Search

Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen–Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing SIN3A. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of SIN3A or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in SIN3A, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to SIN3A in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.

Salivary gland cancers (SGCs) are rare, accounting for less than 5% of all malignancies of the head and neck region, and are morphologically heterogeneous. The diagnosis is mainly based on histology, with the complementary aid of molecular profiling, which is helpful in recognizing some poorly differentiated, borderline, or atypical lesions. Instrumental imaging defines the diagnosis, representing a remarkable tool in the treatment plan. Ultrasound and magnetic resonance are the most common procedures used to describe the primary tumour. The treatment of SGCs is multimodal and consists of surgery, radiotherapy, and systemic therapy; each treatment plan is, however, featured on the patient and disease’s characteristics. On 24 June 2022, in the meeting “Current management and future challenges in salivary gland cancers” many experts in this field discussed the state of the art of SGCs research, the future challenges and developments. After the meeting, the same pool of experts maintained close contact to keep these data further updated in the conference proceedings presented here. This review collects the insights and suggestions that emerged from the discussion during and after the meeting per se.

BackgroundIn triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available.MethodsWe carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years.ResultsOverall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles.ConclusionThe CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Transcatheter aortic valve replacement (TAVR) indications recently extended to lower surgical risk patients with longer life expectancy. Commissural alignment (CA) is one of the emerging concepts and is becoming one of the cornerstones of the TAVR procedure in a patient with increased longevity. Indeed, CA may improve transcatheter heart valve (THV) hemodynamics, future coronary access, and repeatability. The definition of CA has been recently standardized by the ALIGN-TAVR consortium using a four-tier scale based on CT analysis. Progress has been made during the index TAVR procedure to optimize CA, especially with self-expandable platforms. Indeed, specific delivery catheter orientation, THV rotation, and computed-tomography-derived views have been proposed to achieve a reasonable degree of CA. Recent data demonstrate feasibility, safety, and a significant reduction in coronary overlap using these techniques, especially with self-expandable platforms. This review provides an overview of THV CA including assessment methods, alignment techniques during the index TAVR procedure with different THV platforms, the clinical impact of commissural misalignment, and challenging situations for CA.

During the development and assessment of an exoskeleton, many different analyzes need to be performed. The most frequently used evaluate the changes in muscle activations, metabolic consumption, kinematics, and kinetics. Since human-exoskeleton interactions are based on the exchange of forces and torques, the latter of these, kinetic analyzes, are essential and provide indispensable evaluation indices. Kinetic analyzes, however, require access to, and use of, complex experimental apparatus, involving many instruments and implicating lengthy data analysis processes. The proposed methodology in this paper, which is based on data collected via EMG and motion capture systems, considerably reduces this burden by calculating kinetic parameters, such as torque and power, without needing ground reaction force measurements. This considerably reduces the number of instruments used, allows the calculation of kinetic parameters even when the use of force sensors is problematic, does not need any dedicated software, and will be shown to have high statistical validity. The method, in fact, combines data found in the literature with those collected in the laboratory, allowing the analysis to be carried out over a much greater number of cycles than would normally be collected with force plates, thus enabling easy access to statistical analysis. This new approach evaluates the kinetic effects of the exoskeleton with respect to changes induced in the user's kinematics and muscular activation patterns and provides indices that quantify the assistance in terms of torque (AMI) and power (API). Following the User-Center Design approach, which requires driving the development process as feedback from the assessment process, this aspect is critical. Therefore, by enabling easy access to the assessment process, the development of exoskeletons could be positively affected.

In selected low-risk breast cancer patients, accelerated partial breast irradiation (APBI) may represent an alternative option to the whole breast irradiation to reduce the volume of irradiated breast and total treatment duration. In the last few years, preliminary data from clinical trials showed that stereotactic partial breast radiotherapy may have the advantage to be less invasive compared to other APBI techniques, with preliminary good results in terms of local toxicity and cosmesis: the use of magnetic resonance, fiducial markers in the tumor bed, and new breast devices support both a precise definition of the target and radiation planning.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021257856, identifier CRD42021257856.

BackgroundOne-third of ischemic strokes are “cryptogenic” without clearly identified etiology. Although coronary artery disease (CAD) is the main cause of death after stroke, the interest in CAD screening in patients with cryptogenic stroke is still debated.AimThe aim of the study was to assess the incremental prognostic value of stress cardiovascular magnetic resonance (CMR) beyond traditional risk factors for predicting cardiovascular events in patients with a prior cryptogenic ischemic stroke.Materials and methodsBetween 2008 and 2021, consecutive patients with prior cryptogenic strokes referred for stress CMR were included and followed for the occurrence of major adverse cardiovascular events (MACEs), defined by cardiovascular death or non-fatal myocardial infarction (MI). Univariable and multivariable Cox regressions were performed to determine the prognostic value of unrecognized MI and silent ischemia.ResultsOf 542 patients (55.2% male, mean age 71.4 ± 8.8 years) who completed the follow-up (median 5.9 years), 66 (12.2%) experienced MACE. Silent ischemia and unrecognized MI were detected in 18 and 17% of patients, respectively. Using Kaplan–Meier analysis, silent ischemia and unrecognized MI were associated with the occurrence of MACE [hazard ratio, HR: 8.43 (95% CI: 5.11–13.9); HR: 7.87 (95% CI: 4.80–12.9), respectively, p < 0.001]. In multivariable analysis, silent ischemia and unrecognized MI were independent predictors of MACE [HR: 8.08 (95% CI: 4.21–15.5); HR: 6.65 (95% CI: 3.49–12.7), respectively, p < 0.001]. After adjustment, stress CMR findings showed the best improvement in model discrimination and reclassification above traditional risk factors (C-statistic improvement: 0.13; NRI = 0.428; IDI = 0.048).ConclusionIn patients with prior cryptogenic stroke, stress CMR findings have an incremental prognostic value to predict MACE over traditional risk factors.

Liver cancer represents one of the most common causes of death from cancer worldwide. Hepatocellular carcinoma (HCC) accounts for 90% of all primary liver cancers. Among local therapies, evidence regarding the use of radiation therapy is growing. Proton therapy currently represents the most advanced radiation therapy technique with unique physical properties which fit well with liver irradiation. Here, in this review, we aim to 1) illustrate the rationale for the use of proton therapy (PT) in the treatment of HCC, 2) discuss the technical challenges of advanced PT in this disease, 3) review the major clinical studies regarding the use of PT for HCC, and 4) analyze the potential developments and future directions of PT in this setting.

IntroductionThe natural history of acute myocarditis (AM) remains partially unknown and predictors of outcome are debated. We sought to assess the impact of various cardiac magnetic resonance (CMR) parameters on early and long-term prognosis in a population of patients with AM.Materials and MethodsIn a two-center longitudinal study, we included consecutive patients with diagnosis of AM based on CMR and without hemodynamic compromise. The primary endpoint was the occurrence of an event in the acute phase (≤15 days). Secondary endpoints were the occurrence of major adverse cardiac events (MACE) and recurrence of AM during follow-up.ResultsThree hundred and eighty-eight patients were included [mean age 38.5 years, 77.3% male, mean ejection fraction (EF):56%] of which 82% (317) presented with chest pain. CMR was performed 4 ± 2 days after index presentation. Overall, 38 patients (9.8%) had an event at the acute phase, 41 (10.6%) presented at least one MACE during follow-up (median 7.5 years, 6.6–8.9) and 30 (7.7%) experienced a recurrence of AM. By multivariate analysis, the independent predictors of initial complications were absence of chest pain (OR [95%CI] = 0.35 [0.15–0.82]), presence of syncope/pre-syncope (OR [95%CI] = 3.56 [1.26–10.02]), lower EF (OR [95%CI] = 0.94 [0.91–0.98] per%), myocardial extent of late gadolinium enhancement (LGE) (OR [95%CI] = 1.05 [1.002–1.100] per%) and absence of edema (OR [95%CI] = 0.44 [0.19–0.97]). Only age (HR [95%CI] = 1.021 [1.001–1.041] per year) and an initial alteration of EF (HR [95%CI] = 0.94 [0.91–0.97] per%) were associated with MACE during follow-up. Factors independently associated with AM recurrence were myocarditis prior to the index episodes (HR [95%CI] = 5.74 [1.72–19.22]) and viral syndrome at the index episode (HR [95%CI] = 4.21 [1.91–9.28]).ConclusionIn routine consecutive hemodynamically stable patients with diagnosis of AM based on CMR, absence of edema, reduced EF, and extent of LGE were associated with early adverse outcome. Only age and EF were associated with long-term events.

Background: Epidemiological characteristics and prognostic profiles of patients with newly diagnosed coronary artery disease (CAD) are heterogeneous. Therefore, providing individualized cardiovascular (CV) risk stratification and tailored prevention is crucial.Objective: Phenotypic unsupervised clustering integrating clinical, coronary computed tomography angiography (CCTA), and cardiac magnetic resonance (CMR) data were used to unveil pathophysiological differences between subgroups of patients with newly diagnosed CAD.Materials and Methods: Between 2008 and 2020, consecutive patients with newly diagnosed obstructive CAD on CCTA and further referred for vasodilator stress CMR were followed for the occurrence of major adverse cardiovascular events (MACE), defined by cardiovascular death or non-fatal myocardial infarction. For this exploratory work, a cluster analysis was performed on clinical, CCTA, and CMR variables, and associations between phenogroups and outcomes were assessed.Results: Among 2,210 patients who underwent both CCTA and CMR, 2,015 (46% men, mean 70 ± 12 years) completed follow-up [median 6.8 (IQR 5.9–9.2) years], in which 277 experienced a MACE (13.7%). Three mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: (PG1) CAD in elderly patients with few traditional risk factors; (PG2) women with metabolic syndrome, calcified plaques on CCTA, and preserved left ventricular ejection fraction (LVEF); (PG3) younger men smokers with proximal non-calcified plaques on CCTA, myocardial scar, and reduced LVEF. Using survival analysis, the occurrence of MACE, cardiovascular mortality, and all-cause mortality (all p < 0.001) differed among the three PG, in which PG3 had the worse prognosis. In each PG, inducible ischemia was associated with MACE [PG1, Hazards Ratio (HR) = 3.09, 95% CI, 1.70–5.62; PG2, HR = 3.62, 95% CI, 2.31–5.7; PG3, HR = 3.55, 95% CI, 2.3–5.49; all p < 0.001]. The study presented some key limitations that may impact generalizability.Conclusions: Cluster analysis of clinical, CCTA, and CMR variables identified three phenogroups of patients with newly diagnosed CAD that were associated with distinct clinical and prognostic profiles. Inducible ischemia assessed by stress CMR remained associated with the occurrence of MACE within each phenogroup. Whether automated unsupervised phenogrouping of CAD patients may improve clinical decision-making should be further explored in prospective studies.

Objective: To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships.Patients and Methods: Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant (n = 106) or salvage (n = 107) intent with conventional (n = 123, prescribed dose to the prostatic bed: 66.6–79.8Gy in 1.8–2.0Gy/fr) or moderately hypo- (n = 90, 65.8–76.8Gy in 2.1–2.7Gy/fr) fractionation during the period 2011–2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/β values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing p < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated.Results: Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/β = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints (p < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/β = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance.Conclusion: Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged.

Cachexia is a complex metabolic syndrome that determines a severe body weight loss characterized by a marked reduction in muscle mass. About 80% of patients with advanced cancer develop cachexia due to both the tumor itself and cancer treatment (radiotherapy and/or chemotherapy), which is associated to a worse prognosis. Despite its clinical relevance, this syndrome is still under-diagnosed and it lacks effective treatments. Radio-chemotherapy treatment is essential in patients with advanced head and neck cancers (HNSCC). Although this treatment has improved patients’ life expectancy, it has also dramatically increased their need for assistance and support. The management of adverse symptoms, including cachexia, is of great importance in order to avoid delays in therapy, reduction of dosages and hospitalizations. MicroRNAs (miRNAs) are small non-coding RNA molecules, which have emerged as powerful biomarkers in stratifying human cancers. Due to their high stability in body fluids, miRNAs might be excellent non-invasive biomarkers for the early detection and follow-up of cancer patients. Here, we will summarize the current knowledge and debate the strong need to identify circulating biomarkers for the early diagnosis of cachexia. We will propose circulating non-coding RNAs as biomarkers for detecting early cachexia and implementing specific treatment. We will also discuss the potential use of circulating miRNAs as biomarkers of cachexia in HNSCC patients’ blood samples collected before and after radio-chemotherapy treatment. Our intent is to pave the way to the identification of specific circulating miRNAs associated to cachexia occurrence and to the design of specific interventions aimed at improving the quality of life of cancer patients.

Neurological diseases causing motor/cognitive impairments are among the most common causes of adult-onset disability. More than one billion of people are affected worldwide, and this number is expected to increase in upcoming years, because of the rapidly aging population. The frequent lack of complete recovery makes it desirable to develop novel neurorehabilitative treatments, suited to the patients, and better targeting the specific disability. To date, rehabilitation therapy can be aided by the technological support of robotic-based therapy, non-invasive brain stimulation, and neural interfaces. In this perspective, we will review the above methods by referring to the most recent advances in each field. Then, we propose and discuss current and future approaches based on the combination of the above. As pointed out in the recent literature, by combining traditional rehabilitation techniques with neuromodulation, biofeedback recordings and/or novel robotic and wearable assistive devices, several studies have proven it is possible to sensibly improve the amount of recovery with respect to traditional treatments. We will then discuss the possible applied research directions to maximize the outcome of a neurorehabilitation therapy, which should include the personalization of the therapy based on patient and clinician needs and preferences.

The speed of voluntary movements is determined by the conflicting needs of maximizing accuracy and minimizing mechanical effort. Dynamic perturbations, e.g. force fields, may be used to manipulate movements in order to investigate these mechanisms. Here we focus on how the presence of position- and velocity-dependent force fields affects the relation between speed and accuracy during hand reaching movements.Participants were instructed to perform reaching movements under visual control in two directions, corresponding to either low or high arm inertia. The subjects were required to maintain four different movement durations (very slow, slow, fast, very fast). The experimental protocol included three phases: (i) familiarization - the robot generated no force; (ii) force field - the robot generated a force; and (iii) after-effect - again, no force. Participants were randomly assigned to four groups, depending on the type of force that was applied during the `force field' phase. The robot was programmed to generate position-dependent forces -- with positive (K+) or negative stiffness (K-) -- or velocity-dependent forces, with either positive (B+) or negative viscosity (B-). We focused on path curvature, smoothness and endpoint error; in the latter we distinguished between bias and variability components. Movements in the high-inertia direction are smoother and less curved; smoothness also increases with movement speed. Endpoint bias and variability are greater in, respectively, the high and low inertia directions. A robust dependence on movement speed (SAT curve) was only observed in the longitudinal components of both bias and variability.The strongest and more consistent effects of perturbation were observed with negative viscosity (B-), which resulted in increased variability during force field adaptation and in a reduction of the endpoint bias, which was retained in the subsequent after-effect phase. These findings confirm that training with negative viscosity produces lasting effects in the speed/accuracy trade-off in movement accuracy at all speeds.

Brain-machine interfaces (BMIs) are mostly investigated as a means to provide paralyzed people with new communication channels with the external world. However, the communication between brain and artificial devices also offers a unique opportunity to study the dynamical properties of neural systems. This review focuses on bidirectional interfaces, which operate in two ways by translating neural signals into input commands for the device and the output of the device into neural stimuli. We discuss how bidirectional BMIs help investigating neural information processing and how neural dynamics may participate in the control of external devices. In this respect, a bidirectional BMI can be regarded as a fancy combination of neural recording and stimulation apparatus, connected via an artificial body. The artificial body can be designed in virtually infinite ways in order to observe different aspects of neural dynamics and to approximate desired control policies.