Lorenzo Tofani

Acquired somatic mutations are incorporated in the classification and prognosis of myelodysplastic syndromes/neoplasms (MDSs). However, the predictive role of molecular features in MDS needs to be elucidated, especially in the lower-risk subtypes (LR-MDS), where treatment has become heterogeneous and predictive biomarkers are lacking. In this study, we investigated genetic markers associated with erythropoiesis-stimulating agents (ESAs) response in LR-MDS. A European cohort of 535 patients with LR-MDS was analyzed using targeted next-generation sequencing (t-NGS) to calculate molecular prognostic scores (International Prognostic Scoring System, molecular [IPSS-M]). The integration of IPSS-M score among the 2 known variables, serum erythropoietin (sEPO) and transfusion dependence (TD), refined the capability to predict response (area under the curve [AUC], 0.71 vs 0.63, P = .0004). Based on these 3 variables, a molecular predictive score, which we named ESA-PSS-M (–0.05 × [sEPO U/L] –4.5 × [IPSS-M score] –5 × [TD (yes = 1; no = 0)]; specificity 76%; sensitivity 57%), was generated and validated in an external cohort (n = 223 patients with LR-MDS). Despite the impact of IPSS-M score, no single mutated gene was linked to ESA response; however, when we stratified cases by sex at birth, the X-linked STAG2 gene mutations were significantly associated with ESA resistance in males with LR-MDS (odds ratio, 0.13; P = .003). To our knowledge, this is the first study based on a large multicenter cohort of patients suggesting that the integration of IPSS-M score and sex-specific mutations can characterize ESA resistance and guide first-line (1L) therapeutic choices for anemic LR-MDS (ie, ESAs vs luspatercept).

Objectives: As a screening tool for the presence of systemic sclerosis-associated interstitial lung disease (SSc-ILD) on high-resolution computed tomography (HRCT) is missing, we aimed to develop the ILD-RISC score, a risk algorithm to guide physicians in ordering HRCTs, with specific focus on follow-up visits. Methods: The nominal group technique was used to select items for the multivariable logistic regression with backward selection. The ILD-RISC score was developed from baseline visits of the derivation cohort. After identifying a cut-off favoring sensitivity >85% from the ROC curve, it was validated in a separate cross-sectional cohort, and then applied longitudinally in a specific SSc cohort with negative baseline HRCT. Results: In the derivation cohort (533 patients), 13 variables associated with the presence of SSc-ILD on HRCT were tested. The ILD-RISC score, including FVC%, DLCO/SB%, digital ulcers ever, age and SSc autoantibodies, showed an area under the curve of 79.1% (75.3–83.0%) for the presence of SSc-ILD on HRCT. An ILD-RISC score ≥0.3 had sensitivity 85.6% and specificity 53.6%, as confirmed in the validation cohort (247 patients). Among 819 patients with negative baseline HRCT, 170 developed SSc-ILD: a low ILD-RISC score was detected in almost 50% of the follow-up visits, supporting the sparing of HRCTs. Conclusion: The ILD-RISC score was developed and validated to predict the presence of SSc-ILD. Thus, the ILD-RISC score may help to decide when to order HRCTs at follow-up, allowing the reduction of costs and radiation exposure, but also at the time of SSc diagnosis when resources are limited.

Sicca syndrome is a common condition that draws the attention of rheumatologists, and is frequently related to Sjögren’s disease (SjD). This study analyzed 164 patients with sicca syndrome (clinically suspected for SjD) who underwent minor salivary gland biopsy (mSGB). Patients completed the Xerostomia Inventory (XI) and Standard Patient Evaluation of Eye Dryness (SPEED) questionnaires to assess Patient-Reported Outcome Measures (PROMs), and biopsies were graded using the Chisholm and Mason system. Patients were classified as seropositive (SSA, SSB, Ro52, Ro60 positive) or seronegative, and also divided into three groups by age. Positive biopsies (60.37%) were more common in older patients (61–80) and associated with confirmed SjD, more severe xerostomia, and stronger lymphocytic infiltrates. Among these, 37.37% were seropositive, showing higher disease activity, hypergammaglobulinemia, and elevated IgG. Seronegative patients had a heavier symptom burden, confirmed by the PROMs, and more fibrosis and fatty replacement in biopsies. Age-stratified analysis showed younger patients (18–40) were more affected by ocular dryness, while older patients had worse xerostomia and more severe histological and ultrasound changes. Younger individuals had higher IgG/IgA, more anemia, and reduced C3. Hydroxychloroquine was used more in younger and seropositive groups; older patients used more topical therapies. These results highlight mSGB’s diagnostic value, especially in seronegative cases, and stress the importance of combining clinical, histological, imaging, and patient-reported outcomes for optimal care.

BACKGROUND: The prevalence of transthyretin cardiac amyloidosis among older adults (often octogenarians) is increasing. We aimed to determine whether age and geriatric syndromes bear any impact on the management and outcomes in transthyretin cardiac amyloidosis and assess the risk of ageism. METHODS: In a prospective, multicenter cohort study, 256 patients diagnosed with transthyretin cardiac amyloidosis from March 2021 to March 2024 underwent comprehensive geriatric assessment (CGA). The study evaluated the prevalence and clinical associations of CGAs across different disease stages (National Amyloidosis Centre stage). Key CGA domains included disability, malnutrition, depression, frailty, Short Physical Performance Battery, and cumulative deficits (sum of the single CGA items). Associations of these measures with disease-modifying therapy and overall mortality were analyzed. RESULTS: Median age was 82 years (men: n=223 [87%]; variant: n=19 [7.4%]); 129 (50.3%) patients received disease modifiers. Those ≥85 years had significantly lower odds of receiving disease-modifying therapy even after adjusting for disability, frailty, and cumulative deficits. Over 1.9 (interquartile range, 1.0–2.3) years, 45 (17.6%) patients died. After adjustment for National Amyloidosis Centre stage, diuretics and disease modifiers, CGA domains of disability, malnutrition, Short Physical Performance Battery, frailty, and number of deficits, but not age, were significantly associated with mortality. Assessment of CGA domains improved National Amyloidosis Centre prognostic accuracy. CONCLUSIONS: In a national prospective cohort of patients with transthyretin cardiac amyloidosis, older age was associated with lower prescription of disease modifiers, even among individuals with a low burden of geriatric syndromes. However, when adjusted for geriatric domains, age was not associated with survival, indicating potential ageism. Because some geriatric syndromes may be modifiable, a CGA could enhance risk stratification, reduce age-related bias, and improve outcomes.

In pediatric thoracic surgery, reported predictors for increased risk are symptoms and active/previous infections (RAP). We investigated the adverse events related to Video-Assisted Thoracic Surgery (VATS) in pediatric patients when considering RAP predictors. A retrospective analysis of pediatric VATS major lung resections in 2008-2021 was conducted at three institutions. We employed the pediatric surgical risk calculator to define patients’ preoperative predicted risk (PredR). Postoperative complications were classified according to the Thoracic Morbidity & Mortality (TM&M) system. The observed TM&M rate (ObsR) and the PredR were compared. A subgroup analysis by RAP predictors was conducted. 37 patients (54% female) were included. Mean age and weight were 5.8 years and 22.8 kg. 56.7% had respiratory symptoms, 38.9% active infection and 59.5% history of infections (RAP subpopulations). VATS procedures were lobectomy (n=32), segmentectomy (n=3), bilobectomy (n=1) and pneumonectomy (n=1). The conversion rate was 5.4%. The mean PredR was of 4.43% (±1.8) and the overall ObsR was 45.94% with a median severity of II (I-III). This difference was significant and a higher PredR was not associated with complications development. PredR does not show association among the RAP vs non-RAP group. ObsR showed positive association with RAP, even if it reached statistical significance only for “respiratory symptoms” risk factor. ObsR reflected the number of bronchiectasis patients in our series (n=9), aligning with the hypothesis of “earlier and safer surgery”. The risk calculator underestimates VATS morbidity. Multicentre studies will clarify the correlation between inflammation and surgical adverse events.

Objective: Mean lung attenuation, skewness, and kurtosis are histogram-based densitometry variables that quantify systemic sclerosis–associated interstitial lung disease (SSc-ILD) and were recently merged into a computerized integrated index (CII). Our work tested the CII in low-dose 9-slice (reduced) and standard high-resolution computed tomography (CT) scans to evaluate extensive SSc-ILD and predict mortality.Methods: CT scans from patients with SSc-ILD were assessed using the software Horos to compute standard and reduced CIIs. Extensive ILD was determined following the Goh staging system. The association between CIIs and extensive ILD was analyzed with a generalized estimating equation regression model, the predictive ability of CIIs by the area under the receiver-operation characteristic curve (AUC), and the association between CIIs and death by Kaplan-Meier analysis.Results: Among 243 patients with standard and reduced CT scans available, 157 CT scans from 119 patients with SSc-ILD constituted the derivation cohort. The validation cohort included 116 standard and 175 reduced CT scans. Both CIIs from standard (odds ratio [OR] 0.53, 95% CI 0.37-0.75; AUC 0.77, 95% CI 0.68-0.87) and reduced CT scans (OR 0.54, 95% CI 0.35-0.82; AUC 0.78, 95% CI 0.70-0.87) were significantly associated with extensive ILD. A threshold of CII ≤ −0.96 for standard CT scans and CII ≤ −1.85 for reduced CT scans detected extensive ILD with high sensitivity in both derivation and validation cohorts. Extensive ILD according to Goh staging (OR 2.94, 95% CI 1.10-7.82) and standard CII ≤ −0.96 (OR 1.78, 95% CI 1.24-2.56) significantly predicted mortality; a marginalPvalue was observed for reduced CII ≤ −1.85 (OR 1.27, 95% CI 0.93-1.75).Conclusion: Thresholds for both standard and reduced CII to identify extensive ILD were developed and validated, with an additional association with mortality. CIIs might help in clinical practice when radiology expertise is missing.

Background and Objectives: In SSc, ILD is a major cause of morbidity and mortality. We aimed to investigate the performance of DLCO (diffusing capacity of lung carbon monoxide) and FVC (forced vital capacity) delta change (Δ) and baseline values in predicting the development of SSc-ILD. Methods: Longitudinal data of DLCO, FVC, and ILD on the HRCT of SSc patients from the EUSTAR database were evaluated at baseline (t₀) and after 12 (±4) (t₁) and 24 (±4) (t₂) months. Results: 474/17805 patients were eligible for the study (403 females); 46 (9.7%) developed ILD at t₂. Positivity for anti-topoisomerase antibodies (117 patients) showed an association with ILD development at t₂ (p = 0.0031). Neither the mean t₀ to t₁ change (Δ) of DLCO nor the mean t₀ to t₁ FVCΔ predicted the appearance of ILD at t₂. Investigating the possible role of baseline DLCO and FVC values in predicting ILD appearance after 24 (±4) months, we observed a moderate predictive capability of t₀ DLCO < 80%, stronger than that of FVC < 80%. Conclusions: We suggest that an impaired baseline DLCO may be predictive of the appearance of ILD after 2 years of follow-up. This result advances the hypothesis that a reduction in gas exchange may be considered an early sign of lung involvement. However, further rigorous studies are warranted to understand the predictive role of DLCO evaluation in the course of SSc.

BACKGROUND: The 2 sarcomere genes most commonly associated with hypertrophic cardiomyopathy (HCM), MYBPC3 (myosin-binding protein C3) and MYH7 (β-myosin heavy chain), are indistinguishable at presentation, and genotype-phenotype correlations have been elusive. Based on molecular and pathophysiological differences, however, it is plausible to hypothesize a different behavior in myocardial performance, impacting lifetime changes in left ventricular (LV) function. METHODS: We reviewed the initial and final echocardiograms of 402 consecutive HCM patients with pathogenic or likely pathogenic MYBPC3 (n=251) or MYH7 (n=151) mutations, followed over 9±8 years. RESULTS: At presentation, MYBPC3 patients were less frequently obstructive (15% versus 26%; P =0.005) and had lower LV ejection fraction compared with MYH7 (66±8% versus 68±8%, respectively; P =0.03). Both HCM patients harboring MYBPC3 and MYH7 mutations exhibited a small but significant decline in LV systolic function during follow-up; however, new onset of severe LV systolic dysfunction (LV ejection fraction, P =0.013). Prevalence of grade II/III diastolic dysfunction at final evaluation was comparable between MYBPC3 and MYH7 patients ( P =0.509). In a Cox multivariable analysis, MYBPC3-positive status (hazard ratio, 2.53 [95% CI, 1.09–5.82]; P =0.029), age (hazard ratio, 1.03 [95% CI, 1.00–1.06]; P =0.027), and atrial fibrillation (hazard ratio, 2.39 [95% CI, 1.14–5.05]; P =0.020) were independent predictors of severe systolic dysfunction. No statistically significant differences occurred with regard to incidence of atrial fibrillation, heart failure, appropriate implanted cardioverter defibrillator shock, or cardiovascular death. CONCLUSIONS: MYBPC3-related HCM showed increased long-term prevalence of systolic dysfunction compared with MYH7, in spite of similar outcome. Such observations suggest different pathophysiology of clinical progression in the 2 subsets and may prove relevant for understanding of genotype-phenotype correlations in HCM.