Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Production of arabitol from glycerol by immobilized cells of Wickerhamomyces anomalus WC 1501.

Polyalcohols such as arabitol are among the main targets of biorefineries aiming to upcycle wastes and cheap substrates. In previous works Wickerhamomyces anomalus WC 1501 emerged as an excellent arabitol producer utilizing glycerol. Arabitol production by this strain is not growth associated, therefore, in this study, pre-grown cells were entrapped in calcium alginate beads (AB) and utilized for glycerol transformation to arabitol. Flasks experiments aimed to assess the medium composition (i.e., the concentration of inorganic and organic nitrogen sources and phosphates) and to establish the appropriate carrier-to-medium proportion. In flasks, under the best conditions of ammonium limitation and the carrier:medium ratio of 1:3 (w/v), 82.7 g/L glycerol were consumed in 168 h, yielding 31.2 g/L arabitol, with a conversion of 38% and volumetric productivity of 186 mg/mL/h. The process with immobilized cells was transferred to laboratory scale bioreactors with different configurations: stirred tank (STR), packed bed (PBR), fluidized bed (FBR), and airlift (ALR) bioreactors. The STR experienced oxygen limitation due to the need to maintain low stirring to preserve AB integrity and performed worse than flasks. Limitations in diffusion and mass transfer of oxygen and/or nutrients characterized also the PBR and the FBR and were partially relieved only in ALR, where 89.4 g/L glycerol were consumed in 168 h, yielding 38.1 g/L arabitol, with a conversion of 42% and volumetric productivity of 227 mg/mL/h. When the ALR was supplied with successive pulses of concentrated glycerol to replenish the glycerol as it was being consumed, 117 g/L arabitol were generated in 500 h, consuming a total of 285 g/L glycerol, with a 41% and 234 mg/L/h. The study strongly supports the potential of W. anomalus WC 1501 for efficient glycerol-to-arabitol conversion using immobilized cells. While the yeast shows promise by remaining viable and active for extended periods, further optimization is required, especially regarding mixing and oxygenation. Improving the stability of the immobilization process is also crucial for reusing pre-grown cells in multiple cycles, reducing dead times, biomass production costs, and enhancing the economic feasibility of the process.

Management of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is an important cause of heart failure and arrhythmias, including sudden death, with a major impact on the healthcare system. Genetic causes and different phenotypes are now increasingly being identified for this condition. In addition, specific medications, such as myosin inhibitors, have been recently shown as potentially able to modify its symptoms, hemodynamic abnormalities and clinical course. Our article aims to provide a comprehensive outline of the epidemiology, diagnosis and treatment of hypertrophic cardiomyopathy in the current era.

Baseline shift corrections towards the heart: External validation of the impact on survival in early-stage NSCLC patients.

PURPOSE: To externally validate Johnson-Hart et al. findings: the association of tumor baseline shifts towards the heart with overall survival (OS) in SBRT for NSCLC. Further analysis included investigating the presence of interfractional heart baseline shifts and the association of OS with heart dose change during treatment. METHODS: Data from 416 SBRT early-stage NSCLC patients was collected. Pearson's correlations (PCCs) between clinical variables and treatment-averaged tumor shifts towards/away from the heart were explored. Validation of published multivariable Cox model was performed. PCCs between heart and tumor baseline shifts were analyzed. Dose accumulation was performed following daily CBCT-to-pCT deformable registration. Maximum heart dose (D0) was computed for planned and accumulated doses. Differences in OS according to shifts towards/away from the heart or D0 increase/decrease were analyzed. Significant D0 differences between patients with D0 increase/decrease and different tumor locations were explored. RESULTS: Tumor shifts towards/away from the heart showed no significant association with OS (p = 0.91). Distance between PTV and heart correlated significantly (PCC = 0.18) with shifts to the heart. Cox model did not validate in our cohort. Heart presented baseline shifts positively correlated with tumor baseline shifts in all three directions (PCC ≥ 0.38; p < 0.001). Counterintuitively, patients experiencing increased D0 during treatment showed significantly better OS (p = 0.0077). Upper-lobe tumor patients with increased D0 had lower D0 than those with decreased D0 (right-upper-lobe p ≤ 0.018). CONCLUSIONS: In our SBRT cohort, the shifts towards the heart were not associated with worse OS. Moderate correlations were found between tumor and heart baseline shifts in each direction. Moreover, the distance between the PTV and the heart showed a significant correlation with shifts to the heart.

Genomic and functional analysis of the mucinolytic species Clostridium celatum, Clostridium tertium, and Paraclostridium bifermentans.

Mucins are large glycoproteins whose degradation requires the expression of several glycosil hydrolases to catalyze the cleavage of the oligosaccharide chains and release monosaccharides that can be assimilated. In this study, we present a characterization on the strains Clostridium celatum WC0700, Clostridium tertium WC0709, and Paraclostridium bifermentans WC0705. These three strains were previously isolated from enrichment cultures on mucin of fecal samples from healthy subjects and can use mucin as sole carbon and nitrogen source. Genome analysis and in vitro functional analysis of these strains elucidated their physiological and biochemical features. C. celatum WC0700 harbored the highest number of glycosyl hydrolases specific for mucin degradation, while P. bifermentans WC0705 had the least. These predicted differences were confirmed growing the strains on 5 mucin-decorating monosaccharides (L-fucose, N-Acetylneuraminic acid, galactose, N-acetylgalactosamine, and N-acetylglucosamine) as only source of carbon. Fermenting mucin, they all produced formic, acetic, propionic, butyric, isovaleric, and lactic acids, and ethanol; acetic acid was the main primary metabolite. Further catabolic capabilities were investigated, as well as antibiotic susceptibility, biofilm formation, tolerance to oxygen and temperature. The potential pathogenicity of the strains was evaluated through in silico research of virulence factors. The merge between comparative and functional genomics and biochemical/physiological characterization provided a comprehensive view of these mucin degraders, reassuring on the safety of these species and leaving ample scope for deeper investigations on the relationship with the host and for assessing if some relevant health-promoting effect could be ascribed to these SCFA producing species.

Prevalence and clinical outcomes of isolated or combined moderate to severe mitral and tricuspid regurgitation in patients with cardiac amyloidosis.

AIMS: Evidence on the epidemiology and prognostic significance of mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with cardiac amyloidosis (CA) is scarce. METHODS AND RESULTS: Overall, 538 patients with either transthyretin (ATTR, n = 359) or immunoglobulin light-chain (AL, n = 179) CA were included at three Italian referral centres. Patients were stratified according to isolated or combined moderate/severe MR and TR. Overall, 240 patients (44.6%) had no significant MR/TR, 112 (20.8%) isolated MR, 66 (12.3%) isolated TR, and 120 (22.3%) combined MR/TR. The most common aetiologies were atrial functional MR, followed by primary infiltrative MR, and secondary TR due to right ventricular (RV) overload followed by atrial functional TR. Patients with isolated or combined MR/TR had a more frequent history of heart failure (HF) hospitalization and atrial fibrillation, worse symptoms, and higher levels of NT-proBNP as compared to those without MR/TR. They also presented more severe atrial enlargement, atrial peak longitudinal strain impairment, left ventricular (LV) and RV systolic dysfunction, and higher pulmonary artery systolic pressures. TR carried the most advanced features. After adjustment for age, sex, CA subtypes, laboratory, and echocardiographic markers of CA severity, isolated TR and combined MR/TR were independently associated with an increased risk of all-cause death or worsening HF events, compared to no significant MR/TR [adjusted HR 2.75 (1.78-4.24) and 2.31 (1.44-3.70), respectively]. CONCLUSION: In a large cohort of patients with CA, MR, and TR were common. Isolated TR and combined MR/TR were associated with worse prognosis regardless of CA aetiology, LV, and RV function, with TR carrying the highest risk.

Fermentative processes for the upcycling of xylose to xylitol by immobilized cells of Pichia fermentans WC1507.

Xylitol is a pentose-polyol widely applied in the food and pharmaceutical industry. It can be produced from lignocellulosic biomass, valorizing second-generation feedstocks. Biotechnological production of xylitol requires scalable solutions suitable for industrial scale processes. Immobilized-cells systems offer numerous advantages. Although fungal pellet carriers have gained attention, their application in xylitol production remains unexplored. In this study, the yeast strain P. fermentans WC 1507 was employed for xylitol production. The optimal conditions were observed with free-cell cultures at pH above 3.5, low oxygenation, and medium containing (NH4)2SO4 and yeast extract as nitrogen sources (xylitol titer 79.4 g/L, YP/S 66.3%, and volumetric productivity 1.3 g/L/h). Yeast cells were immobilized using inactive Aspergillus oryzae pellet mycelial carrier (MC) and alginate beads (AB) and were tested in flasks over three consecutive production runs. Additionally, the effect of a 0.2% w/v alginate layer, coating the outer surface of the carriers (cMC and cAB, respectively), was examined. While YP/S values observed with both immobilized and free cells were similar, the immobilized cells exhibited lower final xylitol titer and volumetric productivity, likely due to mass transfer limitations. AB and cAB outperformed MC and cMC. The uncoated AB carriers were tested in a laboratory-scale airlift bioreactor, which demonstrated a progressive increase in xylitol production in a repeated batch process: in the third run, a xylitol titer of 63.0 g/L, YP/S of 61.5%, and volumetric productivity of 0.52 g/L/h were achieved. This study confirmed P. fermentans WC 1507 as a promising strain for xylitol production in both free- and entrapped-cells systems. Considering the performance of the wild strain, a metabolic engineering intervention aiming at further improving the efficiency of xylitol production could be justified. MC and AB proved to be viable supports for cell immobilization, but additional process development is necessary to identify the optimal bioreactor configuration and fermentation conditions.

Good and bad dispositions between archaea and bacteria in the human gut: New insights from metagenomic survey and co-occurrence analysis.

Archaea are an understudied component of the human microbiome. In this study, the gut archaeome and bacteriome of 60 healthy adults from different region were analyzed by whole-genome shotgun sequencing. Archaea were ubiquitously found in a wide range of abundances, reaching up to 7.2 %. The dominant archaeal phylum was Methanobacteriota, specifically the family Methanobacteriaceae, encompassing more than 50 % of Archaea in 50 samples. The previously underestimated Thermoplasmatota, mostly composed of Methanomassiliicoccaceae, dominated in 10 subjects (>50 %) and was present in all others except one. Halobacteriota, the sole other archaeal phylum, occurred in negligible concentration, except for two samples (4.6-4.8 %). This finding confirmed that the human gut archaeome is primarily composed of methanogenic organisms and among the known methanogenic pathway: i) hydrogenotrophic reduction of CO2 is the predominant, being the genus Methanobrevibacter and the species Methanobrevibacter smithii the most abundant in the majority of the samples; ii) the second pathway, that involved Methanomassiliicoccales, was the hydrogenotrophic reduction of methyl-compounds; iii) dismutation of acetate or methyl-compounds seemed to be absent. Co-occurrence analysis allowed to unravel correlations between Archaea and Bacteria that shapes the overall structure of the microbial community, allowing to depict a clearer picture of the human gut archaeome.

Profiling of the intestinal community of Clostridia: taxonomy and evolutionary analysis.

Aim: Clostridia are relevant commensals of the human gut due to their major presence and correlations to the host. In this study, we investigated intestinal Clostridia of 51 healthy subjects and reconstructed their taxonomy and phylogeny. The relatively small number of intestinal Clostridia allowed a systematic whole genome approach based on average amino acid identity (AAI) and core genome with the aim of revising the current classification into genera and determining evolutionary relationships. Methods: 51 healthy subjects' metagenomes were retrieved from public databases. After the dataset's validation through comparison with Human Microbiome Project (HMP) samples, the metagenomes were profiled using MetaPhlAn3 to identify the population ascribed to the class Clostridia. Intestinal Clostridia genomes were retrieved and subjected to AAI analysis and core genome identification. Phylogeny investigation was conducted with RAxML and Unweighted Pair Group Method with Arithmetic Mean (UPGMA) algorithms, and SplitsTree for split decomposition. Results: 225 out of 406 bacterial taxonomic units were ascribed to Bacillota [Firmicutes], among which 124 were assigned to the class Clostridia. 77 out of the 124 taxonomic units were referred to a species, altogether covering 87.7% of Clostridia abundance. According to the lowest AAI genus boundary set at 55%, 15 putative genera encompassing more than one species (G1 to G15) were identified, while 19 species did not cluster with any other one and each appeared to belong to a diverse genus. Phylogenetic investigations highlighted that most of the species clustered into three main evolutive clades. Conclusion: This study shed light on the species of Clostridia colonizing the gut of healthy adults and pinpointed several gaps in knowledge regarding the taxonomy and the phylogeny of Clostridia.

Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models.

Background: Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC. Methods: Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, radiotherapy duration, chemotherapy, mean heart and lung doses, and thoracic vertebrae V20Gy. MDACC predictors for grade 4 lymphopenia were age, baseline lymphocyte count, planning target volume (PTV), and BMI. The external performance of both models was assessed. Results: Among 100 patients, 78 patients (78%) developed grade ≥3 lymphopenia, with grade 4 lymphopenia in 17 (17%). For predicting grade ≥3 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.77 and 0.79, respectively. For predicting grade 4 lymphopenia, c-statistics were 0.69 and 0.80, respectively. Calibration for the Christie and MDACC models demonstrated moderate and good agreement, respectively. Conclusion: The PTV-based MDACC prediction model for severe RIL demonstrated superior external performance in NSCLC patients compared to the dosimetry-based Christie model. As such, the MDACC model can aid in identifying patients at high risk for severe lymphopenia. However, to optimize radiotherapy planning, further improvement and external validation of dosimetry-based models is desired.

Activities of daily living in heart failure patients and healthy subjects: when the cardiopulmonary assessment goes beyond traditional exercise test protocols.

Heart failure (HF) patients traditionally report dyspnoea as their main symptom. Although the cardiopulmonary exercise test (CPET) and 6 min walking test are the standardized tools in assessing functional capacity, neither cycle ergometers nor treadmill maximal efforts do fully represent the actual HF patients' everyday activities [activities of daily living (ADLs)] (i.e. climbing the stairs). New-generation portable metabolimeters allow the clinician to measure task-related oxygen intake (VO2) in different scenarios and exercise protocols. In the last years, we have made considerable progress in understanding the ventilatory and metabolic behaviours of HF patients and healthy subjects during tasks aimed to reproduce ADLs. In this paper, we describe the most recent findings in the field, with special attention to the relationship between the metabolic variables obtained during ADLs and CPET parameters (i.e. peak VO2), demonstrating, for example, how exercises traditionally thought to be undemanding, such as a walk, instead represent supramaximal efforts, particularly for subjects with advanced HF and/or artificial heart (left ventricular assist devices) wearers.

This article summarizes the most recent evidence on the cardiometabolic behaviours of a full spectrum of heart failure (HF) patients of different severity during their daily life activities (i.e. walking, making a bed, and taking the stairs).Heart failure patients experience symptoms (mostly dyspnoea) during daily activities that sometimes represent maximal or supramaximal exercises for them, particularly for the most severe patients.Measuring metabolic parameters (O2 intake, ventilation, and CO2 production) through appropriate devices during these activities provides a better understanding of the pathophysiological mechanisms underlying HF patients' symptoms and their adaptation. This can lead to the detection of new parameters that can become novel patient-centred prognostic markers or therapeutic targets for drugs and rehabilitation treatments.

Incidence and determinants of atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening. METHODS: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. RESULTS: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008). CONCLUSIONS: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Prognostic value of cardiopulmonary exercise testing repetition during follow-up of clinically stable patients with severe dilated cardiomyopathy. A preliminary study.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a recognized tool for prognostic stratification in patients with dilated cardiomyopathy (DCM). Given the lack of data currently available, the aim of this study was to test the prognostic value of repeating CPET during the follow-up of patients with DCM. METHODS: This multicenter, retrospective study, analyzed DCM patients who consecutively performed two echocardiographies and CPETs during clinical stability. The study end-point was a composite of death from all causes, heart transplantation, left ventricular assist device implantation, life-threatening ventricular arrhythmias or hospitalization for heart failure. RESULTS: 216 DCM patients were enrolled (52 years, 78% male, NYHA I-II 82%, LVEF 32%, 94% on ACE inhibitors/ARNI, 95% on beta-blockers). The interval between CPETs was 15 months. During a median follow-up of 38 months from the second CPET, 102 (47%) patients experienced the study end-point. Among them, there was stability of echocardiographic values but a significant worsening of functional capacity. Among the 173 patients (80%) who did not show echocardiographic left ventricular reverse remodeling (LVRR), the 1-year prevalence of the study-end point was higher in patients who worsened vs patients who maintained stable their functional capacity at CPET (38 vs. 15% respectively, p-value: 0.001). These results were consistent also when excluding life-threatening ventricular arrhythmias from the composite end-point. CONCLUSION: In clinically stable DCM patients with important depression of LVEF, the repetition of combined echocardiography and CPET might be recommended. When LVRR fails, 1-year repetition of CPET could identify higher-risk patients.

Right ventricular to pulmonary artery coupling and outcome in patients with cardiac amyloidosis.

AIMS: To investigate the prognostic value of the right ventricle-to-pulmonary artery (RV-PA) coupling in patients with either transthyretin (ATTR) or immunoglobulin light-chain (AL) cardiac amyloidosis (CA). METHODS AND RESULTS: Overall, 283 patients with CA from 3 Italian high-volume centres were included (median age 76 years; 63% males; 53% with ATTR-CA, 47% with AL-CA). The RV-PA coupling was evaluated by using the tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP) ratio. The median value of TAPSE/PASP was 0.45 (0.33-0.63) mm/mmHg. Patients with a TAPSE/PASP ratio <0.45 were older, had lower systolic blood pressure, more severe symptoms, higher cardiac troponin and N-terminal pro-B-type natriuretic peptide levels, greater left ventricular (LV) thickness, and worse LV systolic and diastolic function. A TAPSE/PASP ratio <0.45 was independently associated with a higher risk of all-cause death or heart failure (HF) hospitalization [hazard ratio (HR) 1.98, 95% confidence interval (CI) 1.32-2.96; P = 0.001] and all-cause death (HR 2.18, 95% CI 1.31-3.62; P = 0.003). The TAPSE/PASP ratio reclassified the risk of both endpoints [net reclassification index 0.46 (95% CI 0.18-0.74) P = 0.001 and 0.49 (0.22-0.77) P < 0.001, respectively], while TAPSE or PASP alone did not (all P > 0.05). The prognostic impact of the TAPSE/PASP ratio was significant both in AL-CA patients (HR for the composite endpoint 2.47, 95% CI 1.58-3.85; P < 0.001) and in ATTR-CA (HR 1.81, 95% CI 1.11-2.95; P = 0.017). The receiver operating characteristic curve showed that the optimal cut-off for predicting prognosis was 0.47 mm/mmHg. CONCLUSION: In patients with CA, RV-PA coupling predicted the risk of mortality or HF hospitalization. The TAPSE/PASP ratio was more effective than TAPSE or PASP in predicting prognosis.

New perspectives in diagnosis and risk stratification of non-ischaemic dilated cardiomyopathy.

Dilated cardiomyopathy is a primitive heart muscle condition, characterized by structural and functional abnormalities, in the absence of a specific cause sufficient to determine the disease. It is, though, an 'umbrella' term that describes the final common pathway of different pathogenic processes and gene-environment interactions. Performing an accurate diagnostic workup and appropriate characterization of the patient has a direct impact on the patient's outcome. The physician should adapt a multiparametric approach, including a careful anamnesis and physical examination and integrating imaging data and genetic testing. Aetiological characterization should be pursued, and appropriate arrhythmic risk stratification should be performed. Evaluations should be repeated thoroughly at follow-up, as the disease is dynamical over time and individual risk might evolve. The goal is an all-around characterization of the patient, a personalized medicine approach, in order to establish a diagnosis and therapy tailored for the individual patient.

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy.

Dilated cardiomyopathy is a primary disease of the heart muscle, which affects relatively young patients with a low comorbidity profile. It is characterized by structural and/or functional abnormalities leading to systolic dysfunction of the left ventricle or of both ventricles, often associated with dilatation, in the absence of an ischaemic, valvular, or pressure overload cause sufficient to explain the phenotype. Although the prognosis of the disease has greatly improved over the last few decades, prognostic stratification remains a fundamental objective, especially about the prediction of potentially life-threatening arrhythmic events. An accurate diagnostic work-up and an appropriate aetiopathogenetic characterization affect the patients' outcome and represent the essential basis of an adequate prognostic stratification. It is necessary to adopt a multiparametric approach, especially when the aim is the prediction of arrhythmic risk; it includes an integration of medical history and physical examination with cardiac imaging and genetic testing, in order to obtain a personalized diagnosis and therapeutic strategies. Furthermore, the evaluation should be repeated at every clinical check-up, considering the dynamic trend of the pathology and the arrhythmic risk changes over time. This article aims to illustrate how, starting from an exhaustive aetiological and clinical-instrumental characterization, including all diagnostic methods available at present time, it is possible to obtain a tailored diagnostic evaluation and stratification of the arrhythmic risk as accurate as possible.

Sport and exercise in genotype positive (+) phenotype negative (-) individuals: current dilemmas and future perspectives.

Genotype positive-phenotype negative (GEN+PHEN-) individuals harbour a pathogenic or likely pathogenic variant without exhibiting a phenotypic manifestation of the disease. In the last few years, the widespread use of genetic testing in probands and relatives has increasingly led to the identification of these individuals, with emerging dilemmas regarding their clinical management. A genetic variant may exhibit a variable expressivity even in the same family and spontaneous conversion to overt phenotype is largely unpredictable. Little is known about the possible influence of environmental factors, such intense or moderate exercise with open questions regarding their possible role in promoting or worsening the phenotypic expression. Current guidelines for sports participation in this setting acknowledge the weak burden of evidence and the many uncertainties. The recommendations to engage in intensive exercise and competitive sports are usually contingent on annual clinical surveillance, except for pathogenic variants in specific genes, such as lamin A/C or plakophilin-2. In certain conditions, such as arrhythmogenic cardiomyopathy, guidelines do not differentiate between GEN+PHEN- individuals and patients with overt disease and recommend avoiding participation in high-intensity recreational exercise and competitive sports. It should be emphasized that international guidelines, traditionally restrictive in terms of sports participation and focused on disqualification, embraced recently a more liberal attitude promoting a shared decision-making approach in the absence of clinical markers of increased risk. In this review, we will discuss the current state of knowledge on GEN+PHEN- individuals and the dilemmas surrounding the impact of exercise and prognosis, focusing on cardiomyopathies and channelopathies, which are the predominant causes of sudden cardiac death in the young and in young athletes.

Detailed dosimetric evaluation of inter-fraction and respiratory motion in lung stereotactic body radiation therapy based on daily 4D cone beam CT images.

Objective. Periodic respiratory motion and inter-fraction variations are sources of geometric uncertainty in stereotactic body radiation therapy (SBRT) of pulmonary lesions. This study extensively evaluates and validates the separate and combined dosimetric effect of both factors using 4D-CT and daily 4D-cone beam CT (CBCT) dose accumulation scenarios.Approach. A first cohort of twenty early stage or metastatic disease lung cancer patients were retrospectively selected to evaluate each scenario. The planned-dose (3DRef) was optimized on a 3D mid-position CT. To estimate the dosimetric impact of respiratory motion (4DRef), inter-fractional variations (3DAcc) and the combined effect of both factors (4DAcc), three dose accumulation scenarios based on 4D-CT, daily mid-cone beam CT (CBCT) position and 4D-CBCT were implemented via CT-CT/CT-CBCT deformable image registration (DIR) techniques. Each scenario was compared to 3DRef.A separate cohort of ten lung SBRT patients was selected to validate DIR techniques. The distance discordance metric (DDM) was implemented per voxel and per patient for tumor and organs at risk (OARs), and the dosimetric impact for CT-CBCT DIR geometric errors was calculated.Main results.Median and interquartile range (IQR) of the dose difference per voxel were 0.05/2.69 Gy and -0.12/2.68 Gy for3DAcc-3DRefand4DAcc-3DRef.For4DRef-3DRefthe IQR was considerably smaller -0.15/0.78 Gy. These findings were confirmed by dose volume histogram parameters calculated in tumor and OARs. For CT-CT/CT-CBCT DIR validation, DDM (95th percentile) was highest for heart (6.26 mm)/spinal cord (8.00 mm), and below 3 mm for tumor and the rest of OARs. The dosimetric impact of CT-CBCT DIR errors was below 2 Gy for tumor and OARs.Significance. The dosimetric impact of inter-fraction variations were shown to dominate those of periodic respiration in SBRT for pulmonary lesions. Therefore, treatment evaluation and dose-effect studies would benefit more from dose accumulation focusing on day-to-day changes then those that focus on respiratory motion.

Evolving trends in epidemiology and natural history of cardiac amyloidosis: 30-year experience from a tertiary referral center for cardiomyopathies.

Objective: Natural history of cardiac amyloidosis (CA) is poorly understood. We aimed to examine the changing mortality of different types of CA over a 30-year period. Patients and methods: Consecutive patients included in the "Trieste CA Registry" from January 1, 1990 through December 31, 2021 were divided into a historical cohort (diagnosed before 2016) and a contemporary cohort (diagnosed after 2016). Light chain (AL), transthyretin (ATTR) and other forms of CA were defined according to international recommendations. The primary and secondary outcome measures were all-cause mortality and cardiac death, respectively. Results: We enrolled 182 patients: 47.3% AL-CA, 44.5% ATTR-CA, 8.2% other etiologies. The number of patients diagnosed with AL and ATTR-CA progressively increased over time, mostly ATTR-CA patients (from 21% before 2016 to 67% after 2016) diagnosed non-invasively. The more consistent increase in event-rate was observed in the long-term (after 50 months) in ATTR-CA compared to the early increase in mortality in AL-CA. In the contemporary cohort, during a median follow up of 16 [4-30] months, ATTR-CA was associated with improved overall and cardiac survival compared to AL-CA. At multivariable analysis, ATTR-CA (HR 0.42, p = 0.03), eGFR (HR 0.98, p = 0.033) and ACE-inhibitor therapy (HR 0.24, p < 0.001) predicted overall survival in the contemporary cohort. Conclusion: Incidence and prevalence rates of ATTR-CA and, to a less extent, of AL-CA have been increasing over time, with significant improvements in 2-year survival of ATTR-CA patients from the contemporary cohort. Reaching an early diagnosis and starting disease-modifying treatments will improve long-term survival in CA.