The annual incidence of Langerhans cell histiocytosis (LCH) and the prevalence of the BRAFV600E mutation among adults living in Greece

Langerhans cell histiocytosis (LCH) is a rare condition, characterized by tissue infiltration with cells that resemble Langerhans cells, a specialized subset of dendritic cells, which populates the epidermal layer of the skin and the mucosal tissues. LCH can affect any organ and is considered an inflammatory myeloid neoplasm with mutations in the MAPK/ERK pathway being found in all histological examinations. The BRAFV600E is the most common mutation, with a frequency of up to 60% in pediatric studies and an association with the disease extent, number of affected systems and severity of clinical manifestations.LCH is diagnosed in all age groups, but is most commonly seen in children with a mean age of diagnosis at 3 years old and an estimated annual incidence of up to 8.9 cases per million population in children under 15 years old. In adults the disease is rarer and is considered an ''orphan disease'' with an estimated incidence of 1-2 cases per million population and mean age at diagnosis at 33 years old. However, this estimated annual incidence hasn't been further investigated through an organized epidemiological study in the adult population.The aim of this research study is the prospective recording of the annual incidence of LCH in adults for the first time in literature and the investigation of the presence of the BRAFV600E mutation in Greek adults with LCH as well as its association with clinical parameters, such as the disease extent, age at diagnosis, gender, organ involvement, response to initial treatment (chemotherapy, surgical excision, smoking cessation, local radiotherapy or combination therapy), presence of diabetes insipidus, history of malignancy and relapse risk.The recording of new cases took place from the 1st of September 2018 until the 31st of August 2019 after frequent communication with the vast majority of pathology laboratories in theNational Health System in Greece (85%). The annual incidence of the disease in adults in Greece was estimated at 1.58 per million population with a mean age at diagnosis at 43.5 years and a female to male ratio of 1.34.The BRAF V600E mutation was found in 39% of the patients who are followed up in the LCH adult clinic and agreed to take part in the study. Upon written consent, DNA was isolated from 40 formalin fixed, paraffin-embedded tissue blocks, of which 31 yielded sufficient DNA for molecular analysis with PCR. The BRAFV600E mutation was found in 12 patients (38,71%) with the majority being females (83.3%), while 13 patients (41,94%) did not carry the mutation. In 6 patients (2 men), (19,35%), genotyping qPCR studies failed to meet the technical standards required for definitive interpretation of results.There was no statistically significant association of the presence of the mutation with age at diagnosis, organ involvement, disease extent (single system or multi-system), response to initial treatment, development of diabetes insipidus and relapse risk.As targeted therapies become more widespread in the management of LCH, further studies are needed for the discovery of the full spectrum of mutations implicated in disease pathogenesis.Η ιστιοκυττάρωση Langerhans (LCH) αποτελεί μία σπάνια διαταραχή που χαρακτηρίζεται από διήθηση των ιστών από κύτταρα που προσομοιάζουν στα κύτταρα Langerhans, μία υποκατηγορία δενδριτικών κυττάρων που βρίσκεται στο δέρμα και τους βλεννογόνους. Η νόσος μπορεί να προσβάλει οποιοδήποτε όργανο εκτός από την καρδιά και τους νεφρούς και κατηγοριοποιείται ως φλεγμονώδες μυελοειδές νεόπλασμα με μεταλλάξεις στο μονοπάτι MAPK/ERK να ανευρίσκονται στο σύνολο των ιστολογικών διαγνώσεων της νόσου. Η μετάλλαξη BRAFV600E αποτελεί την συχνότερα εντοπιζόμενη με τη συχνότητα της να φτάνει το60% στους παιδιατρικούς πληθυσμούς, στους οποίους αναφέρεται συσχέτιση της με την εντόπιση, την έκταση και την βαρύτητα της νόσου.Η LCH έχει διαγνωσθεί σε όλες τις ηλικιακές ομάδες, αλλά παγκοσμίως συναντάται συχνότερα στα παιδιά με μέση ηλικία διάγνωσης τα 3 έτη, με μία εκτιμώμενη ετήσια επίπτωση έως 8.9 περιπτώσεις ανά εκατομμύριο πληθυσμού σε παιδιά κάτω των 15 ετών. Στους ενήλικες η νόσος είναι σπανιότερη και θεωρείται ''ορφανή νόσος'' με εκτιμώμενη επίπτωση από τα παιδιατρικά δεδομένα 1-2 περιπτώσεις ανά εκατομμύριο πληθυσμού ετησίως και μέση ηλικία διάγνωσης τα 33 έτη χωρίς οι ανωτέρω εκτιμήσεις να έχουν επιβεβαιωθεί μέσω μίας οργανωμένης επιδημιολογικής μελέτης στον ενήλικο πληθυσμό.Σκοπός της παρούσας διδακτορικής διατριβής είναι η προοπτική καταγραφή, για πρώτη φορά στη βιβλιογραφία, της ετήσιας επίπτωσης της LCH στους ενήλικες και η διερεύνηση του επιπολασμού της μετάλλαξης BRAFV600E στον ενήλικο Ελληνικό πληθυσμό καθώς και η συσχέτιση αυτής με κλινικό-εργαστηριακά δεδομένα, όπως η έκταση της νόσου, η ηλικία κατά τη διάγνωση, το φύλο, η προσβολή οργάνων, η ανταπόκριση στην αρχική θεραπεία (χημειοθεραπεία, χειρουργική εκτομή, διακοπή καπνίσματος, τοπική ακτινοθεραπεία ή συνδυαστική θεραπεία), η παρουσία άποιου διαβήτη, το ιστορικό κακοήθειας και ο κίνδυνος υποτροπής.Η καταγραφής των νέων περιπτώσεων LCH πραγματοποιήθηκε από την 1η Σεπτεμβρίου 2018 έως τις 31 Αυγούστου 2019 μέσω τακτικής επικοινωνίας με τα παθολογοανατομικά εργαστήρια που λειτουργούν στο Ελληνικό Σύστημα Υγείας, φθάνοντας συνολικά σε ποσοστό κάλυψης το 85%. Η ετήσια επίπτωση της LCH μεταξύ των ενηλίκων στην Ελλάδα υπολογίστηκε σε 1,58 ανά εκατομμύριο πληθυσμού ανά έτος, με μέση ηλικία διάγνωσης τα 43,5 έτη και αναλογία θήλεων / αρρένων 1.34.Η μετάλλαξη BRAF V600E ανευρέθηκε στο 39% των ασθενών της κλινικής ενηλίκων με LCH που έλαβαν μέρος στη μελέτη. Συγκεκριμένα, κατόπιν έγγραφης συγκατάθεσης, απομονώθηκε DNA από 40 κύβους παραφίνης, εκ των οποίων 31 απέδωσαν επαρκές υλικό για περαιτέρω ανάλυση με PCR. Η μετάλλαξη BRAFV600E εντοπίστηκε σε 12 ασθενείς (38.71%) με επικράτηση των γυναικών (83.3%), ενώ 13 ασθενείς (41.94%) δεν έφεραν τη μετάλλαξη. Σε 6 ασθενείς (2 άνδρες), (19.35%), η qPCR μελέτη του BRAFV600E δεν πληρούσε τα τεχνικά πρότυπα που απαιτούνται για την οριστική ερμηνεία των αποτελεσμάτων.Δεν υπήρξε στατιστικά σημαντική συσχέτιση της παρουσίας της μετάλλαξης με την ηλικία κατά τη διάγνωση, τη συμμετοχή συγκεκριμένων οργάνων, την έκταση της νόσου (μονοσυστηματική ή πολυσυστηματική), την ανταπόκριση στην αρχική θεραπεία, την ανάπτυξη άποιου διαβήτη και τον κίνδυνο υποτροπής.Καθώς οι νεότερες θεραπευτικές παρεμβάσεις στοχεύουν σε μοριακά μονοπάτια της νόσου απαιτούνται περαιτέρω μελέτες για τον εντοπισμό ολόκληρου του φάσματος μεταλλάξεων που σχετίζονται με την παθογένεια της νόσου και τις κλινικές της εκδηλώσεις

Presentation of new onset type 1 diabetes with diabetic ketoacidosis and hyperosmolar hyperglycaemia after a single dose of nivolumab and ipilimumab

A Caucasian man in his 60s with recent diagnosis of metastatic renal cell carcinoma presented to the emergency department with a 5-day history of severe polyuria, polydipsia and fatigue and 1-day history of confusion, abdominal pain, nausea and vomiting. Investigations revealed an overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS). He had received the first dose of immunotherapy with nivolumab and ipilimumab 3 weeks prior to this attendance. New-onset type 1 diabetes (T1DM) was confirmed based on the clinical features at presentation, seropositivity for glutamic acid decarboxylase antibodies and significant insulin deficiency. He is currently on a multiple daily injections of insulin and uses intermittent-scanned glucose monitoring. Given the irreversible impact on beta-cell function and clinical response with insulin resulting in improved diabetes control, immunotherapy was resumed for his metastatic cancer with good radiological response. Although rare, new-onset T1DM can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes

The annual incidence of Langerhans cell histiocytosis among adults living in Greece

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a variable clinical course and outcome. Although there are some data regarding its incidence in children, such information in adults is lacking. To address the actual annual LCH incidence among adults, we prospectively recorded, during a 12-month period, any new case with a definitive histological diagnosis of LCH, among persons aged 18 and older living in Greece. Fourteen new cases were recorded corresponding to an annual incidence of 1.58 per million population. Female to male ratio was 1.34, and mean age at diagnosis was 43.5 years

Diabetes technology including automated insulin delivery systems to manage hyperglycemia in a failing pancreatic graft: Case series of people with type 1 diabetes and a pancreas kidney or pancreas‐only transplant

Abstract We share our experience of using continuous subcutaneous insulin infusion (CSII) therapy and diabetes technology in six people (5 men) with type 1 diabetes (mean duration 36 years), who developed hyperglycemia post‐simultaneous kidney/pancreas (n = 5) or pancreas only (n = 1) transplant. All were on immunosuppression and multiple daily injections of insulin prior to CSII. Four people were started on automated insulin delivery, and two people on CSII and intermittently scanned continuous glucose monitoring. With diabetes technology, the median time in range glucose improved from 37% (24–49%) to 56.6% (48–62%), and similarly, glycated hemoglobin fell from 72.7 mmol/mol (72–79 mmol/mol) to 64 mmol/mol (42–67 mmol/mol; P < 0.05 for both) with no concomitant increase in hypoglycemia. Use of diabetes technology improved glycemic parameters in people with type 1 diabetes with failing pancreatic graft function. Early use of such technology should be considered to improve diabetes control in this complex cohort

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial

OBJECTIVE: The mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear. DESIGN/SETTING: A 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study. RESULTS: In total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm. CONCLUSIONS: The combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging

Prevalence of the BRAF (V600E) mutation in Greek adults with Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations. The activation of the MAP kinase pathway plays an integral role in its pathogenesis with genetic alterations found in the majority of cases that most frequently involve a somatic mutation of the oncogenic BRAF(V600E) variant. In this study we investigated the prevalence of the BRAF(V600E) mutation and its clinical relevance in adult Greek patients with LCH. Among 37 patients studied, the BRAF(V600E) mutation was identified in 12 out of 31 (38.7%), whereas in six patients (19.3%) the results were in conclusive. The presence of the mutation did not correlate with age at diagnosis, organ involvement, disease extent, response to initial treatment, development of diabetes insipidus and relapse risk. In our series the prevalence of the BRAF(V600E) mutation is at the lower range of the relative percentage found in children, but in line to that obtained in previous studies of adult patients with LCH that have found an up to 50% prevalence of the BRAF(V600E) mutation in these patients. Further studies with a larger number of adults are needed to identify the exact prevalence of mutations in the RAS-RAF-MEK-ERK pathway and their role on clinical parameters and disease outcomes. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2029988

Quality assessment of the included studies.

BackgroundThe newly developed COVID-19 vaccines are highly effective and safe. However, a small portion of vaccine recipients experience a wide range of adverse events. Recently, glomerular disease, including the development of Minimal Change Disease (MCD), has been observed after administration of different COVID-19 vaccines, although causality remains a matter of debate.AimThe aim of this systematic review was to comprehensively examine the available literature and provide an overview of reported cases of MCD following vaccination against SARS-CoV-2.ResultsWe identified 46 eligible articles which included 94 cases with MCD following COVID-19 vaccination of which one case was reported twice due to a second relapse. Fifty-five participants were males (59.1%, 55/93) and 38 (40.9%, 38/93) were females with a mean age of 45.02 years (SD:20.95). From the included patients 50 (50/94, 53.1%) were described as new-onset and 44 (46.9%, 44/94) as relapse. On average, symptomatology developed 16.68 days (SD: 22.85) after the administration of the vaccine irrespective of the dose. Data about symptoms was reported in 68 cases with the most common being oedema (80.8%, 55/68), followed by weight gain (26.5%, 18/68) and hypertension (16.1%, 11/68). In terms of outcome, more than half of the patients went into remission (61%, 57/94), while 18 recovered or improved post treatment (19.1%, 18/94). Two people relapsed after treatment (2.1%, 2/94) and two cases (2.1%, 2/94) were reported as not recovered.ConclusionMCD is possibly a condition clinicians may see in patients receiving COVID-19 vaccines. Although this adverse event is uncommon, considering the limited published data and the absence of confirmed causality, increased clinical awareness is crucial for the early recognition and optimal management of these patients.</div