue infiltration patterns of the human peripheral blood mononuclear cells. Our data show the development of fibrosis, predominantly near blood vessels, and reveal different cell populations and specific cell migration patterns in the affected organs. The combination of immunohistochemical cell characterization and mRNA expression analysis of both human (donor)- and murine (host)-derived cytokines reveals an interaction between host tissues and donor-derived cells in an entangled cytokine profile, in which both donor- and host-derived cytokines contribute to the formation of fibrosis.

No non-sentinel node involvement in melanoma patients with limited Breslow thickness and low sentinel node tumour load.

AIMS: Most melanoma patients with a positive sentinel node (SN) undergo completion lymph node dissection and frequently experience associated morbidity. However, only 10-30% of SN-positive patients have further lymph node metastases. The aim of the present study was to predict the absence of non-SN metastases in a multicentre study of patients with a positive SN based on primary melanoma features and SN tumour load. METHODS AND RESULTS: Of 70 SN positive patients, 18 had non-SN metastases. Penetrative depth of metastatic cells into the SN and SN tumour load was assessed by morphometry. None of the 14 patients (20%) with a Breslow thickness <2.0 mm and an SN tumour load <0.2 mm2 had non-SN metastases. Similarly, none of the 15 patients (21%) with a Breslow thickness <2.0 mm and SN penetrative depth <600 µm had non-SN metastases. Lastly, none of the 14 patients (20%) with a Breslow thickness <2.0 mm and a diameter of the largest SN deposit <500 µm had non-SN metastases. CONCLUSIONS: A combination of limited Breslow thickness and low SN tumour load predicts absence of non-SN metastases in melanoma patients with a positive SN with high accuracy. We propose that this subgroup may be spared completion lymph node dissection.

Diagnosis of Sweet's syndrome in otolaryngology.

Sweet's syndrome (acute febrile neutrophilic dermatosis) consists of acute onset of painful cutaneous erythematous lesions, mostly found in the upper extremities followed by the head and neck region, particularly in patients with underlying malignancies. We describe the case of a woman in her mid-30s, who was treated for acute myeloid leukaemia and presented with a severe painful and progressive erythematous lesion of the retroauricular skin. Clinical features, laboratory tests, blood cultures and histological biopsy yielded a diagnosis of Sweet's syndrome. The treatment consisted of oral and topical corticosteroids and her signs and symptoms resolved within 1 week. Although Sweet's syndrome is uncommon, awareness among otolaryngologists is crucial to ensure a prompt diagnosis, cure and referral to an oncologist (if not already involved) for patients with Sweet's syndrome in the head and neck area.

Systemic and local evidence for complement involvement in chronic spontaneous urticaria.

BACKGROUND: The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment. METHODS: Thirty CSU patients (median age 42 [range 21-70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow-up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab. RESULTS: Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components. CONCLUSIONS: Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.

Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings.

Pseudoxanthoma elasticum (PXE) is a systemic disorder affecting elastic tissues most markedly in skin, retina, and blood vessels. It is caused by mutations in the ABCC6 gene and is transmitted in an autosomal recessive fashion. In 1994 a new classification system for PXE was published as the result of a consensus conference. Since then the ABCC6 gene has been discovered. We propose that there is a need for a classification system incorporating all relevant systemic symptoms and signs, based on standardized clinical, histological, and molecular biological examination techniques. We re-evaluated the histopathologic PXE signs and propose a classification system with unambiguous criteria leading to a consistent diagnosis of definitive, probable, or possible PXE world-wide. We put this proposed classification forward to encourage further debate on the diagnosis of this multi-organ disorder.

Digital pathology in the time of corona.

The 2020 COVID-19 crisis has had and will have many implications for healthcare, including pathology. Rising number of infections create staffing shortages and other hospital departments might require pathology employees to fill more urgent positions. Furthermore, lockdown measures and social distancing cause many people to work from home. During this crisis, it became clearer than ever what an asset digital diagnostics is to keep pathologists, residents, molecular biologists and pathology assistants engaged in the diagnostic process, allowing social distancing and a 'need to be there' on-the-premises policy, while working effectively from home. This paper provides an overview of our way of working during the 2020 COVID-19 crisis with emphasis on the virtues of digital pathology.

Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6.

PURPOSE: : Pseudoxanthoma elasticum is an autosomal recessive disorder of elastic tissue in the skin, eyes, and cardiovascular system, caused by mutations in the ABCC6 gene. The purpose of this study was to check variability in expression within one genotype and look for pseudoxanthoma elasticum signs in heterozygotes. METHODS: : We examined a relatively large, in comparison with the present literature, group of adult persons homozygous or heterozygous for the c.3775delT mutation in the ABCC6 gene, from a genetically isolated population in the Netherlands. All participants filled out a questionnaire and underwent standardized dermatologic and ophthalmologic examinations with photography of skin and fundus abnormalities. Skin biopsies from affected skin or a predilection site and/or a scar were examined and compared with biopsies from controls. RESULTS: : Skin abnormalities, ophthalmologic signs, and cardiovascular problems varied greatly among the 15 homozygous participants. There was no correlation among severity of skin, eyes, or cardiovascular abnormalities. None of the 44 heterozygous participants had any sign of pseudoxanthoma elasticum on dermatologic, histopathologic, and/or ophthalmologic examination, but 32% had cardiovascular disease. CONCLUSION: : Individuals homozygous for the c.3775delT mutation can have a highly variable phenotype. We did not find pseudoxanthoma elasticum eye or skin abnormalities in the heterozygous family members.

Occurrence of an Abscopal Radiation Recall Phenomenon in a Glioblastoma Patient Treated with Nivolumab and Re-Irradiation.

Glioblastoma multiforme is the most frequent primary brain tumor. The clinical course of glioblastoma is almost invariably fatal. Combined chemo-irradiation with temozolomide is currently the standard of care for newly diagnosed glioblastoma and concurrent Nivolumab, an anti-PD-1 monoclonal antibody is being studied for de novo glioblastoma. We present a 62-year old patient with glioblastoma, which was discovered during evaluation of sudden-onset moderate ataxia. Following craniotomy of the glial tumour he received chemo radiation. During this first-line treatment the patient participated in the CA209-548 phase III placebo controlled study investigating the addition of concurrent nivolumab. One month after the last administration of nivolumab after 60 weeks of study participation, magnetic resonance imaging scan showed progressive disease. Therefore stereotactic re-irradiation was given. Five days after completing radiation therapy and 50 days after his last nivolumab course he developed a mild diffuse generalized pruritic maculopapular exanthema. Skin biopsy was very indicative for a drug hypersensitivity reaction. The maculopapular rash and pruritus was successfully treated with moderate potency topical corticosteroids and prednisone. With the introduction of PD1/PD-L1 inhibitors and other immunotherapies tweaking the immune system to target cancer cells one can argue that once local radiation triggers a local immune mediated hypersensitivity reaction as seen in radiation recall dermatitis, the subsequent hypersensitivity reaction which would traditionally only be a local reaction is now possible to advance to more pronounced (systemic) reactions as seen in an abscopal effect. Therefore, we propose a combined name to coin this effect, the abscopal radiation recall phenomenon.

Modifying Graft-versus-Host Disease in a Humanized Mouse Model by Targeting Macrophages or B-Cells.

Humanized mouse models can well be modified to study specific aspects of Graft-versus-Host Disease (GvHD). This paper shows the results of both macrophage depletion and (early) B-cell depletion in a humanized mouse model using RAG2-/- γc-/- mice injected with HuPBMCs. Macrophage depletion showed a significant decrease in survival and also lead to a change in the histomorphology of the xenogeneic reaction. Higher levels of infiltrating B-cells were observed in various organs of mice depleted for macrophages. With (early) B-cell depletion using Rituximab, a clear improvement on clinical symptoms was observed, even when probably only inactivated B-cells were deleted. However, the histological examinations only showed a significant morphological effect on liver fibrosis. This may be related to a difference in the mRNA levels of TGF-ß. Also, lower mRNA levels of Tregs in some organs were observed after Rituximab treatment, which contradicts that a higher number of Tregs would always be related to less severe GvHD. Our data show that both macrophage depletion and (early) B-cell depletion in a xenogeneic mouse model can influence the clinical, histological, and cytokine production of a GvHD response.

Diagnosis of ocular toxocariasis by establishing intraocular antibody production.

PURPOSE: To investigate the role of Toxocara canis in posterior uveitis of undetermined origin. DESIGN: Retrospective case-study. METHODS: Paired ocular fluid (47 aqueous humor [AH] and two vitreous fluids) and serum samples of 37 adults and 12 children with undetermined posterior uveitis were retrospectively analyzed for intraocular IgG antibody production against Toxocara canis by enzyme-linked immunosorbent assay and Goldmann-Witmer coefficient (GWC) determination. Previous diagnostic investigation by polymerase chain reaction and GWC for Herpes simplex virus, Varicella zoster virus, and Toxoplasma gondii had not provided a cause of the posterior uveitis. RESULTS: Three of 12 (25%) children showed intraocular IgG production against Toxocara canis. One child had vitritis, one presented with a low-grade uveitis and a peripheral retinal lesion, and the third had posterior uveitis and a chorioretinal scar. All three children had AH IgG titers exceeding those of the corresponding serum. In fact, two children had low Toxocara serum IgG titers (<1:32) and would have been considered seronegative upon routine serology screening. Intraocular antibody production against Toxocara canis was absent in all 37 adults, including five seropositive patients. CONCLUSIONS: Our results indicate that ocular toxocariasis is mainly a pediatric disease. Serological screening is not informative for the diagnosis of intraocular Toxocara infection. Toxocara GWC analysis, however, can be of value when diagnosing patients with posterior focal lesions or vitritis of unknown etiology.

Sneddon syndrome and the diagnostic value of skin biopsies - three young patients with intracerebral lesions and livedo racemosa.

Sneddon syndrome is a rare disorder characterised by generalised livedo racemosa of the skin with extracutaneous neurological symptoms like headache, vertigo, transient ischaemic attacks (TIA), stroke, and seizures. Diagnosis of Sneddon syndrome is based on these clinical features and positive findings in skin biopsies, namely the histological proof of occlusion of arterioles by intimal proliferation. We describe three cases of young patients with clinical characteristics of Sneddon syndrome, but in only two cases could this diagnosis be confirmed by skin biopsies. These cases stress the difficulty of diagnosing Sneddon syndrome and show the additive value of skin biopsies in this process.