A novel flow cytometry panel to identify prognostic markers for steroid-sensitive forms of idiopathic nephrotic syndrome in childhood.

Introduction: The clinical evolution of steroid-sensitive forms of pediatric idiopathic nephrotic syndrome (INS) is highly heterogeneous following the standard treatment with prednisone. To date, no prognostic marker has been identified to predict the severity of the disease course starting from the first episode. Methods: In this monocentric prospective cohort study we set up a reproducible and standardized flow cytometry panel using two sample tubes (one for B-cell and one for T-cell subsets) to extensively characterized the lymphocyte repertoire of INS pediatric patients. A total of 44 children with INS at disease onset were enrolled, sampled before and 3 months after standard induction therapy with prednisone and followed for 12 months to correctly classify their disease based on relapses. Age-matched controls with non immune-mediated renal diseases or with urological disorders were also enrolled. Demographical, clinical, laboratory and immunosuppressive treatment data were registered. Results: We found that children with INS at disease onset had significantly higher circulating levels of total CD19+ and specific B-cell subsets (transitional, mature-naïve, plasmablasts/plasmacells, CD19+CD27+, unswitched, switched and atypical memory B cells) and reduced circulating levels of Tregs, when compared to age-matched controls. Prednisone therapy restored most B- and T-cell alterations. When patients were subdivided based on disease relapse, relapsing patients had significantly more transitional, CD19+CD27+ memory and in particular unswitched memory B cells at disease onset, which were predictive of a higher risk of relapse in steroid-sensitive patients by logistic regression analysis, irrespective of age. In accordance, B-cell dysregulations resulted mainly associated with steroid-dependence when patients were stratified in different disease severity forms. Of note, Treg levels were reduced independently from the disease subgroup and were not completely normalized by prednisone treatment. Conclusion: We have set up a novel, reproducible, disease-specific flow cytometry panel that allows a comprehensive characterization of circulating lymphocytes. We found that, at disease onset, relapsing patients had significantly more transitional, CD19+CD27+ memory and unswitched memory B cells and those who are at higher risk of relapse had increased circulating levels of unswitched memory B cells, independently of age. This approach can allow prediction of clinical evolution, monitoring of immunosuppression and tailored treatment in different forms of INS.

All for one: Collaboration between dermatologist, radiation oncologist and radiologist in the clinical management of "difficult to treat" non melanoma skin cancer.

This series introduces the clinical management of difficult-to-treat non-melanoma skin cancers (NMSCs) through a multidisciplinary approach, emphasizing the integration of dermoscopy and Ultra high-frequency ultrasound (UHFUS) for accurate diagnosis and treatment planning, particularly in cases referred for radiotherapy (RT). Dermoscopy aids in diagnosing both pigmented and non-pigmented skin lesions, guiding treatment margins and reducing the benign-to-malignant biopsy ratio. UHFUS provides valuable insights into tumor size, depth, and vascularity, complementing clinical evaluations and assisting in RT planning. Three challenging cases are presented, highlighting the pivotal role of dermoscopy and UHFUS in decision-making and treatment optimization. Collaboration between dermatologists, radiation oncologists, and radiologists enhances diagnostic accuracy, tailoring treatment plans to individual patient needs and preferences, ultimately improving patient outcomes and experience. The integration of these imaging techniques holds promise for optimizing non-surgical treatments like RT and monitoring treatment progress, offering a personalized approach to NMSC management.

Propionate functions as a feeding state-dependent regulatory metabolite to counter proinflammatory signaling linked to nutrient load and obesity.

Generally, fasting and refeeding confer anti- and proinflammatory effects, respectively. In humans, these caloric-load interventions function, in part, via regulation of CD4+ T cell biology. However, mechanisms orchestrating this regulation remain incomplete. We employed integrative bioinformatics of RNA sequencing and high-performance liquid chromatography-mass spectrometry data to measure serum metabolites and gene expression of peripheral blood mononuclear cells isolated from fasting and refeeding in volunteers to identify nutrient-load metabolite-driven immunoregulation. Propionate, a short chain fatty acid (SCFA), and the SCFA-sensing G protein-coupled receptor 43 (ffar2) were coordinately and inversely regulated by fasting and refeeding. Propionate and free fatty acid receptor agonists decreased interferon-γ and interleukin-17 and significantly blunted histone deacetylase activity in CD4+ T cells. Furthermore, propionate blunted nuclear factor κB activity and diminished interleukin-6 release. In parallel, propionate reduced phosphorylation of canonical T helper 1 (TH1) and TH17 regulators, STAT1 and STAT3, respectively. Conversely, knockdown of free fatty acid receptors significantly attenuated the anti-inflammatory role of propionate. Interestingly, propionate recapitulated the blunting of CD4+ TH cell activation in primary cells from obese individuals, extending the role of this metabolite to a disease associated with low-grade inflammation. Together, these data identify a nutrient-load responsive SCFA-G protein-coupled receptor linked pathway to regulate CD4+ TH cell immune responsiveness.

Conventional Radiology Evaluation of Neonatal Intravascular Devices (NIVDs): A Case Series.

Our radiology department conducted an assessment of 300 neonatal radiographs in the neonatal intensive care unit over almost two years. The purpose was to evaluate the correct positioning of intravascular venous catheters. Our case series revealed that out of a total of 95 cases with misplaced devices, 59 were umbilical venous catheters and 36 were peripherally inserted central catheters. However, all of the central venous catheters were found to be properly positioned. Misplacements of neonatal intravascular devices were found to occur more frequently than expected. The scientific literature contains several articles highlighting the potential complications associated with misplaced devices. Our goal is to highlight the potential misplacements and associated complications that radiologists may encounter while reviewing conventional radiology imaging. Based on our experience, which primarily involved placing UVCs and PICCs, we discovered that conventional radiology is the most effective method for assessing proper device placement with the lowest possible radiation exposure. Given the high number of neonatal vascular device placement procedures, it is essential for radiologists to maintain a high level of vigilance and stay updated on the latest developments in this field.

The role of an artificial intelligence software in clinical senology: a mammography multi-reader study.

PURPOSE: To evaluate the diagnostic role of a dedicated AI software in detecting anomalous breast findings on mammography and tomosynthesis images in the clinical setting, stand-alone and as aid of four readers. METHODS: A total of 210 patients with complete clinical and radiologic records were retrospectively analyzed. Pathology was used as the reference standard for patients undergoing surgery or biopsy, and a 1-year follow-up was used to confirm no change in the remaining patients. The image evaluation was performed by four readers with different levels of experience (a junior and three senior breast radiologists) using a 5-point Likert scale moving from 1 (definitively no cancer) to 5 (definitively cancer). The positivity of mammograms was assessed on the presence of any breast lesion (masses, architectural distortions, asymmetries, calcifications), including malignant and benign ones. A multi-reader multi-case analysis was performed. A p value < 0.05 was considered statistically significant. RESULTS: The stand-alone AI system achieved an accuracy of 71% (69% sensitivity and 73% specificity), which is overall lower than the value achieved by readers without AI. However, with the aid of AI, a significant increase of accuracy (p value = 0.004) and specificity (p value = 0.04) was achieved for the less experienced radiologist and a senior one. CONCLUSION: The use of AI software as a second reader for breast lesions assessment could play a crucial role in the clinical setting, by increasing sensitivity and specificity, especially for less experienced radiologists.

Imaging diagnosis of a rare case of intermittent intestinal pneumatosis: A consequence of ileocecal valve clip dysfunction?

Pneumatosis intestinalis is a condition characterized by the presence of gas or air pockets within the walls of the intestines. It can occur in any section of the gastrointestinal tract but it is most commonly found in the colon. Etiology and pathogenesis of PI are not yet fully understood, but several potential factors have been suggested to play a pivotal role in the development of this pathologic condition. Pneumatosis intestinalis seems to arise from a complex interplay between various factors, such as the integrity of the intestinal lining, pressure within the portal vein, the composition of the microbiological flora in the gut. Pneumatosis intestinalis can be caused by a variety of underlying conditions, such as bowel obstruction, intestinal ischemia, infection, inflammatory bowel disease, or certain medications. Symptoms may include abdominal pain, bloating, diarrhea, vomiting, and bloody stools. We present a case report of a 63-year-old male patient who underwent laparoscopic cholecystectomy for symptomatic cholelithiasis with recurrent cholecystitis. Following the surgery, the patient experienced a rapid drop in hemoglobin levels, necessitating an urgency regimen laparoscopic abdominal exploration which revealed Meckel's diverticulitis with active bleeding leading to diverticulectomy. The next day, the patient developed a radiological condition characterized by the co-presence of intermittent pneumatosis intestinalis, Portal pneumatosis and intermittent small bowel obstruction.

Late-onset mucopolysaccharidosis type IIIA mimicking Usher syndrome.

Mucopolysaccharidosis type IIIA (MPS IIIA or Sanfilippo syndrome type A) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the SGSH gene encoding N-sulfoglucosamine sulfohydrolase, an enzyme involved in the degradation of heparan sulfate. MPS IIIA is typically characterized by neurocognitive decline and hepatosplenomegaly with childhood onset. Here, we report on a 53-year-old male subject initially diagnosed with Usher syndrome for the concurrence of retinitis pigmentosa and sensorineural hearing loss. Clinical exome sequencing identified biallelic missense variants in SGSH, and biochemical assays showed complete deficiency of sulfamidase activity and increased urinary glycosaminoglycan excretion. Reverse phenotyping revealed left ventricle pseudo-hypertrophy, hepatosplenomegaly, bilateral deep white matter hyperintensities upon brain MRI, and decreased cortical metabolic activity by PET-CT. On neuropsychological testing, the proband presented only partial and isolated verbal memory deficits. This case illustrates the power of unbiased, comprehensive genetic testing for the diagnosis of challenging mild or atypical forms of MPS IIIA.

Pregnancy experience in women with spinal muscular atrophy: a case series.

Many women with spinal muscular atrophy (SMA) types II, III, and IV reach fertile age, and some of them may consider pregnancy. However, limited data are available about the potential effects of pregnancy on the course of SMA and the outcomes of pregnancies in these patients. Furthermore, the use of several disease-modifying therapies for the treatment of all types of SMA is expected to increase the number of female SMA patients considering pregnancy in the coming years. The aim of this report is to provide clinicians with an overview of the patients in our cohort who have experienced pregnancies. We conducted a retrospective analysis on these women, through the administration of a questionnaire, which investigated how they experienced the different stages of the pregnancy. Ten patients (3 SMAII; 7 SMA III) participated in the survey; 40% had pregnancies for a total of nine, six of which were term-pregnancies. The mean age of first pregnancy was 32.5 ± 7.8 years for SMA II patients, and 30.5 ± 2.1 years for SMA III. All pregnancies ended in cesarean sections. Interestingly, the sitters had more frequent complications in pre-term labor and delivery, but the newborns were all healthy. This report shows that a successful pregnancy is possible in female patients with SMA. However, the ideal approach should involve a standardized multidisciplinary team capable of effectively addressing every possible scenario. For this reason, it is critically important that clinicians working with SMA patients gain more in-dept knowledge about this topic.

What Is the Role of Palmitoylethanolamide Co-Ultramicronized with Luteolin on the Symptomatology Reported by Patients Suffering from Long COVID? A Retrospective Analysis Performed by a Group of General Practitioners in a Real-Life Setting.

Long COVID is a recognized post-viral syndrome characterized by neurological, somatic and neuropsychiatric symptoms that might last for long time after SARS-CoV-2 infection. An ever-growing number of patients come to the observation of General Practitioners complaining of mild or moderate symptoms after the resolution of the acute infection. Nine General Practitioners from the Rome area (Italy) performed a retrospective analysis in order to evaluate the role of the supplementation with Palmitoylethanolamide co-ultramicronized with Luteolin (PEALUT) on neurologic and clinical symptoms reported by their patients after COVID-19 resolution. Supplementation with PEALUT helped to improve all patient-reported symptoms, especially pain, anxiety and depression, fatigue, brain fog, anosmia and dysgeusia, leading to an overall improvement in patients' health status. To our knowledge these are the first data presented on Long COVID patients collected in a territorial setting. Despite their preliminary nature, these results highlight the pathogenetic role of "non-resolving" neuroinflammation in Long COVID development and consequently the importance of its control in the resolution of the pathology and put the focus on the General Practitioner as the primary figure for early detection and management of Long COVID syndrome in a real-life setting. Future randomized, controlled, perspective clinical trials are needed to confirm this preliminary observation.

Magnetic Resonance Imaging Evaluation of Bone Metastases Treated with Radiotherapy in Palliative Intent: A Multicenter Prospective Study on Clinical and Instrumental Evaluation Assessment Concordance (MARTE Study).

Metastasis to bone is a common occurrence among epithelial tumors, with a high incidence rate in the Western world. As a result, bone lesions are a significant burden on the healthcare system, with a high morbidity index. These injuries are often symptomatic and can lead to functional limitations, which in turn cause reduced mobility in patients. Additionally, they can lead to secondary complications such as pathological fractures, spinal cord compression, hypercalcemia, or bone marrow suppression. The treatment of bone metastases requires collaboration between multiple healthcare professionals, including oncologists, orthopedists, neurosurgeons, physiatrists, and radiotherapists. The primary objective of this study is to evaluate the correlation between two methods used to assess local control. Specifically, the study aims to determine if a reduction in the volume of bone lesions corresponds to better symptomatic control in the clinical management of patients, and vice versa. To achieve this objective, the study evaluates morphological criteria by comparing pre- and post-radiotherapy treatment imaging using MRI and RECIST 1.1 criteria. MRI without contrast is the preferred diagnostic imaging method, due to its excellent tolerance by patients, the absence of exposure to ionizing radiation, and the avoidance of paramagnetic contrast media side effects. This imaging modality allows for accurate assessment of bone lesions. One of the secondary objectives of this study is to identify potentially useful parameters that can distinguish patients into two classes: "good" and "poor" responders to treatment, as reported by previous studies in the literature. These parameters can be evaluated from the imaging examinations by analyzing morphological changes and radiomic features on different sequences, such as T1, STIR (short tau inversion recovery), and DWI-MRI (diffusion-weighted).

Experimental and theoretical studies on the acetaldehyde reaction with (+)-catechin.

Acetaldehyde plays a key role in determining some wine properties. Interesting is the reaction of acetaldehyde with flavonoids, as the ensuing products can alter wine color, astringency, colloidal stability. Many studies reported on the formation of ethylidene-bridged flavan-3-ols as products of the reaction between acetaldehyde and either (+)-catechin or (-)-epicatechin. In white wines after one year of incubation with acetaldehyde only vinyl-(+)-catechin and vinyl-(-)-epicatechin were observed, while no ethylidene linked oligomers were detected. This observation prompted us to study the reaction of (+)-catechin with acetaldehyde in wine model solution through an experimental and theoretical approach, with the purpose of exploring the nature of the species involved along with the mechanisms leading to them. The products of the reaction were observed over 38 days. The results showed that ethylidene-bridged catechins are the first products to be formed but over time the dissociation of these dimers causes vinyl-catechins to accumulate.

MRI findings in patient with primary cutaneous nocardiosis: A case report.

Nocardia is a genus of gram-positive, filamentous, aerobic bacteria that belongs to the Actinomycetales order. With over 50 species, it is ubiquitous in dust, soil, decaying organic matter, and stagnant water. Inhalation of the pathogen often leads to pulmonary nocardiosis, while extrapulmonary nocardiosis can affect the central nervous system, skin, and subcutaneous tissues. Primary cutaneous nocardiosis occurs when the pathogen is introduced through a skin lesion or insect bite, for example, this report presents a case of primary cutaneous nocardiosis in a patient with Minimal Change Glomerulonephritis and iatrogenic immunosuppression. Magnetic resonance imaging revealed extensive involvement of the skin, subcutaneous tissue, and lower limb muscles.

The conserved AAA ATPase PCH-2 distributes its regulation of meiotic prophase events through multiple meiotic HORMADs in C. elegans.

During meiotic prophase, the essential events of homolog pairing, synapsis, and recombination are coordinated with meiotic progression to promote fidelity and prevent aneuploidy. The conserved AAA+ ATPase PCH-2 coordinates these events to guarantee crossover assurance and accurate chromosome segregation. How PCH-2 accomplishes this coordination is poorly understood. Here, we provide evidence that PCH-2 decelerates pairing, synapsis and recombination in C. elegans by remodeling meiotic HORMADs. We propose that PCH-2 converts the closed versions of these proteins, which drive these meiotic prophase events, to unbuckled conformations, destabilizing interhomolog interactions and delaying meiotic progression. Further, we find that PCH-2 distributes this regulation among three essential meiotic HORMADs in C. elegans: PCH-2 acts through HTP-3 to regulate pairing and synapsis, HIM-3 to promote crossover assurance, and HTP-1 to control meiotic progression. In addition to identifying a molecular mechanism for how PCH-2 regulates interhomolog interactions, our results provide a possible explanation for the expansion of the meiotic HORMAD family as a conserved evolutionary feature of meiosis. Taken together, our work demonstrates that PCH-2's remodeling of meiotic HORMADs has functional consequences for the rate and fidelity of homolog pairing, synapsis, recombination and meiotic progression, ensuring accurate meiotic chromosome segregation.

Ultra-High-Frequency Ultrasound: A Modern Diagnostic Technique for Studying Melanoma. / Ultrahochfrequenz-Ultraschall: Eine moderne Diagnosetechnik zur Untersuchung von Melanomen.

The development of new ultra-high-frequency devices with a resolution of 30 µm makes it possible to use ultrasound in the study of new small anatomical units and to apply this tool to new fields of pathology. Cutaneous melanoma is a severe skin disease with an incidence of approximately 160 000 new cases each year and 48 000 deaths. In this paper, we evaluate the role of HFUS in the diagnosis of cutaneous melanoma, describe the sonographic appearance of skin layers in the pre-excision phase as well as of lesion features, and correlate the characteristics with pathological examination.

Preaxial polydactyly of the foot in an adult patient diagnosed by X-ray after a trauma.

Polydactyly, or hyperdactyly, is a frequent malformation, with a reported incidence between 0.37 and 1.2 per 1000 live births. Most cases encountered in medical practice are sporadic cases, usually presenting one-sided manifestations. More frequently, polydactyly can be detected prenatally through an ultrasound examination, if not, it is usually diagnosed at birth, during the first physical examination. Although the clinical diagnosis is relatively easy in patients with manifest cases, it can sometimes be present with mild or partial forms that are not clinically evident on physical examination, resulting in later diagnosis and treatment. We reported a particular case of polydactyly of the foot not clinically manifest, diagnosed in a 39-year-old Caucasian Male patient with a history of recurrent localized pain in the big toe often associated with subungual bleeding, since he was a child who came to our emergency room following a car accident. Polydactyly is a frequently reported congenital malformation which may present in many different varieties of deformities. In this case, the X-ray, which was required after a car accident, leads to the incidental diagnosis of polydactyly in an adult patient. As described, because of the functional limitations related to this malformation, as well as to limit recurrent pain, and subungual anomalies, the patient underwent to a surgical correction to improve its quality of life.

Management of Non-Melanoma Skin Cancer: Radiologists Challenging and Risk Assessment.

Basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma are the three main types of nonmelanoma skin cancers and their rates of occurrence and mortality have been steadily rising over the past few decades. For radiologists, it is still difficult to treat patients with advanced nonmelanoma skin cancer. Nonmelanoma skin cancer patients would benefit greatly from an improved diagnostic imaging-based risk stratification and staging method that takes into account patient characteristics. The risk is especially elevated among those who previously received systemic treatment or phototherapy. Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors. Risk stratification and staging tools are crucial in treatment planning and prognostic evaluation. PET/CT appears more sensitive and superior to CT and MRI for nodal and distant metastasis as well as in surveillance after surgery. The patient treatment response improved with advent and utilization of immunotherapy and different immune-specific criteria are established to standardized evaluation criteria of clinical trials but none of them have been utilized routinely with immunotherapy. The advent of immunotherapy has also arisen new critical issues for radiologists, such as atypical response pattern, pseudo-progression, as well as immune-related adverse events that require early identification to optimize and improve patient prognosis and management. It is important for radiologists to have knowledge of the radiologic features site of the tumor, clinical stage, histological subtype, and any high-risk features to assess immunotherapy treatment response and immune-related adverse events.

Peritransplant Radiation Therapy in Patients With Refractory or Relapsed Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant: Long-Term Results of a Retrospective Study of the Fondazione Italiana Linfomi.

PURPOSE: In this multicenter collaboration, we report real-world data in the largest published series of long-term outcomes for patients with relapsed/refractory (r/r) Hodgkin lymphoma (HL) treated with peritransplant radiation therapy (pt-RT) and high-dose chemotherapy with autologous stem cell transplant (ASCT). METHODS AND MATERIALS: We conducted a retrospective analysis including data from 12 institutions. Eligibility required histologic diagnosis of HL, receipt of ASCT plus pt-RT between 2004 and 2014 for r/r HL, and age ≥18 years at the time of ASCT. All patients received salvage chemotherapy for maximum debulking before ASCT. Metabolic responses were scored according to the Lugano Classification. The primary endpoint was overall survival (OS). Univariate and multivariate Cox proportional hazards were calculated to estimate the effect of covariates on patients' outcome. RESULTS: One hundred thirty-one patients were eligible: 68 were male (52%), and median age at ASCT was 32 years (range, 18-70). At the time of diagnosis with r/r HL, 92 patients (70%) had limited (stage I-II) disease, and 10 patients (8%) had bulky disease. Pt-RT was given pre-ASCT in 32 patients (24%) and post-ASCT in 99 (76%); median prescribed dose was 30.6 Gy (range, 20-44 Gy). With median follow-up of 60 months, 3- and 5-year OS were 84% and 77%, while 3- and 5-year progression-free survival were 75% and 72%, respectively. On univariate and multivariate analysis, advanced stage at relapse (hazard ratio [HR], 2.18; P = .04), irradiation of >3 sites (HR, 3.69; P = .01), and incomplete metabolic response after salvage chemotherapy (HR, 2.24; P = .01) had a negative effect on OS. The sequencing of pt-RT (pre- vs post-ASCT) did not affect outcomes. CONCLUSIONS: Overall, the addition of pt-RT to ASCT for patients with r/r HL is associated with very good outcomes. Limited relapsed disease with ≤3 sites involved and achievement of complete metabolic response after salvage chemotherapy were predictive of more favorable prognosis.

Bösch osteotomy for hallux valgus correction: results at a mean 10-year follow-up.

INTRODUCTION: Bösch osteotomy (BO), which is a first metatarsal subcapital osteotomy stabilised with a K-wire, is a surgical option to correct hallux valgus (HV). The aim of this study was to assess the long-term clinical and radiographic results in a cohort of patients treated at our institution with such osteotomy. METHODS: In this retrospective monocentric single-surgeon cohort study, we included 58 HVs (46 patients) who underwent HV correction by BO and were followed at a minimum of 7 years. The range of motion (ROM), the American Orthopaedic Foot and Ankle Society's Forefoot scale (AOFAS-FS) and the Visual Analogic Scale (VAS) for pain were recorded. On weightbearing radiographs, the Hallux Valgus Angle (HVA), Intermetatarsal Angle (IMA), the Distal Metatarsal Articular Angle (DMAA), and the Lateral Sesamoid Position (LSP) were measured and compared with pre-operative values. The complication rate and first metatarsophalangeal joint stiffness were also assessed. RESULTS: At a mean follow-up of 10 ± 2 (7-17) years, mean ± standard deviation AOFAS-FS and VAS were 89 ± 11 (67-93) and 2.1 ± 2.8 (0-7) points, respectively. In 42 (72%) cases there was no limitation in the choice of footwears. Radiographically, we found a significant improvement in the HVA (from 33.9° ± 6.7 to 18.8° ± 5.6, p < 0.001), in the IMA (14.2° ± 3.1 to 9.4° ± 2.7, p < 0.001), in the DMAA (from 30.3° ± 6.8 to 11.5° ± 5.1, p < 0.001) and in LSP (median value from 3 to 1, p < 0.001). In 36 (62%) cases the ROM was greater than 75° while in 22 (38%) it ranged between 30° and 75°. Minor complications occurred in six (10%) cases, which did not require any further surgery at the longest follow-up. CONCLUSION: Bösch technique provided satisfactory clinical and radiographic outcomes in the treatment of hallux valgus which persisted at a mean 10-year follow-up. The complication rate did not differ from more recent techniques described in literature. LEVEL OF EVIDENCE: Level IV, retrospective cohort study.

New steps on an old path: Novel estrogen receptor inhibitors in breast cancer.

Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in hormone receptor positive (HR+) breast cancer (BC). Thus, endocrine therapy (ET) alone or in combination with targeted agents constitutes the mainstay of the treatment for this BC subtype. Despite its efficacy, intrinsic or acquired resistance to ET occurs in a large proportion of cases, mainly due to aberrant activation of ER signaling (i.e. through ligand-independent ER activation, in the presence of estrogen receptor 1 (ESR1) gene aberration or ER protein phosphorylation) and/or the upregulation of escape pathways, such as the PI3K/AKT/mTOR pathway. Therefore, the development of new ER pathway targeting agents remains essential to delay and overcome ET resistance, enhance treatment efficacy and tolerability, and ultimately prolong patient survival and improve their quality of life. Several novel ER targeting agents are currently under investigation. Among these, the oral selective ER degraders (SERDs) represent the pharmacological class at the most advanced stage of development and promise to enrich the therapeutic armamentarium of HR+ BC in the next few years, as they showed promising results in several clinical trials, either as single ET agents or in combination with targeted therapies. In this manuscript, we aim to provide a comprehensive overview on the clinical development of novel ER targeting agents, reporting the most up-to-date evidence on oral SERDs and other compounds, including new selective ER modulators (SERMs), ER proteolysis targeting chimera (PROTACs), selective ER covalent antagonists (SERCAs), complete ER antagonists (CERANs), selective human ER partial agonists (ShERPAs). Furthermore, we discuss the potential implications of introducing these novel treatment strategies in the evolving and complex therapeutic scenario of HR+ BC.

Clinical Application of Ultra-High-Frequency Ultrasound.

Musculoskeletal ultrasound involves the study of many superficial targets, especially in the hands, wrists, and feet. Many of these areas are within the first 3 cm of the skin surface and are ideal targets for ultra-high-frequency ultrasound. The high spatial resolution and the superb image quality achievable allow foreseeing a wider use of this novel technique, which has the potential to bring innovation to diagnostic imaging.