Systemic therapy timing and use in patients with advanced melanoma at the end of life: A retrospective cohort study.

Novel systemic therapies for advanced melanoma improve survival, but carry potential serious side effects and high costs. This study aimed to assess the timing and use of systemic therapies in the months before death. Patients diagnosed with advanced melanoma (July 2017-June 2020) who died before July 2020 were selected from the Netherlands Cancer Registry. We evaluated the timing of systemic therapies within 30 days and 3 months before death, and studied patient and tumor characteristics associated with systemic therapy use between diagnosis and death. Out of 1097 patients 68% received systemic therapy. Almost 25% and 10% started a new therapy within 90 days and within 30 days before death, respectively. Female sex, elevated LDH, BRAF mutation, poor ECOG performance status (≥3), and high comorbidity index reduced the odds of receiving immune therapy. Poor performance status and high comorbidity decreased the odds for both therapies. A considerable number of patients started systemic therapy shortly before death, emphasizing the importance of considering potential benefits and drawbacks through shared decision-making.

Clinicopathological features, MCPyV status and outcomes of Merkel cell carcinoma in solid-organ transplant recipients: a retrospective, multicentre cohort study.

BACKGROUND: The proportion of Merkel cell carcinomas (MCCs) in solid-organ transplant recipients (SOTR) harbouring Merkel cell polyomavirus (MCPyV) is unknown, as are factors affecting their outcomes. OBJECTIVE: To describe clinicopathological features of MCC in SOTR, investigate the tumoral MCPyV-status and identify factors associated with tumour outcomes. METHODS: Retrospective, international, cohort-study. MCPyV-status was investigated by immunohistochemistry and polymerase chain reaction. RESULTS: A total of 30 SOTR and 44 consecutive immunocompetent patients with MCC were enrolled. SOTR were younger at diagnosis (69 vs. 78 years, P < 0.001). Thirty-three percent of SOTR MCCs were MCPyV-positive vs. 91% of immunocompetent MCCs (P = 0.001). Solid-organ transplantation was associated with an increased cumulative incidence of progression (SHR: 3.35 [1.57-7.14], P = 0.002), MCC-specific mortality (SHR: 2.55 [1.07-6.06], P = 0.034) and overall mortality (HR: 3.26 [1.54-6.9], P = 0.002). MCPyV-positivity and switching to an mTOR inhibitor (mTORi) after MCC diagnosis were associated with an increased incidence of progression (SHR: 4.3 [1.5-13], P = 0.008 and SHR: 3.6 [1.1-12], P = 0.032 respectively) in SOTR. LIMITATIONS: Retrospective design and heterogeneity of SOTR cohort. CONCLUSIONS: MCPyV appears to play a less prominent role in the aetiopathogenesis of MCC in SOTR. SOTR have a worse prognosis than their immunocompetent counterparts and switching to an mTORi after the diagnosis of MCC does not improve progression.

Treatment of keratinocyte carcinoma in elderly patients - a review of the current literature.

A large percentage of the patients with keratinocyte carcinoma (KC, formerly known as non-melanoma skin cancer) is of advanced age and often too frail for standard therapies. However, no specific treatment recommendations are given for this population. This review aimed to give an overview of the current literature on the best practice for the treatment of elderly patients with KC. A literature search was performed in MEDLINE, using 'keratinocyte carcinoma', 'elderly', 'treatment' and various synonyms. Case reports, reviews, comments, non-English literature and studies with a sample size <15 were excluded. After selection, a total of 47 studies were reviewed. Two types of studies were identified, focusing on (I) the effect of age on treatment outcomes and (II) alternative treatment schedules for elderly patients. Studies on surgery, the gold standard, describe larger lesions and defect size in the elderly population. Recurrence rate, complication rate and disease-specific survival were not affected by age. Depending on the expected morbidity of a suggested (re-)excision and patient preferences, a conservative watchful waiting policy can be agreed upon as a shared decision. Other common treatment modalities, such as adjuvant radiotherapy, photodynamic therapy and systemic therapy for basal cell carcinoma (BCC), show comparable results in the elderly and younger population. Alternative treatment schedules for elderly patients include primary hypofractionated radiotherapy, which seems effective and well-tolerated, although research is limited to case series. Additionally, localized and topical treatments seem safe and effective especially for low-risk tumours. Data are lacking on the efficacy of systemic therapies of metastatic KC in elderly patients. Efficacy of most treatments (with the exception of photodynamic therapy) is not dependent on age. There is need for more research on the efficacy of adjusted treatment modalities, such as hypofractionated radiotherapy and palliative or curative systemic treatment.

Is it Necessary to Perform Sentinel Lymph Node Biopsy in Thin Melanoma? A Retrospective Single Center Analysis.

Sentinel lymph node biopsy (SLNB) is a standard procedure for regional lymph node staging and still has the most important prognostic value for the outcome of patients with thin melanoma. In addition to ulceration, SLNB had to be considered even for a single mitotic figure in thin (<1 mm) melanoma according to AJCC7th guideline, therefore, a retrospective review was conducted involving 403 pT1 melanoma patients. Among them, 152 patients suffered from pT1b ulcerated or mitotic rate ≥ 1/ mm2 melanomas according to the AJCC7th staging system. SLNB was performed in 78 cases, of which nine (11.5%) showed SLN positivity. From them, interestingly, we found a relatively high positive sentinel rate (6/78-8%) in the case of thin primary melanomas ˂0.8 mm. Moreover, the presence of regression increased the probability of sentinel positivity by 5.796 fold. After reassessing pT stage based on the new AJCC8th, 37 pT1b cases were reordered into pT1a category. There was no significant relation between other characteristics examined (age, gender, Breslow, Clark level, and mitosis index) and sentinel node positivity. Based on our data, we suggest that mitotic rate alone is not a sufficiently powerful predictor of SLN status in thin melanomas. If strict histopathological definition criteria are applied, regression might be an additional adverse feature that aids in identifying T1 patients most likely to be SLN-positive. After reassessing of pT1b cases according to AJCC8th regression proved to be independent prognostic factor on sentinel lymph node positivity. Our results propose that sentinel lymph node biopsy might also be considered at patients with regressive thin (˂0.8 mm) melanomas.

Adjunctive role of manual lymph drainage in the healing of venous ulcers: A comparative pilot study.

Compression therapy plays a pivotal role in the treatment of venous leg ulcers and clinical observations include lymph stasis as contributing to the maintenance of chronic wounds. This finding raises the question whether further improvement in lymph circulation with manual lymph drainage (MLD) as a part of complex decongestive physiotherapy (CDP) can improve ulcer healing. We examined whether CDP improves healing of venous leg ulcers and compared the efficacy of CDP with that of multilayered compression with short-stretch bandages. Eight patients (mean age: 64.8 years, mean ulcer area: 23.07 cm2, duration of ulcers: 25.37 months) were treated with a 5-day-course of CDP and 9 patients (mean age: 70.77 years, mean ulcer area: 21.47 cm2, duration of ulcers: 15.8 months) were included in a 10-day-course of CDP. Control goup consisted of 9 patients (mean age: 56.33 years, mean ulcer area: 13.87 cm2, duration of ulcers: 6.11 months) receiving multilayered compression. Wound surface measurement was carried out on days 5 and 10 and ulcer area reduction rate was calculated as area (initial)-area (final)/time unit. There was no statistical difference between the 5-daycourse of CDP and compression of the same duration regarding ulcer healing (t=-1.62, df=15, p= 0.125). A 10-day-course of CDP significantly increased ulcer healing compared to compression of the same duration (t=-2.42, df=16, p= 0.039). Our preliminary results suggest that MLD as a part of CDP supports healing of venous leg ulcers.

Measurement of capillary fragility: a useful tool to differentiate lipedema from obesity?

Lipedema is a disproportional obesity featuring spontaneous or light pressure-induce pain and frequent hematoma formation due to even minor traumatic injuries. It is generally distinguished from general obesity primarily based on clinical hallmarks; however, this becomes difficult when appearing in a concomitant form (combination of obesity and lipedema). Our study group has recently demonstrated that lipedema-associated bruising is correlated with increased capillary fragility (CF) and also that CF could be significantly improved by complex decongestive physiotherapy (CDP). In this study, we measured CF in female subjects with lipedema (15) or non-complicated obesity (15) who were body mass index (BMI) and waist-to-hip ratio (WHR) matched. CF was evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer in both groups. Application of VSM resulted in a significantly higher number of petechiae in subjects with lipedema. Capillary fragility measurement appears to be a useful differential diagnostic tool between lipedema and obesity under these trial parameters.

Heterogeneous expression of extracellular matrix molecules in the red nucleus of the rat.

Previous studies in our laboratory showed that the organization and heterogeneous molecular composition of extracellular matrix is associated with the variable cytoarchitecture, connections and specific functions of the vestibular nuclei and two related areas of the vestibular neural circuits, the inferior olive and prepositus hypoglossi nucleus. The aim of the present study is to reveal the organization and distribution of various molecular components of extracellular matrix in the red nucleus, a midbrain premotor center. Morphologically and functionally the red nucleus is comprised of the magno- and parvocellular parts, with overlapping neuronal population. By using histochemical and immunohistochemical methods, the extracellular matrix appeared as perineuronal net, axonal coat, perisynaptic matrix or diffuse network in the neuropil. In both parts of the red nucleus we have observed positive hyaluronan, tenascin-R, link protein, and lectican (aggrecan, brevican, versican, neurocan) reactions. Perineuronal nets were detected with each of the reactions and the aggrecan showed the most intense staining in the pericellular area. The two parts were clearly distinguished on the basis of neurocan and HAPLN1 expression as they have lower intensity in the perineuronal nets of large cells and in the neuropil of the magnocellular part. Additionally, in contrast to this pattern, the aggrecan was heavily labeled in the magnocellular region sharply delineating from the faintly stained parvocellular area. The most characteristic finding was that the appearance of perineuronal nets was related with the neuronal size independently from its position within the two subdivisions of red nucleus. In line with these statements none of the extracellular matrix molecules were restricted exclusively to the magno- or parvocellular division. The chemical heterogeneity of the perineuronal nets may support the recently accepted view that the red nucleus comprises more different populations of neurons than previously reported.

Multiple venous aneurysms in a patient with hypereosinophilic syndrome.

Hypereosinophilic syndrome (HES) is a diverse group of rare disorders, defined by persistent peripheral blood eosinophilia (>1500 per mm(3)), the absence of a primary cause of eosinophilia (such as parasitic or allergic disease), and evidence of eosinophil-mediated end-organ damage. Arterial aneurysms have been previously reported in these patients. This is the first report of a patient with HES and multiple venous aneurysms, causing recurrent pulmonary thromboembolism. Venous aneurysms can represent eosinophil-mediated, potentially fatal end-organ damage in patients with HES.

Extracellular matrix molecules exhibit unique expression pattern in the climbing fiber-generating precerebellar nucleus, the inferior olive.

Extracellular matrix (ECM) accumulates around different neuronal compartments of the central nervous system (CNS) or appears in diffuse reticular form throughout the neuropil. In the adult CNS, the perineuronal net (PNN) surrounds the perikarya and dendrites of various neuron types, whereas the axonal coats are aggregations of ECM around the individual synapses, and the nodal ECM is localized at the nodes of Ranvier. Previous studies in our laboratory demonstrated on rats that the heterogeneous distribution and molecular composition of ECM is associated with the variable cytoarchitecture and hodological organization of the vestibular nuclei and may also be related to their specific functions in gaze and posture control as well as in the compensatory mechanisms following vestibular lesion. Here, we investigated the ECM expression pattern in the climbing fiber-generating inferior olive (IO), which is functionally related to the vestibular nuclei. By using histochemical and immunohistochemical methods, the most characteristic finding was the lack of PNNs, presumably due to the absence of synapses on the perikarya and proximal dendrites of IO neurons. On the other hand, the darkly stained dots or ring-like structures in the neuropil might represent the periaxonal coats around the axon terminals of olivary synaptic glomeruli. We have observed positive ECM reaction for the hyaluronan, tenascin-R, hyaluronan and proteoglycan link protein 1 (HAPLN1) and various chondroitin sulfate proteoglycans. The staining intensity and distribution of ECM molecules revealed a number of differences between the functionally different subnuclei of IO. We hypothesized that the different molecular composition and intensity differences of ECM reaction is associated with different control mechanisms of gaze and posture control executed by the visuomotor-vestibular, somatosensory and integrative subnuclei of the IO.

Regulated genes in psoriatic skin during treatment with fumaric acid esters.

BACKGROUND: Fumaric acid esters (FAEs) are widely used in Europe for the treatment of psoriasis because of their clinical efficacy and favourable safety profile. However, the mechanisms of action by which FAEs improve psoriasis remain largely unknown. OBJECTIVES: To identify pathways and mechanisms affected by FAE treatment and to compare these with pathways affected by treatment with the antitumour necrosis factor (anti-TNF)-α biologic etanercept. METHODS: In a prospective cohort study, 50 patients with plaque psoriasis were treated with FAEs for 20 weeks. Nine patients were randomly selected for gene expression profiling of plaque biopsies from week 0 and week 12. The groups consisted of FAE responders [> Psoriasis Area and Severity Index (PASI)-75 improvement] and nonresponders (< PASI-50 improvement). Changes in gene expression profiles were analysed using Ingenuity Pathway Analysis (IPA) and the outcome was compared with gene expression affected by etanercept. RESULTS: Response to FAE treatment was associated with a ≥ 2-fold change (P < 0.05) in the expression of 458 genes. In FAE responders the role of interleukin-17A in the psoriasis pathway was most significantly activated. Glutathione and Nrf2 pathway molecules were specifically induced by FAE treatment and not by etanercept treatment, representing an FAE-specific effect in psoriatic skin. In addition, FAE treatment specifically induced the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ in responding patients. CONCLUSIONS: FAE treatment induces glutathione and Nrf2 pathway genes in lesional skin of patients with psoriasis. In responders, FAEs specifically regulate the transcription factors PTTG1, NR3C1, GATA3 and NFκBIZ, which are important in normal cutaneous development, and the T-helper (Th)2 and Th17 pathways, respectively.

Distribution of extracellular matrix macromolecules in the vestibular nuclei and cerebellum of the frog, Rana esculenta.

The axons of transected and re-apposed vestibulocochlear nerve of the frog, in contrast to mammalian species, regenerate and establish functional contacts within their original termination areas of the vestibular nuclear complex and the cerebellum. The lack of regenerative capability of the mammalian central nervous system (CNS) is partially attributed to various extracellular matrix (ECM) molecules, such as chondroitin sulfate proteoglycans (CSPG) and tenascin-R (TN-R), which exert inhibition on axon regeneration. In contrast to these molecules, hyaluronan (HA) was reported to be permissive for CNS regeneration. Using histochemical and immunohistochemical methods, we investigated the distribution pattern of these molecules in the medial (MVN), lateral (LVN), superior and descending vestibular nuclei and the cerebellum of the frog and detected regional differences in the organization of the ECM. In the vestibular nuclear complex, pericellular condensation of the ECM, the perineuronal nets (PNNs) were recognizable in the LVN and MVN and were positive only for HA. The neuropil of the vestibular nuclei showed either a diffuse appearance with varying intensity of reactions, or dots and ring-like structures, which may represent the perinodal ECM of the vestibular fibers. In the cerebellum, indistinct PNNs that were only labeled for HA were present in the granular layer. Our findings suggest that the HA-rich, but CSPG and TN-R-free PNNs may be associated with the high degree of plasticity and regenerative potential of the amphibian vestibular system.

Treatment of frontal fibrosing alopecia and lichen planopilaris: a systematic review.

Frontal fibrosing alopecia (FFA) is a primary lymphocytic cicatricial alopecia with characteristic clinical pattern of progressive frontotemporal hairline recession, perifollicular erythema and hyperkeratosis and symptoms of itch and burning, occurring mainly in post-menopausal women. FFA is considered a subtype of lichen planopilaris (LPP), based on their identical histopathology. Currently, no evidence-based treatment is available for FFA. Our aim was to determine the effectiveness of available treatment options for FFA, and to identify promising treatment options for future studies. For this, literature search was conducted to find all primary studies on the treatment of FFA and LPP. From the primary studies, data were subtracted and analysed. No randomized controlled trials were found, and one controlled trial. Treatment of 114 patients is described in the literature. They received 10 different regimes, of which oral 5-alpha-reductase inhibitors were provided most often, resulting in good clinical response in 45% of them. Hydroxychloroquine resulted in good clinical response in 30% of the 29 treated patients. Topical corticosteroid preparations are ineffective in FFA. The remaining treatments were all reported in less than 10 patients. For the treatment of LPP, topical corticosteroid preparations are the first line of treatment, followed by oral cyclosporine and systemic corticosteroids, although they are characterized by a high relapse rate. Summarizing, there is currently no effective treatment of FFA, the most effective being oral 5-alpha-reductase inhibitors that possibly affect the accompanying androgenetic alopecia. We argue that oral cyclosporine A might be a good candidate for future studies on the treatment of FFA.

Lymphedema treatment decreases pain intensity in lipedema.

Lipedema is a disproportional obesity featuring light pressure-induced or spontaneous pain. On the basis of our clinical observations, lymphedema therapy, as practiced in our clinic, reduces the perception of pain beyond leg volume reduction. We therefore aimed to measure pain intensity prior and subsequent to treatment. 38 women with lipedema were enrolled in the study with 19 patients undergoing treatment and 19 serving as the control group using exclusively moisturizers. Treatment consisted of once daily manual lymph drainage (MLD), intermittent pneumatic compression (IPC), and multilayered short-stretch bandaging performed throughout a 5-day-course. Pain was evaluated with a 10-item questionnaire, a pain rating scale (PRS), and the Wong-Baker Faces scale. Treatment resulted in a significant reduction of pain with a decrease in mean scores of all three measures. In the control group, only PRS showed significant decrease. Our study results indicate that this treatment regimen not only reduces leg volume and capillary fragility, but also improves pain intensity in patients with lipedema.

Narrowband ultraviolet B inhibits innate cytosolic double-stranded RNA receptors in psoriatic skin and keratinocytes.

BACKGROUND: The mode of action of narrowband ultraviolet B (NB-UVB) therapy in clearing psoriasis is incompletely understood, and in vivo studies at the molecular level in patients undergoing NB-UVB therapy are limited. We previously demonstrated increased expression and activity of double-stranded RNA (dsRNA) receptors in psoriasis lesions, and suggested that this enhanced innate signalling contributed to the maintenance of psoriatic inflammation. OBJECTIVES: We investigated whether NB-UVB affects dsRNA receptor expression and function in vivo as well as in vitro. METHODS: Skin samples of patients with psoriasis undergoing NB-UVB treatment were analysed for epidermal messenger RNA (mRNA) expression of the various dsRNA receptors by microarray and quantitative reverse transcription-polymerase chain reaction. Primary human keratinocytes were irradiated with NB-UVB and stimulated with interferon (IFN)-α or IFN-γ, critical cytokines in psoriasis. The dsRNA analogue polyriboinosinic-polyribocytidylic acid was used to assess the functional responsiveness of the cells to dsRNA. RESULTS: NB-UVB therapy of patients with psoriasis resulted in a significantly reduced mRNA expression of the activating dsRNA receptors MDA5 (IFIH1) and RIG-I (DDX58). On the other hand, expression of LGP2 (DHX58), toll-like receptor 3 (TLR3) and PKR (EIF2AK2) was not affected. In vitro, NB-UVB irradiation completely blocked the upregulation of four of the dsRNA receptors in primary human keratinocytes stimulated with IFN-α or IFN-γ, resulting in an attenuated inflammatory response to dsRNA. CONCLUSIONS: Our results show that NB-UVB irradiation inhibits the local innate inflammatory response to dsRNA, and suggest a novel mechanism of action of NB-UVB phototherapy in psoriasis.

The prevalence of melanocytic naevi among schoolchildren in South Hungary.

BACKGROUND: Malignant melanoma is an increasing public health problem worldwide; accordingly, identification of the constitutional and environmental factors which contribute to the development of the disease, and hence identification of the individuals at high risk of melanoma, is an indispensable step in all primary prevention efforts. OBJECTIVES: This paper aims to assess the prevalence of different pigmented lesions among schoolchildren and to investigate their relationship with phenotypic pigmentary characteristics, sun exposure and other factors. PATIENTS/METHODS: A cross-sectional study was performed in two secondary schools in Szeged, Hungary. A total of 1320 schoolchildren, aged 14 to 18 years, underwent a whole-body skin examination. A standardized questionnaire was used to collect data on phenotypic, sun exposure and other variables. RESULTS: One to 10 common melanocytic naevi were found in 27% of the participants, and the naevus numbers were in the range of 10-100 in 67%; 5.4% of them had more than 100 common melanocytic naevi. The prevalence of clinically atypical naevi was 24.3%. Statistically significant associations were found between the number of pigmented lesions and gender, hair colour, eye colour, skin phototype, a history of severe painful sunburns and a family history of a large number of melanocytic naevi. CONCLUSION: Our study population displayed a markedly high prevalence of clinically atypical melanocytic naevi. Moreover, a considerable proportion of the investigated individuals had multiple common melanocytic naevi. Since the presence of a large number of melanocytic naevi is a strong predictor for future melanoma development, health educational programmes on melanoma prevention should be aimed at young age groups.

Complex decongestive physiotherapy decreases capillary fragility in lipedema.

Lipedema is a disproportional obesity featuring frequent hematoma formation due to even minor traumatic injuries. On the basis of clinical observations, complete decongestive physiotherapy diminishes the incidence of hematomas due to minor injuries beyond leg volume reduction. Hematoma development may be caused by altered capillary resistance (CR) or altered capillary fragility (CF). We measured capillary fragility (CF) before and after complex decongestive physiotherapy (CDP) to examine, whether CDP could reduce CF. 38 women with lipedema were included in the study. Twenty-one (21) patients were treated with CDP and 17 using exclusively moisturizers as the control group. CDP comprised once daily manual lymph drainage, intermittent pneumatic compression and multilayered short-stretch bandaging performed throughout a 5-day-course. CF was evaluated with the vacuum suction method (VSM) using Parrot's angiosterrometer in both groups. Decongestive therapy resulted in a significant reduction of the number of petechiae while no change was detected within the control group. Complete decongestive physiotherapy significantly reduced CF in patients with lipedema and this reduction may lead to reduced hematoma formation.

Novel mutations in the ATP2C1 gene in two patients with Hailey-Hailey disease.

Benign familial chronic pemphigus (Hailey-Hailey disease, HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion, 1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.

Identification of mutations in the ATP2A2 gene in patients with Darier's disease from Hungary.

Mutation analysis in the ATP2A2 gene had been performed in eight Hungarian patients with Darier's disease (DD), to get more information about phenotype-genotype relations. All patients had moderate to severe skin symptoms. Polymerase chain reaction (PCR) amplification of the entire coding region of ATP2A2 was performed. Mutation detection strategies included heteroduplex scanning by conformation-sensitive gel electrophoresis (CSGE) and direct nucleotide sequencing. We found distinct, heterozygous mutations (five missense, one nonsense, one deletion, and one insertion), six of which were novel. In a 31-year-old DD woman with learning difficulties we disclosed a previously described missense mutation (D702N) in exon 15. A 44-year-old DD woman had a novel T insertion at nucleotide 559 in exon 7 of the ATP2A2 gene, which resulted in a premature termination codon (PTC) at codon 192. A woman, whose skin symptoms developed unusually late, at the age 50, had a new T deletion (1320delT) in exon 11 resulting in a PTC at codon 448. Our most severe case had a known missense mutation N39T, resulting in a non-conservative amino acid change at the upstream stalk region. Three new missense mutations (A161D, R164S, and Q790P) affected conservative regions of the SERCA2 protein within the activation (A)-domain and the M6 transmembrane region. A further new nonsense mutation (C909X) was detected in the M8 transmembrane domain. Our data suggest that differences in DD phenotypes are probably also related to factors different from the type of causative mutation.