The concept of pre-diabetes has led to provision of measures to reduce disease progression through identification of subjects at risk of diabetes. We previously considered the idea of pre-asthma in relation to allergic asthma and considered that, in addition to the need to improve population health via multiple measures, including reduction of exposure to allergens and pollutants and avoidance of obesity, there are several possible specific means to reduce asthma development in those most at risk (pre- asthma). The most obvious is allergen immunotherapy (AIT), which when given for allergic rhinitis (AR) has reasonable evidence to support asthma prevention in children (2) but also needs further study as primary prevention. In this second paper we explore the possibilities for similar actions in late onset eosinophilic asthma.
- Klíčová slova
- S. aureus biofilm, chronic rhinosinusitis with nasal polyps, eosinophils, late onset asthma, mast cells, non-allergic rhinitis, virulence genes,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
IMPORTANCE: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but potentially fatal drug hypersensitivity reaction. To our knowledge, there is no international consensus on its severity assessment and treatment. OBJECTIVE: To reach an international, Delphi-based multinational expert consensus on the diagnostic workup, severity assessment, and treatment of patients with DRESS. DESIGN, SETTING, AND PARTICIPANTS: The Delphi method was used to assess 100 statements related to baseline workup, evaluation of severity, acute phase, and postacute management of DRESS. Fifty-seven international experts in DRESS were invited, and 54 participated in the survey, which took place from July to September 2022. MAIN OUTCOMES/MEASURES: The degree of agreement was calculated with the RAND-UCLA Appropriateness Method. Consensus was defined as a statement with a median appropriateness value of 7 or higher (appropriate) and a disagreement index of lower than 1. RESULTS: In the first Delphi round, consensus was reached on 82 statements. Thirteen statements were revised and assessed in a second round. A consensus was reached for 93 statements overall. The experts agreed on a set of basic diagnostic workup procedures as well as severity- and organ-specific further investigations. They reached a consensus on severity assessment (mild, moderate, and severe) based on the extent of liver, kidney, and blood involvement and the damage of other organs. The panel agreed on the main lines of DRESS management according to these severity grades. General recommendations were generated on the postacute phase follow-up of patients with DRESS and the allergological workup. CONCLUSIONS AND RELEVANCE: This Delphi exercise represents, to our knowledge, the first international expert consensus on diagnostic workup, severity assessment, and management of DRESS. This should support clinicians in the diagnosis and management of DRESS and constitute the basis for development of future guidelines.
Asthma, which affects some 300 million people worldwide and caused 455,000 deaths in 2019, is a significant burden to suffers and to society. It is the most common chronic disease in children and represents one of the major causes for years lived with disability. Significant efforts are made by organizations such as WHO in improving the diagnosis, treatment and monitoring of asthma. However asthma prevention has been less studied. Currently there is a concept of pre- diabetes which allows a reduction in full blown diabetes if diet and exercise are undertaken. Similar predictive states are found in Alzheimer's and Parkinson's diseases. In this paper we explore the possibilities for asthma prevention, both at population level and also investigate the possibility of defining a state of pre-asthma, in which intensive treatment could reduce progression to asthma. Since asthma is a heterogeneous condition, this paper is concerned with allergic asthma. A subsequent one will deal with late onset eosinophilic asthma.
- Klíčová slova
- asthma, asthma natural history, pre-asthma, predisposition, quality of life, risk factors,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BAP1-inactivated melanocytic tumor (BIMT) is a group of melanocytic neoplasms with epithelioid cell morphology molecularly characterized by the loss of function of BAP1, a tumor suppressor gene located on chromosome 3p21, and a mutually exclusive mitogenic driver mutation, more commonly BRAF. BIMTs can occur as a sporadic lesion or, less commonly, in the setting of an autosomal dominant cancer susceptibility syndrome caused by a BAP1 germline inactivating mutation. Owing to the frequent identification of remnants of a conventional nevus, BIMTs are currently classified within the group of combined melanocytic nevi. "Pure" lesions can also be observed. We studied 50 BIMTs from 36 patients. Most lesions were composed of epithelioid melanocytes of varying size and shapes, resulting extreme cytomorphological heterogeneity. Several distinctive morphological variants of multinucleated/giant cells were identified. Some hitherto underrecognized microscopic features, especially regarding nuclear characteristics included nuclear blebbing, nuclear budding, micronuclei, shadow nuclei, peculiar cytoplasmic projections (ant-bear cells) often containing micronuclei and cell-in-cell structures (entosis). In addition, there were mixed nests of conventional and BAP1-inactivated melanocytes and squeezed remnants of the original nevus. Of the 26 lesions studied, 24 yielded a BRAF mutation, while in the remaining two cases there was a RAF1 fusion. BAP1 biallelic and singe allele mutations were found in 4/22 and 16/24 neoplasms, respectively. In five patients, there was a BAP1 germline mutation. Six novel, previously unreported BAP1 mutations have been identified. BAP1 heterozygous loss was detected in 11/22 lesions. Fluorescence in situ hybridization for copy number changes revealed a related amplification of both RREB1 and MYC genes in one tumor, whereas the remaining 20 lesions studied were negative; no TERT-p mutation was found in 14 studied neoplasms. Tetraploidy was identified in 5/21 BIMTs. Of the 21 patients with available follow-up, only one child had a locoregional lymph node metastasis. Our results support a progression of BIMTs from a conventional BRAF mutated in which the original nevus is gradually replaced by epithelioid BAP1-inactivated melanocytes. Some features suggest more complex underlying pathophysiological events that need to be elucidated.
- MeSH
- dítě MeSH
- epiteloidní a vřetenobuněčný névus * genetika MeSH
- hybridizace in situ fluorescenční MeSH
- lidé MeSH
- nádorové supresorové proteiny genetika MeSH
- nádory kůže * genetika patologie MeSH
- névus * MeSH
- pigmentový névus * genetika patologie MeSH
- protoonkogenní proteiny B-Raf genetika MeSH
- thiolesterasa ubikvitinu genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- BAP1 protein, human MeSH Prohlížeč
- nádorové supresorové proteiny MeSH
- protoonkogenní proteiny B-Raf MeSH
- thiolesterasa ubikvitinu MeSH
IMPORTANCE: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. OBJECTIVE: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. DESIGN, SETTING, AND PARTICIPANTS: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). MAIN OUTCOMES AND MEASURES: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. RESULTS: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. CONCLUSIONS AND RELEVANCE: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.
- MeSH
- dítě MeSH
- dospělí MeSH
- konsensus MeSH
- kyselina listová MeSH
- lidé MeSH
- methotrexát * MeSH
- průzkumy a dotazníky MeSH
- psoriáza * terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kyselina listová MeSH
- methotrexát * MeSH
IMPORTANCE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug reactions associated with a high rate of mortality and morbidity. There is no consensus on the treatment strategy. OBJECTIVE: To explore treatment approaches across Europe and outcomes associated with the SJS/TEN disease course, as well as risk factors and culprit drugs. DESIGN, SETTING, AND PARTICIPANTS: A retrospective pan-European multicenter cohort study including 13 referral centers belonging to the ToxiTEN ERN-skin subgroup was conducted. A total of 212 adults with SJS/TEN were included between January 1, 2015, and December 31, 2019, and data were collected from a follow-up period of 6 weeks. MAIN OUTCOMES AND MEASURES: Risk factors for severe acute-phase complications (acute kidney failure, septicemia, and need for mechanical ventilation) and mortality 6 weeks following admission were evaluated using a multivariable-adjusted logistic regression model. One tool used in evaluation of severity was the Score of Toxic Epidermal Necrolysis (SCORTEN), which ranges from 0 to 7, with 7 the highest level of severity. RESULTS: Of 212 patients (134 of 211 [63.7%] women; mean [SD] age, 51.0 [19.3] years), the mean (SD) body surface area detachment was 27% (32.8%). In 176 (83.0%) patients, a culprit drug was identified. Antibiotics (21.2%), followed by anticonvulsants (18.9%), nonsteroidal anti-inflammatory drugs (11.8%), allopurinol (11.3%), and sulfonamides (10.4%), were the most common suspected agents. Treatment approaches ranged from best supportive care only (38.2%) to systemic glucocorticoids (35.4%), intravenous immunoglobulins (23.6%), cyclosporine (10.4%), and antitumor necrosis factor agents (3.3%). Most patients (63.7%) developed severe acute-phase complications. The 6-week mortality rate was 20.8%. Maximal body surface area detachment (≥30%) was found to be independently associated with severe acute-phase complications (fully adjusted odds ratio [OR], 2.49; 95% CI, 1.21-5.12; P = .01) and SCORTEN greater than or equal to 2 was significantly associated with mortality (fully adjusted OR, 10.30; 95% CI, 3.82-27.78; P < .001). Cyclosporine was associated with a higher frequency of greater than or equal to 20% increase in body surface area detachment in the acute phase (adjusted OR, 3.44; 95% CI, 1.12-10.52; P = .03) and an increased risk of infections (adjusted OR, 7.16; 95% CI, 1.52-33.74; P = .01). Systemic glucocorticoids and intravenous immunoglobulins were associated with a decreased risk of infections (adjusted OR, 0.40; 95% CI, 0.18-0.88; P = .02). No significant difference in 6-week mortality was found between treatment groups. CONCLUSIONS AND RELEVANCE: This cohort study noted differences in treatment strategies for SJS/TEN in Europe; the findings suggest the need for prospective therapeutic studies to be conducted and registries to be developed.
- MeSH
- cyklosporin terapeutické užití MeSH
- dospělí MeSH
- intravenózní imunoglobuliny terapeutické užití MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- retrospektivní studie MeSH
- Stevensův-Johnsonův syndrom * diagnóza epidemiologie etiologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- Názvy látek
- cyklosporin MeSH
- intravenózní imunoglobuliny MeSH
The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.
- Klíčová slova
- allergen immunotherapy, molecular diagnosis, omics, personalized medicine, treatable traits,
- MeSH
- alergeny MeSH
- alergie * diagnóza terapie MeSH
- desenzibilizace imunologická MeSH
- genomika MeSH
- individualizovaná medicína * MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- alergeny MeSH
BACKGROUNDS: Folate Hydrolase-1 (FOLH1; PSMA) is a type II transmembrane protein, luminally expressed by solid tumour neo-vasculature. Monoclonal antibody (mAb), J591, is a vehicle for mAb-based brachytherapy in FOLH1+ cancers. Brachytherapy is a form of radiotherapy that involves placing a radioactive material a short distance from the target tissue (e.g., on the skin or internally); brachytherapy is commonly accomplished with the use of catheters, needles, metal seeds and antibody or small peptide conjugates. Herein, FOLH1 expression in primary (p) and metastatic (m) Merkel cell carcinoma (MCC) is characterized to determine its targeting potential for J591-brachytherapy. MATERIALS & METHODS: Paraffin sections from pMCC and mMCC were evaluated by immunohistochemistry for FOLH1. Monte Carlo simulation was performed using the physical properties of conjugated radioisotope lutetium-177. Kaplan-Meier survival curves were calculated based on patient outcome data and FOLH1 expression. RESULTS: Eighty-one MCC tumours were evaluated. 67% (54/81) of all cases, 77% (24/31) pMCC and 60% (30/50) mMCC tumours were FOLH1+. Monte Carlo simulation showed highly localized ionizing tracks of electrons emitted from the targeted neo-vessel. 42% (34/81) of patients with FOLH1+/- MCC had available survival data f or analysis. No significant differences in our limited data set were detected based on FOLH1 status (p = 0.4718; p = 0.6470), staining intensity score (p = 0.6966; p = 0.9841) or by grouping staining intensity scores (- and + vs. ++, +++, +++) (p = 0.8022; p = 0.8496) for MCC-specific survival or recurrence free survival, respectively. CONCLUSIONS: We report the first evidence of prevalent FOLH1 expression within MCC-associated neo-vessels, in 60-77% of patients in a large MCC cohort. Given this data, and the need for alternatives to immune therapies it is appropriate to explore the safety and efficacy o f FOLH1-targeted brachytherapy for MCC.
- Publikační typ
- časopisecké články MeSH
Sebaceous neoplasms with an organoid pattern (rippled, labyrinthine/sinusoidal, carcinoid-like, and petaloid) are rare. Previous studies suggested that the above patterns likely represent variations along a morphological continuum. The objectives of this study were to (1) validate this proposition by studying a large number of cases, (2) determine whether there are specific associations with clinical features, (3) establish their frequency, and (4) determine whether they have any association with Muir-Torre syndrome. Fifty-seven sebaceous neoplasms (54 sebaceomas and 3 sebaceous carcinomas) with organoid growth patterns were studied. These occurred in 36 men and 18 women (sex unknown in 3), with ages at diagnosis ranging from 22 to 89 years (mean, 63 years). All patients presented with a solitary nodule (mean size, 11 mm) on the head and neck area. Of the 57 tumors, 24 manifested a single growth pattern, 23 had a combination of 2 patterns, and 10 a combination of 3 patterns, indicating that these patterns are part of a morphological continuum of changes. The carcinoid-like pattern was the most frequent in the "monopatterned" neoplasms (13 cases), whereas the labyrinthine/sinusoidal pattern comprised most of the "polypatterned" lesions, in which various combinations occurred. Immunohistochemically, mismatch repair protein deficiency was detected in 3 of the 22 cases studied, whereas 5 of the 33 patients with available follow-up had an internal malignancy/premalignancy. In conclusion, sebaceous neoplasms with organoid growth patterns are predominantly sebaceomas having a predilection for the scalp, occurring as solitary lesions in elderly patients (male to female ratio of 2:1). Such patterns are expected to be found in a quarter of sebaceomas. In most cases, more than one of the organoid patterns is present. These lesions do not appear to be associated with internal malignancy or mismatch repair deficiency in most cases. However, confirmation of the absence of any significant association with Muir-Torre syndrome syndrome will require genetic studies.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory mazových žláz etiologie patologie MeSH
- oprava chybného párování bází DNA genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Torrého-Muirův syndrom komplikace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
