The VASCERN PPL working group patient pathway for primary and paediatric lymphoedema.

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.

Paediatric lymphoedema: An audit of patients seen by the paediatric and primary lymphoedema group of vascular European Reference Network (VASCERN).

Little is known about the overall prevalence of lymphoedema in children and the types of paediatric lymphoedema seen by specialist centres. Therefore, this study was aimed to provide a profile of children with primary or secondary lymphoedema seen by the expert centres of the paediatric and primary lymphoedema working group (PPL-WG) of VASCERN and to compare the profile between the different countries. A retrospective review of all children (aged up to 18 years) seen for the first time by the expert centres over one year (2019) was carried out. Lymphoedema-, patient- and genetics-related data was collected and described for the whole group and compared between the different European countries/UK. In 2019, a total of 181 new children were seen by eight expert centres. For primary lymphoedema, the phenotype was based on the St George's classification of lymphatic anomalies. The percentages diagnosed according to each category were: 7.2% for syndromic lymphoedema, 2.8% for systemic/visceral involvement, 30.4% for congenital, 35.9% for late-onset lymphoedema and 19.3% for vascular/lymphatic malformations. 4.4% had secondary lymphoedema. Nearly 10% of all children had had at least one episode of cellulitis. The median delay from onset of symptoms to being seen by an expert centre was 2.4 years. In 44.4% of the children with primary lymphoedema a genetic test was performed, of which 35.8% resulted in a molecular diagnosis. Across the different centres, there was a wide variety in distribution of the different categories of paediatric lymphoedema diagnosed and the frequency of genetic testing. In conclusion, this paper has demonstrated that there is a large delay between the onset of paediatric lymphoedema and the first visit in the expert centres and that an episode of cellulitis is a relatively common complication. Diagnostic variation across the centres may reflect different referral criteria. Access to genetic testing was limited in some centres. It is recommended that these issues are addressed in the future work of the PPL-WG to improve the referral to the expert centres and the consistency in service provision for paediatric lymphoedema in Europe.

Occupational burn injuries in Finland 2011-2015.

BACKGROUND: This study comprises all hospitalized work-related burn injuries in one country during 2011-2015. The purpose was to describe demographics, causes and risk factors of occupational burn injuries with special focus on the outcome of return to work. MATERIAL AND METHODS: This is a retrospective study on two data sources of which Finnish Workers' Compensation Center's (FWCC) register includes all work-related burn cases at a given time. Additional data have been obtained from those patients, who were referred to the National Burn Centre (NBC) during the same time according to the Emergency Management of Severe Burns (EMSB) criteria. We compare demographics, injury mechanisms and general burn data of these two patient groups. RESULTS: Based on FWCC register, in 2011-2015 occurred 11,623 work-related burn cases of whom 54% were men. During the study period, NBC admitted 26 patients fulfilling EMSB criteria. The most severe patients treated in NBC had injuries affecting multiple body parts. In FWCC data, hand was most injured body part. Kitchen/bakery work was the most common profession in FWCC register but in NBC material industrial and transport professions dominated. In FWCC register, patients had lower mean age (37 years vs. 43 years). Most severe injuries occurred among older patients: In NBC data, those with total body surface area 40% or over had mean age 53 years. Majority of patients returned to work. CONCLUSION: Safety at work in Finland has improved during last decades, and the vast majority of work-related burn injuries are minor. Minor burn injuries are common in young adults working in kitchen and bakery work, whereas elderly men working in transports and industry sustain the most severe burn accidents. Retirement after work-related injury becomes very expensive for all parties, and this data can be used in preventing those cases as well as the minor accidents.

Clinical Study of Nanofibrillar Cellulose Hydrogel Dressing for Skin Graft Donor Site Treatment.

Objective: Skin graft donor site management is a concern particularly for elderly patients and patients with poor wound healing competence, and also because donor sites are a source of pain and discomfort. Although different types of dressings exist, there is no consensus regarding optimal dressing type on donor site care to promote healing, reduce pain, and improve patients' comfort. Approach: This prospective, single-center clinical trial evaluated the performance of nanofibrillar cellulose (NFC) wound dressing (FibDex® by UPM-Kymmene Corporation) for treatment of donor sites compared with a polylactide-based copolymer dressing. The study enrolled 24 patients requiring skin grafting with mean age of 49 ± 18. The primary outcome measure was wound healing time. Secondary outcomes, the epithelialization, subjective pain, the scar appearance assessed using the Patient and Observer Scar Assessment Scale (POSAS), and skin elasticity and transepidermal water loss (TEWL), were evaluated at 1 and 6 months postoperatively. Results: No statistically significant differences were observed between NFC and copolymer dressings regarding wound healing time, epithelialization, experience of pain, or TEWL. Significant differences were observed in the POSAS results for thickness and vascularity in the Observer score, in the favor of NFC over copolymer dressing. Moreover, skin elasticity was significantly improved with NFC dressing in terms of viscoelasticity and elastic modulus at 1 month postoperatively. Innovation: NFC dressing is a new, green sustainable product for wound treatment without animal or human-origin components. Conclusion: NFC dressing provides efficient wound healing at skin graft donor sites and is comparable or even preferable compared with the copolymer dressing.

The evolution of the Helsinki frostbite management protocol.

BACKGROUND: Severe frostbite can result in devastating injuries leading to significant morbidity and loss of function from distal extremity amputation. The modern day management approach to frostbite injuries is evolving from a historically very conservative approach to the increasingly reported use of early interventional angiography and fibrinolysis with tPA. The aim of this study was to evaluate the results of our frostbite treatment protocol introduced 3 years ago. METHODS: All frostbite patients underwent first clinical and then Doppler ultrasound examination. Angiography was conducted if certain clinical criteria indicated a severe frostbite injury and if there were no contraindications to fibrinolysis. Intra-arterial tissue plasminogen activator (tPA) was then administered at 0.5-1mg/h proximal to the antecubital fossa (brachial artery) or popliteal fossa (femoral artery) if angiography confirmed thrombosis, as well as unfractionated intravenous heparin at 500 units/h. The vasodilator iloprost was administered intravenously (0.5-2.0ng/kg/min) in selected cases. RESULTS: 20 patients with frostbite were diagnosed between 2013-2016. Fourteen patients had a severe injury and angiography was performed in 10 cases. The total number of digits at risk was 111. Nine patients underwent fibrinolytic treatment with tPA (including one patient who received iloprost after initial non response to tPA), 3 patients were treated with iloprost alone and 2 patients received neither treatment modality (due to contraindications). The overall digital salvage rate was 74.8% and the Hennepin tissue salvage rate was 81.1%. One patient developed a catheter-site pseudoaneurysm that resolved after conservative treatment. CONCLUSIONS: Prompt referral to a facility where interventional radiology and 24/7 laboratory services are available, and the combined use of tPA and iloprost, may improve outcome after severe frostbite.

Trichodysplasia spinulosa-associated polyomavirus (TSV) and Merkel cell polyomavirus: correlation between humoral and cellular immunity stronger with TSV.

Merkel Cell Polyomavirus (MCV) is a common infectious agent likely to be involved in the pathogenesis of most Merkel cell carcinomas (MCC). Trichodysplasia spinulosa-associated polyomavirus (TSV), which exhibit high seroprevalence in general population, has been detected in trichodysplasia spinulosa (TS) skin lesions suggesting an etiological role for this disease. Previous studies have shown strong MCV-specific T-cell responses, while no data exist on T-cell immunity against TSV. In order to characterize Th-cell immunity against TSV, and to allow comparisons with the MCV-specific Th-cell immunity, we studied TSV-specific proliferation, IFN-γ, IL-10 and IL-13, and MCV-specific IFN-γ and IL-10 responses in 51 healthy volunteers, and in one MCC patient. Recombinant TSV and MCV VP1 virus-like particles (VLPs) were used as antigens. A significant correlation was found between virus-specific Th-cell and antibody responses with TSV; with MCV it proved weaker. Despite significant homology in amino acid sequences, Th-cell crossreactivity was not evident between these viruses. Some subjects seronegative to both TSV and MCV exhibited Th-cell responses to both viruses. The agent initially priming these Th-cells remains an enigma. As CD8(+) cells specific to MCV T-Ag oncoprotein clearly provide an important defense against established MCC, the MCV VP1-specific Th-cells may, by suppressing MCV replication with antiviral cytokines such as IFN-γ, significantly contribute to preventing the full process of oncogenesis.

Bcl-2 expression indicates better prognosis of Merkel cell carcinoma regardless of the presence of Merkel cell polyomavirus.

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. The recently found Merkel cell polyomavirus (MCV) integrates clonally in the tumour genome, which suggests an important role in the pathogenesis of the disease. Previous small-scale studies have detected anti-apoptotic protein bcl-2 in 80 % of MCC tumours, but its correlation to the prognosis of MCC remains controversial. Our aim was to clarify the correlation of immunohistochemical expression of bcl-2 to MCV presence and MCC prognosis. We analyzed 116 primary MCC specimens with corresponding clinical data by immunohistochemistry for bcl-2. The presence of MCV DNA had been analyzed by quantitative PCR for 108 tumours. The correlations were analyzed statistically. Of the primary MCC samples, 85 % were bcl-2 positive. No significant differences in MCV DNA occurred between the bcl-2-positive and bcl-2-negative tumours. Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33 %) than in patients with bcl-2-positive tumours (12 %; p = 0.04) at the time of diagnosis. The mean overall survival was higher in patients with bcl-2-positive tumours than of those with negative tumours (mean survival 1,814 days (5.0 years) vs. 769 days (2.1 years), p = 0.01). Bcl-2 positivity indicates better clinical stage at the time of diagnosis and a longer survival in MCC.

Tumor infiltrating immune cells and outcome of Merkel cell carcinoma: a population-based study.

PURPOSE: Merkel cell carcinoma (MCC) is a rare skin cancer that often harbors Merkel cell polyomavirus (MCPyV) DNA. The clinical importance of intratumoral immune cells and their associations with MCPyV infection are poorly understood. EXPERIMENTAL DESIGN: We identified T lymphocytes (CD3-positive cells), T-cell subsets (CD4, CD8, and FoxP3-positive cells), natural killer cells (small CD16-positive cells), and macrophages (CD68 and CD163-positive cells) in tumors of 116 individuals diagnosed with MCC in Finland from 1979 to 2004 using immunohistochemistry and detected MCPyV DNA with quantitative PCR. The associations between immune cell counts, MCPyV DNA, patient and tumor characteristics, and patient outcome were examined. RESULTS: MCPyV DNA-positive cancers contained higher numbers of CD3(+), CD8(+), CD16(+), FoxP3(+), and CD68(+) cells as compared with MCPyV DNA-negative carcinomas (all P values < 0.05). High intratumoral numbers of CD3(+), CD8(+), or FoxP3(+) cells, and high CD8(+)/CD4(+) or FoxP3(+)/CD4(+) ratios, were significantly associated with favorable overall survival. Individuals with a high tumor CD3(+) count had metastases less often and survived longer, irrespective of the tumor MCPyV status. Tumor CD3(+) count and MCPyV DNA status had independent influence on survival in a Cox multivariable model that also included presence of locoregional metastases at diagnosis and gender as covariates. CONCLUSIONS: High intratumoral T-lymphocyte counts are associated with favorable survival in MCC. Although the numbers of T cells are generally higher in MCPyV-positive than in MCPyV-negative MCC, high intratumoral T-cell counts are also associated with favorable survival in MCPyV-negative MCC.