Case report: Cytopenias in VEXAS syndrome - a WHO 2022 based approach in a single-center cohort

VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by cytopenias and macrocytic anemia. Dyshematopoiesis is a frequent finding in chronic inflammatory conditions and therefore, cytopenias are not easily classified in VEXAS patients. Here we report a series of 7 patients affected by VEXAS associated cytopenias, treated at our center. The use of NGS, together with morphological assays, integrated with the WHO 2022 criteria, allowed to identify three subsets of VEXAS associated cytopenias: ICUS (idiopathic cytopenia of uncertain significance), CCUS (clonal cytopenia of uncertain significance) at high risk of clonal evolution, and MDS. This approach could help to better understand the nature of VEXAS associated cytopenias and to guide the use of specific targeted treatments in order to achieve long lasting responses

Treatment of Refractory Adrenocortical Carcinoma with Thalidomide: Analysis of 27 Patients from the European Network for the Study of Adrenal Tumours Registry

OBJECTIVE Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often temporary and salvage treatments are warranted. METHODS Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tumours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radiologists, and overall survival (OS). RESULTS Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was administered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and progressive disease (n=25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontinued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints). CONCLUSION Thalidomide was overall well tolerated but resulted in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino

Clinical pregenetic screening for stroke monogenic diseases: Results from lombardia GENS registry

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series