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Context.—: Increased band neutrophils in blood smear differential counts ("bandemia") are entrenched in medicine as a flag for sepsis. However, laboratory hematology experts have long advocated for discontinuation of reporting bands separately from segmented neutrophils because of poor sensitivity and specificity, poor interobserver agreement, and availability of alternative biomarkers for sepsis., Objective.—: To describe band neutrophil reporting practices and reproducibility of band classification among laboratories participating in the College of American Pathologists (CAP) proficiency testing (PT) program., Design.—: A survey questionnaire was distributed to hematology PT participants. A subsequent morphologic challenge included 12 preselected cell identifications of segmented neutrophils, bands, and metamyelocytes, and a 100-cell manual differential count of a digitally scanned blood smear., Results.—: Among laboratories that reported manual differentials, most respondents reported bands (4554 of 5268; 86.4%). Only 3222 of 4412 respondents (73.0%) provided band reference ranges. Though participants classified "easy" band neutrophils well (78.0%-98.3%), categorization of cell identifications for "moderate" and "difficult" bands was poor (3.1%-39.0% of laboratories), with classification instead as segmented neutrophils. This pattern was seen regardless of laboratory demographic characteristics. Marked variability in band counts was observed on the 100-cell differential count for both CAP PT participants and CAP Hematology and Clinical Microscopy Committee (HCMC) members (coefficients of variation, 55.8% and 32.9%, respectively). Variability was significantly improved when segmented and band neutrophils were grouped together (coefficients of variation, 6.2% and 5.0%, respectively)., Conclusions.—: Most CAP PT-participating laboratories report band counts, many without reference ranges. The survey confirms significant interlaboratory variability of band enumeration when bands are separately identified from segmented neutrophils. This study reaffirms the CAP Hematology and Clinical Microscopy Committee's strong recommendation to group segmented and band neutrophils together in manual differential counts., Competing Interests: All authors are past or present members of the College of American Pathologists Hematology and Clinical Microscopy subcommittee., (© 2024 College of American Pathologists.)

Background: Granulomatous mycosis fungoides (GMF) is a rare form of cutaneous T-cell lymphoma characterized by a granulomatous inflammatory infiltrate., Objective: The impact of granulomatous inflammation on the prognosis of the disease remains controversial as there have been both favorable and unfavorable outcomes documented., Methods: We performed a systematic review of 116 GMF cases previously described in the literature., Results: In contrast to the classic Alibert-Bazin type of mycosis fungoides (MF), cutaneous lesions in GMF tend to involve distal extremities (lower legs, feet, hands) early in the disease course. In the literature, 30% of GMF patients developed organ metastasis, most frequently to the lung. The median time to stage progression was 25 months., Conclusion: GMF is an aggressive form of MF. Therefore, screening for distant metastases should be considered at presentation and repeated during follow-up., (© 2024 S. Karger AG, Basel.)

FMS-like tyrosine kinase 3 ( FLT3 ) mutations are detected in approximately 20-30% of patients with acute myeloid leukemia (AML), with the presence of a FLT3 internal tandem duplication ( FLT3 -ITD) mutation being associated with an inferior outcome. Assessment of FLT3 mutational status is now essential to define optimal upfront treatment in both newly diagnosed and relapsed AML, to support post-induction allogeneic hematopoietic stem cell transplantation (alloSCT) decision-making, and to evaluate treatment response via measurable (minimal) residual disease (MRD) evaluation. In view of its importance in AML diagnosis and management, the Canadian Leukemia Study Group/Groupe canadien d'étude sur la leucémie (CLSG/GCEL) undertook the development of a consensus statement on the clinical utility of FLT3 mutation testing, as members reported considerable inter-center variability across Canada with respect to testing availability and timing of use, methodology, and interpretation. The CLSG/GCEL panel identified key clinical and hematopathological questions, including: (1) which patients should be tested for FLT3 mutations, and when?; (2) which is the preferred method for FLT3 mutation testing?; (3) what is the clinical relevance of FLT3 -ITD size, insertion site, and number of distinct FLT3 -ITDs?; (4) is there a role for FLT3 analysis in MRD assessment?; (5) what is the clinical relevance of the FLT3 -ITD allelic burden?; and (6) how should results of FLT3 mutation testing be reported? The panel followed an evidence-based approach, taken together with Canadian clinical and laboratory experience and expertise, to create a consensus document to facilitate a more uniform approach to AML diagnosis and treatment across Canada.

Background: Preeclampsia (PE) is a hypertensive disorder during pregnancy that results in significant adverse maternal and neonatal outcomes. Platelet activation is present in PE and contributes to the thrombo-hemorrhagic states of the disorder. However, the mechanisms that initiate and/or sustain platelet activation in PE are ill-defined., Objectives: We aimed to characterise this mechanism and the procoagulant potentials of platelets in PE., Methods: In this quantitative observational study, we analyzed platelet procoagulant membrane dynamics in patients with PE (n = 21) compared with age-matched normotensive pregnancies (n = 20), gestational hypertension (n = 10), and non-pregnant female controls (n = 19). We analyzed fluorescently labeled indicators of platelet activation, bioenergetics, and procoagulation (phosphatidylserine exposure and thrombin generation), coupled with high-resolution imaging and thrombelastography. We then validated our findings using flow cytometry, immunoassays, classical pharmacology, and convolutional neural network analysis., Results: PE platelets showed significant ultra-structural remodeling, are more extensively preactivated than in healthy pregnancies and can circulate as microaggregates. Preactivated platelets of PE externalized phosphatidylserine and thrombin formed on the platelet membranes. Platelets' expression of facilitative glucose transporter-1 increased in all pregnant groups. However, PE platelets additionally overexpress glucose transporter-3 to enhance glucose uptake and sustain activation and secretion events. Although preeclampsia platelets exposed to subendothelial collagen showed incremental activation, the absolute hemostatic response to collagen was diminished, and likely contributed to greater blood loss perioperatively., Conclusions: We revealed 2 bioenergetic mediators in the mechanism of sustained platelet procoagulation in preeclampsia. Although glucose transporter-1 and glucose transporter-3 remain elusive antiprocoagulant targets, they may be sensitive monitors of PE onset and progression., Competing Interests: Declaration of competing interests E.O.A. holds a patent “Facilitative Glucose Transporters 1 And 3 as an Anti-Thrombotic and Diagnostic Target” US Prov (US 63/275767); and Canadian Patent Applic #: (3,137,826). Other authors report no competing interests., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Introduction: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR., Patients and Methods: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients., Results: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate., Conclusion: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: No study has assessed the risk factors of progression from discoid lupus erythematosus (DLE) to severe systemic lupus erythematosus (sSLE) (defined as requiring hospitalization and specific treatment)., Objective: To identify the risks factors of and generate a predicting score for progression to sSLE among patients with isolated DLE or associated with systemic lupus erythematosus with mild biological abnormalities., Methods: In this registry-based cohort study, multivariable analysis was performed using risk factors identified from literature and pruned by backward selection to identify relevant variables. The number of points was weighted proportionally to the odds ratio (OR)., Results: We included 30 patients with DLE who developed sSLE and 134 patients who did not. In multivariable analysis, among 12 selected variables, an age of <25 years at the time of DLE diagnosis (OR, 2.8; 95% CI, 1.1-7.0; 1 point), phototype V to VI (OR, 2.7; 95% CI, 1.1-7.0; 1 point), and antinuclear antibody titers of ≥1:320 (OR, 15; 95% CI, 3.3-67.3; 5 points) were selected to generate the score. Among the 54 patients with a score of 0 at baseline, none progressed to sSLE, whereas a score of ≥6 was associated with a risk of approximately 40%., Limitations: Retrospective design., Conclusion: In our cohort, an age of <25 years at the time of DLE diagnosis, phototype V to VI, and antinuclear antibody titers of ≥1:320 were risk factors for developing sSLE., Competing Interests: Conflict of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Despite surviving a SARS-CoV-2 infection, some individuals experience an intense post-infectious Multisystem Inflammatory Syndrome (MIS) of uncertain etiology. Children with this syndrome (MIS-C) can experience a Kawasaki-like disease, but mechanisms in adults (MIS-A) are not clearly defined. Here we utilize a deep phenotyping approach to examine immunologic responses in an individual with MIS-A. Results are contextualized to healthy, convalescent, and acute COVID-19 patients. The findings reveal systemic inflammatory changes involving novel neutrophil and B-cell subsets, autoantibodies, complement, and hypercoagulability that are linked to systemic vascular dysfunction. This deep patient profiling generates new mechanistic insight into this rare clinical entity and provides potential insight into other post-infectious syndromes., Competing Interests: MF is the medical director of Mitogen Diagnostics Corporation MitogenDx and Eve Technologies, and has received honoraria from Inova Diagnostics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gillrie, Rosin, Sinha, Kang, Farias, Nguyen, Volek, Mah, Mahe, Fritzler, Yipp and Biernaskie.)

Carpal tunnel syndrome (CTS) is common in patients with transthyretin amyloidosis (ATTR), and many experience residual symptoms and/or develop recurrent disease following routine carpal tunnel release (CTR). An extended CTR with median nerve neurolysis is recommended for thorough nerve decompression. Tissue confirmation of amyloidosis can be performed at the time of CTR with biopsies of the transverse carpal ligament and/or tenosynovium., Methods: We describe a retrospective, single-center experience performing an extended CTR technique including unilateral and bilateral cases for 13 consecutive patients (18 wrists) with ATTR and symptomatic median neuropathy at the wrist., Results: The mean patient age was 83 (range 67-90) years and 11 (85%) were men. Notable intraoperative findings in all cases included thickened tenosynovium and median nerve epineurium, and adherence of the median nerve to the deep surface of transverse carpal ligament. Pathology findings were positive for amyloidosis from both the transverse carpal ligament and the tenosynovium biopsies in all patients., Conclusions: Extended CTR with simultaneous wrist tissue biopsy can be safely performed for ATTR patients with CTS. Characteristic intraoperative findings should increase clinical suspicion for undiagnosed ATTR and prompt performance of biopsy for diagnostic confirmation. Volar wrist tenosynovial biopsy is our preferred tissue for confirmation of ATTR, for patients with and without CTS, given its safety profile and 100% pathological yield in our series., Competing Interests: Disclosure: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Severe acute respiratory syndrome coronavirus (SARS-CoV2) and associated COVID-19 infection continue to impact patients globally. Patients with underlying health conditions are at heightened risk of adverse outcomes from COVID-19; however, research involving patients with rare health conditions remains scarce. The amyloidoses are a rare grouping of protein deposition diseases. Light-chain and transthyretin amyloidosis are the most common disease forms, often present with systemic involvement of vital organs including the heart, nerves, kidneys, and GI tracts of affected individuals. The Amyloidosis Program of Calgary examined 152 ATTR patients and 103 AL patients analyzing rates of vaccination, COVID-19 testing, infection outcomes, influence referrals, and excess deaths. Results showed 15 total PCR-confirmed COVID-19 infections in the tested population of amyloid patients, with a higher frequency of infections among patient with AL compared to the ATTR cohort (26.2% vs 5.1%). Four patients (26.6%) required hospital admission for COVID-19 infection, 2 ATTR, and 2 AL patients. Of the confirmed cases, 1 (0.07%) unvaccinated ATTR patient died of a COVID-19 infection. An excess of deaths was found in both the ATTR and AL cohorts when comparing pre-pandemic years 2018 and 2019 to the pandemic years of 2020 and 2021. The finding suggests that amyloidosis patients are likely at a high risk for severe COVID-19 infection and mortality, especially those of advanced age, those on an active treatment with chemotherapy, and those with concomitant B-cell or plasma cell disorder. The impact of virtual healthcare visits and pandemic measures on the excess of deaths observed requires further research., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/objectives: We observed isolated cases of perialar intertrigo in children and teenagers that did not appear to correspond to any known clinical entity. The objective of this study was to describe the clinical features of this dermatosis and the clinical characteristics of the patients., Methods: We conducted a prospective, multicenter cohort study in France from August 2017 to November 2019. All the patients under 18 years of age with chronic perinasal intertrigo were included. A standardized questionnaire detailing the clinical characteristics of the patients and the description of the intertrigo. If possible, a Wood's lamp examination of the intertrigo was done., Results: Forty-one patients were included (25 boys and 16 girls, average age: 12.1 years). Intertrigo was bilateral in 38 patients (93%). The majority of patients had no symptoms (54%). Pruritus was present in 39% of cases. Orange red follicular fluorescence was present in the perialar region on Wood's light examination in 78% of cases with active fluorescence. The presumptive diagnoses suggested by the investigators were acne (24.4%), seborrheic dermatitis (19.5%), rosacea (9.8%), psoriasis (9.8%) and perioral dermatitis (7.3%). No diagnosis was proposed in 22% of the cases., Conclusions: We describe a previously undescribed clinical sign which is characterized by a chronic bilateral erythematous intertrigo located in the perialar region. It can be isolated or associated with various facial dermatoses., (© 2022 The Authors. Pediatric Dermatology published by Wiley Periodicals LLC.)

Context.—: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious agent, with the propensity to cause severe illness. While vaccine uptake has been increasing in recent months, many regions remain at risk of significant coronavirus disease 19 (COVID-19)-related health care burden. Health systems will continue to benefit from the availability of a variety of clinical and laboratory models when other triaging models are equivocal., Objective.—: To validate previously reported clinical laboratory abnormalities seen in COVID-19 patients and identify what laboratory parameters might be outcome predictive., Design.—: We undertook an observational study of hospital-admitted COVID-19 patients (n = 113), looking at a broad selection of clinical, laboratory, peripheral blood smear, and outcome data during discrete discovery and validation periods from March 2020 to November 2020., Results.—: We confirmed the findings of previous studies noting derangement of a variety of laboratory parameters in COVID-19 patients, including peripheral blood morphologic changes. We also devised a simple-to-use decision tree by which patients could be risk stratified on the basis of red blood cell count, creatinine, urea, and atypical plasmacytoid lymphocyte ("covidocyte") count. This outcome classifier performed comparably to the World Health Organization clinical classifier and the neutrophil-lymphocyte ratio., Conclusions.—: Our data add to the increasing number of studies cataloguing laboratory changes in COVID-19 and support the clinical utility of incorporating blood morphologic assessment in the workup of hospitalized COVID-19 patients.

Background: In 2018 in France, overall mean health-related out-of-pocket (OOP) expenditures were 214.00€/year/patient., Aim: To evaluate OOP expenditures for psoriasis patients in France., Methodology: Observational, cross-sectional, non-comparative, multicentre study in 3000 patients with clinically confirmed psoriasis who responded to a specific digital questionnaire collecting demographic and socio-economic characteristics, assessing the 3 domains (severity, psychosocial impact and past history and interventions) of the patient's Simplified Psoriasis Index (sa-SPI) and expenditures to manage psoriasis, including OOP. Multivariate linear regression was conducted to search for factors associated with higher OOP., Results: In total, 2681 patients completed the questionnaire and, of those, 2562 provided clinically validated data. Overall, 60% were women; the mean age was 49.4 ± 14.8 years. 30% of the patients declared that they suffered from psoriatic arthritis. The final mean sa-SPI core was 10.86 ± 9.70. Of these 2562 patients, 243 (9.5%) had severe, 442 (17.3%) moderate and 1877 (73.3%) mild psoriasis. In addition, 932 (36.4%) patients reported facial involvement, 724 (28.25%) genital impairment and 1124 (43.8%) lesions on the limbs. Mean OOP expenditures to manage psoriasis per patient were 531.00€, 439.74€ ± 939.85€ for patients with mild, 791.06€ ± 1367.67€ with moderate and 1077.64€ ± 1680.14€ for patients with severe psoriasis. For patients with psoriasis in the genital area, the median amount of expenditures (251.17€; CI95% [138.35;363.99]) was significantly higher than that for the face (183.85€; CI95% [78.76;288.94]) or limbs (199.96€; CI95% [93.77;306.15); (P < 0.001). More than 90% of the patients had OOP expenditures for over-the-counter products (97.5%) and alternative care (92.0%), especially for emollients and/or hydrating products., Conclusion: In France, in 2019, OOP expenditures to manage psoriasis were on average more than twice as high as the overall mean health-related OOP expenditures estimated by the French Health Agency in 2018. These results should lead health authorities to review certain standards of healthcare reimbursement., (© 2020 European Academy of Dermatology and Venereology.)

Topical treatments are first-line therapies, prescribed to most patients with chronic plaque psoriasis. This non-interventional, longitudinal study examined data regarding the treatment pathways of French patients with psoriasis vulgaris using a pharmacy database. From this database, patients with an initial prescription of a topical treatment of interest (ie, calcipotriol alone and/or calcipotriol/betamethasone) between March and October 2013 were included in the study. The primary objective was to capture the switch from a topical treatment, from treatment initiation to receipt of a systemic therapy over a period of 3 years. A total of 26 605 patients were included in the study. The mean age was 58.5 years. The majority of patients (94.7%) maintained topical treatment during the 3 years, receiving a mean of 1.1 different therapies. Of 1400 patients who switched to a systemic therapy, 93.1% switched to a non-biological (mean time to switching >400 days), maintaining this for the remainder of the follow-up period. The most commonly prescribed first non-biological systemic therapy was methotrexate (37%). Less than 1% of patients switched to a biological therapy during follow up. Cohort analyses suggest that patients progressing to use of a systemic therapy within 12 months were those with more severe disease. There was a low rate of transition from topical to systemic therapies in patients with chronic plaque psoriasis during the first 3 years of treatment, suggesting stability of disease severity over time with topical therapy alone, potentially due to good patient adherence., (© 2021 Wiley Periodicals LLC.)

Background: The multimorbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse outcomes of coronavirus disease 2019 (COVID-19), but the data are limited., Objective: Our aim was to characterize the course of COVID-19 in patients with psoriasis and identify factors associated with hospitalization., Methods: Clinicians reported patients with psoriasis with confirmed/suspected COVID-19 via an international registry, Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection. Multiple logistic regression was used to assess the association between clinical and/or demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviors., Results: Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% were receiving a nonbiologic, and 10% were not receiving any systemic treatment for psoriasis. In all, 348 patients (93%) were fully recovered from COVID-19, 77 (21%) were hospitalized, and 9 (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted odds ratio [OR] = 1.59 per 10 years; 95% CI = 1.19-2.13), male sex (OR = 2.51; 95% CI = 1.23-5.12), nonwhite ethnicity (OR = 3.15; 95% CI = 1.24-8.03), and comorbid chronic lung disease (OR = 3.87; 95% CI = 1.52-9.83). Hospitalization was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31-6.18). No significant differences were found between classes of biologics. Independent patient-reported data (n = 1626 across 48 countries) suggested lower levels of social isolation in individuals receiving nonbiologic systemic therapy than in those receiving biologics (OR = 0.68; 95% CI = 0.50-0.94)., Conclusion: In this international case series of patients with moderate-to-severe psoriasis, biologic use was associated with lower risk of COVID-19-related hospitalization than with use of nonbiologic systemic therapies; however, further investigation is warranted on account of potential selection bias and unmeasured confounding. Established risk factors (being older, being male, being of nonwhite ethnicity, and having comorbidities) were associated with higher hospitalization rates., (Copyright © 2020. Published by Elsevier Inc.)

Background: Drug addiction causes chronic wounds (CW) responsible for severe complications. Very few studies are available on this topic. The aim of our study was to describe the demographic, clinical and etiological characteristics as well as the course of CW in drug addicts., Patients and Methods: This was a retrospective and prospective multicenter study including all drug addicts with CW., Results: We included 58 patients (17 prospectively), 84.5% of whom were male, of median age 43 years, presenting multiple CW as a result of intravenous (78.2%), inhaled (41.1%) and/or snorted (20%) drug abuse. Addiction to opioids (68.4%), cocaine (47.4%) and/or cannabis (40.4%) was ended and/or treated through substitution in 79.3% of patients. CW were fibrinous and necrotic (42.9 to 53.6%), recurrent (54.2%), and in some cases had been present for more than 1 year (61.5%). Intravenous drug addiction was associated with large, fibrinous, ulcers in a setting of venous and lymphatic insufficiency (74%). Only 23% of these wounds involved the upper limbs. Necrotic ulcers associated with clinical arteriopathy were described mainly with inhaled addiction. Abscesses (50%) and erysipelas (29.3%) were the most common cutaneous complications. After 3 months, 50% of CW were improved and 29.2% of patients were lost to follow-up., Discussion: Drug abuse-related CW occurred preferentially in young men with history of intravenous abuse. For the most part, CW were seen on the legs and were associated with venous and lymphatic insufficiency, and the resulting major risk for cutaneous infection increased morbidity and mortality in this population in whom medical follow-up is inherently complicated., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics., Objectives: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children., Methods: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS)., Results: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease., Conclusions: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes., (© 2019 European Academy of Dermatology and Venereology.)

Dipeptidyl peptidase-4 inhibitors have been suspected to induce bullous pemphigoid (BP). The objective of this study was to compare the observed frequency of gliptin intake in a large sample of 1,787 BP patients diagnosed between 2012 and 2015 in France, with the expected frequency after indirect age standardization on 225,412 individuals extracted from the database of the National Healthcare Insurance Agency. The secondary objective was to assess the clinical characteristics and the course of gliptin-associated BP, depending on whether gliptin was continued or stopped. The observed frequencies of intake of the whole gliptin class and that of vildagliptin in the BP population were higher than those in the general population after age standardization (whole gliptin class: 6.0%; 95% confidence interval = 4.9-7.1% vs. 3.6%, observed-to-expected drug intake ratio = 1.7; 95% confidence interval = 1.4-2.0; P < 0.0001; vildagliptin = 3.3%; 95% confidence interval = 2.5-4.1% vs. 0.7%, ratio = 4.4; 95% confidence interval = 3.5-5.7; P < 0.0001). The association of any gliptin+metformin was also higher than in the general population, ratio = 1.8 (95% confidence interval = 1.3-2.4; P < 0.0001). Gliptin-associated BP had no specific clinical characteristics. Gliptin was stopped in 48 (45.3%) cases. Median duration to achieve disease control, rate, and delay of relapse were not different whether gliptin was stopped or continued. This study strongly supports the association between gliptin intake, particularly vildagliptin, and the onset of BP., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: The JAK2 V617F mutation is highly recurrent in many of the myeloproliferative neoplasms, a molecular variant that can be easily detected using sensitive and minimally invasive techniques. Given the ease of JAK2 V617F testing, this test may be improperly requested for the purposes of patient 'screening' and to optimise laboratory resource utilisation, it behooves clinicians and laboratorians to perform JAK2 V617F testing only when most appropriate., Methods: To assist with the screening of patients being considered for JAK2 V617F testing, we developed a clinical decision rule, "JAK2-tree", which can be easily applied to basic CBC parameters (haemoglobin, platelet and white blood cell counts)., Results: We tested JAK2-tree on two independent datasets, one an unselected population-based sample (the Copenhagen General Population Study) and the other an historical clinical laboratory referral set, with sensitivities for JAK2 V617F detection of 91% and 94%, respectively. As applied to the historical laboratory referral dataset, moreover, the JAK2-tree algorithm would have reduced JAK2 V617F testing volume over the period of evaluation by 15%., Conclusions: Our work supports a simple decision-tree-based screening approach to optimize the selection of patients most appropriate for JAK2 V617F testing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: To assess the prevalence of nail involvement in children <16 years old with a confirmed diagnosis of scabies., Study Design: Observational, prospective study in 7 French dermatology departments between June 2015 and January 2017. Children were included if they had scabies confirmed by dermoscopy and/or microscopy and if nails could be sampled. The first toenails and thumbnails as well as clinically affected nails were systematically sampled for microscopic examination. Individual data were recorded via a standardized questionnaire., Results: A total of 47 children with scabies were included (26 females [55.3%], mean age 3.6 ± 4.0 years). Pruritus was present in 42 children (89.3%); the relapse rate was 38.3% (n = 18). In 3 infants (6.4%), Sarcoptes mites were revealed by dermoscopy or microscopy of the first toenails (2 cases) and a thumbnail (1 case), but nails were normal in 2 children. Two of the 3 infants had already received treatment for scabies in the previous weeks., Conclusion: Prevalence of nail involvement in children with confirmed scabies was 6.4%. Nails should not be overlooked during scabies treatment., (Copyright © 2018 Elsevier Inc. All rights reserved.)

T cell clonality testing has important clinical and research value, providing a specific and reproducible assessment of clonal diversity in T cell proliferations. Here we review the conceptual foundations of T cell clonality assays, including T cell ontogeny and T cell receptor structure and function; we also provide an introduction to T cell receptor genomics and the concept of the T cell clonotype. This is followed by a review of historical and current methods by which T cell clonality may be assayed, including current assay limitations. Some of these assay limitations have been overcome by employing next-generation sequencing (NGS)-based technologies that are becoming a mainstay of modern molecular pathology. In this vein, we provide an introduction to NGS technologies, including a review of the preanalytical, analytical and postanalytical technologies relevant to T cell clonality NGS assays., Competing Interests: Competing interests: TP and EM are listed as inventors on a patent for profiling immune cell repertoires using hybrid capture and next-generation sequencing methods. SK-R has not competing interest to declare., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon systemic inflammatory condition that can result from infections, autoimmune diseases and malignancies. It is a rarely reported life threatening complication of an acute HIV infection, with only ten documented case reports per our literature search. We present a case of HLH secondary to acute HIV infection with a negative HIV antibody-based assay and high plasma viral load., Case Presentation: A 45 year old male with a past medical history of well controlled hypertension presented with fever, dizziness and non-bloody diarrhea. Initial lab work revealed a new thrombocytopenia, marked renal failure and an elevated creatine kinase, ferritin, lactate dehydrogenase and D-dimer. A bone marrow biopsy revealed HLH. As part of the work up for thrombocytopenia, a rapid HIV antibody based assay was done and was negative. The sample was later routinely tested with a fourth generation antigen/antibody assay as per local protocol and was strongly positive. The plasma RNA viral load was >10,000,000 copies /mL confirming the diagnosis of an acute HIV infection. The patient was urgently started on antiretroviral therapy and recovered., Conclusion: This case illustrates a diagnostic approach to HLH which is an uncommon but life threatening multisystem disease, requiring the involvement of a multidisciplinary team of experts. Following any diagnosis of HLH, rapid identification and treatment of the underlying condition is critical. A negative rapid HIV antibody test can be misleading in the context of early HIV infection and the additional use of fourth generation antigen/antibody test or plasma RNA viral load may be required within the right clinical context for diagnosis.

Background: Biotherapies or targeted therapies are fairly new treatments indicated for moderate to severe psoriasis. The side effects appear to be mainly infectious or cancerous. The role of biotherapies in the development of a pre-cancerous condition, monoclonal gammopathy of undetermined significance (MGUS), has recently been debated in the literature., Objectives: To evaluate the incidence of MGUS in psoriasis patients treated with biotherapy., Materials and Methods: This study was a French multicenter retrospective study carried out through the French multicenter study group RESOPSO. Data on the results of serum protein electrophoreses performed before and within at least six months after the start of the biotherapy were collected. Demographic data, medical history, and psoriasis treatment history were specified., Results: Four hundred and forty three patients were eligible for inclusion. Of these, three presented with monoclonal gammopathy for which the assessment was in favor of MGUS. The average treatment period was 19.7 months. Six patients presented with MGUS prior to the treatment. These patients' immunoglobulin levels remained stable, with an average remission of 24 months. Only psoriatic rheumatism appeared to be statistically linked to MGUS., Conclusion: The incidence and frequency of MGUS in psoriasis patients treated with biotherapy do not appear to increase relative to the general population.

Mantle cell lymphoma (MCL) is an aggressive disease with poor overall survival, attributable in part to frequent defects of the DNA repair genes. In such malignancies, additional inhibition of the ubiquitous DNA damage repair protein, poly-ADP ribose polymerase-1 (PARP1) has shown enhanced cytotoxicity (so-called synthetic lethality). We studied PARP1 expression in a series of clinical cases of MCL, with the secondary aim to ascertain the relationship between PARP1 expression and DNA repair gene expression (namely ATM and p53) by immunohistochemical methods. We also examined the relationship between PARP1 expression and the well-established prognostic biomarker Ki-67, in addition to correlating PARP1 expression with the overall survival. From amongst our series of 79 unselected cases of MCL, we detected PARP1 expression in all but two cases with variable intensity. We also noted correlations between PARP1 expression and ATM and p53 expression. As described in previous studies, we identified a significant survival difference on the basis of Ki-67 and p53 expression. When digital H-score analysis of PARP1 expression was performed, there was a distinct survival advantage noted in patients with lower levels of expression. When our biomarker data were assessed by Cox regression, furthermore, the dominant effects of p53 and PARP1 expression were highlighted. Our data support the need for further research into the potential utility of PARP1 as a biomarker in MCL and for the potential direction of future PARP1 inhibitor-targeted therapy studies., (Copyright © 2014 John Wiley & Sons, Ltd.)

Background: Mantle cell lymphoma (MCL) is an aggressive disease with genetic heterogeneity and discrete clinical subtypes. MCL is rarely CD10 positive. These cases raise the question whether a subset of MCL may be germinal centre (GC) derived, and have distinct clinicopathological characteristics., Aims and Methods: A series of nine CD10-positive MCL cases is described herein. The clinicopathological and immunophenotypic features, immunoglobulin somatic hypermutation (SHM) status and gene expression profile (GEP) data are detailed. These features were compared with two independent sets (n=20, each) of CD10-negative MCL cases (controls), which were randomly selected from our institutional registry., Results: GEP showed distinct expression of a GC signature in CD10-positive MCL cases with minimal impact on downstream signalling pathways. There were no significant differences in the clinicopathological features or clinical outcome between our CD10-positive and CD10-negative MCL cases. The frequency of SHM was comparable with established data., Conclusions: This study provides convincing evidence that CD10 expression is related to a distinct GC signature in MCL cases, but without clinical or biological implications., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Among plasma cell myeloma (PCM) patients, gene expression profiling (GEP)-based molecular classification has proven to be an independent predictor of survival, after autologous stem cell transplantation. However, GEP has limited routine clinical applicability given its complex methodology, high cost, and limited availability in clinical laboratories. In this study, we have evaluated biomarkers identified from GEP discoveries, utilizing immunohistochemistry (IHC) platform in a cohort of PCM patients. IHC staining for cyclins B1, B2, D1, D2, D3, FGFR3, PAX5, and integrin β7 (ITGβ7) was performed on the bone marrow biopsies of 93 newly diagnosed PCM patients. Expression of FGFR3 was noted in 10 (11%) samples correlating completely with t(4;14)(p16;q32) results (P<0.001); however, the association between FGFR3 and cyclin D2 expression was not significant (P=0.14). ITGβ7 expression was present in 9/93 (9%) patients and all these samples also demonstrated upregulated expression of cyclin D2 (P=0.014). Expression of cyclins D1, D2, and D3 was variable in this cohort. Positive protein expression of cyclin D1 was noted in 30/93 (32%), D2 in 17/93 (18%), and D3 in 5/93 (5%) samples. Coexpression of cyclins D1 and D2 was observed in 13/93 (14%) samples, whereas 28 (30%) samples were negative for all the 3 cyclin D proteins. Cyclin B1 was not expressed in any sample, despite adequate staining in positive controls. Cyclin B2 was expressed in 33/93 (35%) and PAX5 protein was noted in 7/93 (8%) samples. In summary, we have demonstrated that mRNA-based prognostic markers can be detected by routine IHC in decalcified bone marrow samples. This approach may provide a useful tool for the wider adoption of prognostic makers for risk stratification of PCM patients. We anticipate that such an approach might allow patients with high-risk immunoprofiles to be considered for other potential novel therapeutic agents, potentially sparing some patients the toxicity of stem cell transplant.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL) is a distinct and aggressive lymphoma that is confined to CNS. Since, central nervous system is barrier-protected and immunologically silent; role of TLR/BCR signaling in pathogenesis and biology of CNS DLBCL is intriguing. Genomic mutations in key regulators of TLR/BCR signaling pathway (MYD88/CD79B/CARD11) have recently been reported in this disease. These observations raised possible implications in novel targeted therapies; however, expression pattern of molecules related to TLR/BCR pathways in this lymphoma remains unknown. We have analyzed the expression of 19 genes encoding TLR/BCR pathways and targets in CNS DLBCLs (n = 20) by Nanostring nCounter™ analysis and compared it with expression patterns in purified reactive B-lymphocytes and systemic diffuse large B cell lymphoma (DLBCL) (n = 20). Relative expression of TLR4, TLR5, TLR9, CD79B and BLNK was higher in CNS DLBCLs than in control B-lymphocytes; where as TLR7, MALT1, BCL10, CD79A and LYN was lower in CNS DLBCLs (P < 0.0001). When compared with systemic DLBCL samples, higher expression of TLR9, CD79B, CARD11, LYN and BLNK was noted in CNS DLBCL (>1.5 fold change; P < 0.01). The B cell receptor molecules like BLNK and CD79B were also associated with higher expression of MYD88 dependent TLRs (TLR4/5/9). In conclusion, we have shown over expression of TLR/BCR related genes or their targets, where genomic mutations have commonly been identified in CNS DLBCL. We have also demonstrated that TLR over expression closely relate with up regulation of genes associated with BCR pathway like CD79B/BLNK and CARD11, which play an important role in NF-kB pathway activation. Our results provide an important insight into the possibility of TLR and/or B-cell receptor signaling molecules as possible therapeutic targets in CNS DLBCL.

Objectives: We devised a rapid frozen section (FS) assessment technique of placental tissues and performed the first rigorous assessment of FS relative to conventional workup., Methods: We evaluated 49 placentas with clinical/gross suspicion of intra-amniotic infection by FS. Relative to formalin-fixed and paraffin-embedded tissues, we compared the grading, staging, and interobserver variability., Results: FS assessment demonstrated a sensitivity of 0.91 (95% CI, 0.77-0.97) and a specificity of 0.60 (95% CI, 0.36-0.80) for the presence of chorioamnionitis and a sensitivity of 0.89 (95% CI, 0.75-0.96) and a specificity of 0.69 (95% CI, 0.42-0.87) for the presence of funisitis. The χ2 goodness of fit for grade and stage in both placental membrane and umbilical cord sections was significant (P<.001). There was no significant difference in interobserver variability in comparison with permanent section results (P=0.06)., Conclusions: We conclude that FS is a reasonably sensitive screening technique, correlating well with conventional assessment, without significantly different interobserver variability., (Copyright© by the American Society for Clinical Pathology.)

Crinophagy is a well-described ultraphysiological phenomenon encountered in a variety of cells and tissues. This process reflects a form of autophagy in which degradation of excess or nonfunctional cellular constituents occurs, specifically of neuroendocrine granules. The diagnostic ultrastructural features are the identification of neuroendocrine granules within lysosomes, often encased in or accompanied by myelin bodies. An impressive variety of neuroendocrine/secretory cells and tumors have demonstrated crinophagy from the neuroendocrine cells of the pancreas, small bowel, prostate, and urinary tract. To our knowledge, however, crinophagy has not been previously described in neuroblastoma, despite the fact that these tumors characteristically produce neuroendocrine granules in abundance. This case further supports the idea that crinophagy represents a common ultrastructural mechanism for the disposal and degradation of excess neuroendocrine granules.

Micropapillary breast carcinoma has been recognized as a morphologically and biologically distinct form of breast carcinoma. Although data suggest that patient outcomes in cases of micropapillary breast carcinoma do not differ significantly from other breast carcinomas, the impact that a micropapillary component might have on the pathological work-up of a case of breast carcinoma remains an important point of discussion (especially as pertaining to the risk of lymphovascular disease). In this study, we perform an extensive retrospective study of the pathological parameters of seven years of breast surgical pathology cases to explore the relationship that micropapillary morphology might have with other important pathological parameters of a breast cancer case work-up (e.g. tumour size, lymphovascular invasion, lymph node status). We also analyze our data set to see if a micropapillary component would influence hierarchical classification by pathological parameters. Micropapillary features correlated with a higher frequency of ER positivity and lymphovascular invasion; there was no statistical difference between those cases with and without a micropapillary component from the perspective of other clinicopathological parameters, however. The presence of micropapillary features did influence classification, however, and produced a distinct cluster amidst comparison of other pathological variables.

Studies have suggested serous tubal intraepithelial carcinoma (STIC) of the fallopian tube to be a putative precursor to ovarian and peritoneal serous carcinoma. It has been recommended that resected fallopian tube specimens should be rigorously examined for STIC, especially in women at high risk of serous carcinoma, such as those with BRCA mutations or with a strong family history. The SEE-FIM protocol allows for the greatest surface area of the tube to be histologically assessed. There have been suggestions that multiple deeper sections should be examined if the initial hematoxylin and eosin (H&E) sections are negative; however, whether this identifies more cases of STIC has not rigorously examined. We examined deeper sections from 56 cases of pelvic carcinoma in which the initial H&E sections of the fallopian tubes were negative for STIC. All initial and deeper sections underwent consensus review by panel of experts in gynecologic pathology. These cases are part of a larger study in which we had examined 300 consecutive bilateral salpingectomies using the SEE-FIM protocol and a single-H&E section per block and had identified 68 cases of pelvic serous carcinoma, of which 12 were associated with STIC. We calculated the sensitivity of a single-H&E section to detect STIC, as compared with examination of multiple deeper sections, and reevaluated the clinicopathologic data of the parent study in light of the additional cases of STIC. In the 56 cases initially negative for STIC, 4 cases of STIC were identified after examination of multiple deeper sections of the fallopian tubes. The single-H&E section SEE-FIM approach therefore detected only 75% (95% confidence interval, 51%-90%) of STIC that was present. Three of these new cases were associated with primary ovarian serous carcinoma and 1 with primary peritoneal serous carcinoma. All 3 new cases associated with ovarian carcinoma were noted in women without neoadjuvant chemotherapy. In considering the data from the parent study, we calculated a statistically significant lower incidence of STIC in women with ovarian serous carcinoma who received neoadjuvant chemotherapy as compared with those who did not (P=0.042). Our study demonstrated that additional cases of STIC can be detected if deeper sections are examined. These additional cases also highlighted a statistically significant difference in the incidence of STIC associated with ovarian serous carcinoma who received neoadjuvant chemotherapy relative to those who did not. Consideration to this should be given in future studies of the prevalence of STIC and to routine examination of salpingectomy specimens from women at high risk for pelvic serous carcinoma.

Background: Correlation of intraoperative frozen section diagnosis with final diagnosis can be an important component of an institution's quality assurance process., Methods: We performed a quality assurance review of 1207 frozen section diagnoses from 812 surgical cases performed in the Hamilton Regional Laboratory Medicine Programme during a 6-month period in 2007. We reviewed the frozen section and permanent slides from all potentially discordant cases using a multiheaded microscope to arrive at a consensus pertaining to the type and reason for error. We reviewed the clinical record to determine whether there had been a potential adverse impact on immediate clinical management., Results: Frozen sections were most commonly requested for head and neck, nervous system and female genital tract specimens. Twenty-eight frozen sections (3%) were deferred. We identified 24 discordant diagnoses involving 3% of cases and 2% of specimens. The organ systems showing the greatest frequency of discordance relative to the total number from that system were the nervous system, head and neck, and the lungs. Of the errors identified, most occurred owing to diagnostic misinterpretation, followed by problems related to tissue sampling. There was a potential adverse impact on immediate clinical management in 14 cases., Conclusion: Our results add to the Canadian data on the correlation between frozen sections and permanent sections; we note comparability to the concordance rates reported in the literature.