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Breast Cancer (BC) prevention strategies range from lifestyle changes such as increasing physical activity and reducing body weight to preventive drugs like tamoxifen, known to reduce BC incidence in high-risk women. Sex Hormone Binding Globulin (SHBG) is related to BC risk due to its ability to bind circulating estradiol at high affinity and to regulate estradiol action. A study protocol is presented based on the assessment of the effect of different interventions such as tamoxifen at 10 mg every other day (LDT), intermittent caloric restriction (ICR) two days per week, lifestyle intervention (LI, step counter use) and their combination on the modulation of SHBG and several other biomarkers associated to BC. A randomized phase II biomarker study will be conducted in 4 Italian centers. Unaffected women aged between 18 and 70 years, carriers of a germline pathogenetic variant (BRCA1, BRCA2, PALB2, or other moderate penetrance genes), or with a >5% BC risk at 10 years (according to the Tyrer-Cuzick or the Breast Cancer Surveillance Consortium Risk models) or with a previous diagnosis of intraepithelial neoplasia will be eligible. A total of 200 participants will be randomized to one of the four arms: LDT; LDT + ICR; LI; LI + ICR. Interventions will span six months, with baseline and follow-up clinic visits and interim phone calls. The aim of the study is to verify whether LDT increases circulating SHBG more than LI with or without ICR after 6 months. Secondary objectives include assessing HOMA-index, inflammatory markers, adiponectin/leptin ratio, quality of life (QoL), safety, toxicity, mammographic density, and changes in microbiome composition across groups. The study's innovation lies in its inclusion of diverse BC risk categories and combination of pharmaceutical and behavioral interventions, potentially enhancing intervention efficacy while balancing tamoxifen's side effects on QoL, especially menopausal symptoms. EuCT number:2023-503994-39-00; Clinical trials.gov NCT06033092.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare necrotizing vasculitis characterized by eosinophilic inflammation that was traditionally treated with corticosteroids associated with other immunosuppressants. Over the last years different biological therapies targeting IL-5/IL-5 receptor have become available and have been employed to tackle this challenging condition. Aim of the present study is to synthesis the evidence on the clinical presentation of this disease and on the efficacy of the newly available therapeutic strategies. In June 2024 PubMed, Embase and the Cochrane library were searched for studies reporting on EGPA patients being treated by means of different anti IL-5 or anti eosinophils biological therapies. Risk of bias was assessed through the ROBINS-I and RoB2 tools according to study design. Proportion meta-analysis was employed to synthetize data on EGPA clinical manifestations, while data on treatment outcomes was analyzed descriptively due to the high heterogeneity. The present systematic review included 25 studies on a total of 1131 patients. Asthma was present in 99.2% of the patients, Sinonasal involvement in 87.0% and ANCA positivity in 22.8%. The explored treatments consisted in Benralizumab 30 mg every 4 weeks, Mepolizumab 100 mg or 300 mg every 4 weeks and Reslizumab 3mg/Kg every 4 weeks. All the anti-IL-5/IL-5 receptor molecules proved efficacious in remission control and corticosteroid tapering. The available data strongly suggests integrating anti IL-5/IL-5 receptor therapies into EGPA treatment strategies, to enhance patients' outcomes and reduce the long term side effects of prolonged corticosteroid therapy.

Background/Objectives: Compared to single gene testing (SGT), multigene panel testing (MGPT) improves pathogenic variants (PVs) detection. However, MGPT yields complex results, including secondary findings, heterozygous PVs in recessive genes, low-penetrance PVs, and variants of uncertain significance. We reported our mono-institutional experience of germline testing in breast cancer (BC), comparing SGT and MGPT. Methods: We retrospectively analyzed clinical and molecular data from 1084 BC patients: 308 underwent SGT (BRCA1/BRCA2) and 776 MGPT (for 28 cancer-related genes). We compared these approaches regarding the genetic classification of the findings (positive, uncertain, uninformative) and their impact on clinical management (primary findings (PFs); complex and inconclusive results). Additionally, we described clinical features supporting one approach over the other and focused on copy number variation (CNV) frequency in non-BRCA genes. Results: We found ≥1 PV in 165 patients (165/1084 = 15.2%), including 91 in BRCA1/BRCA2 (91/1084 = 8.4%), with 42 identified by SGT (42/308 = 13.6%) and 49 by MGPT (49/776 = 6.3%). MGPT detected PVs in non-BRCA genes in 74 patients (74/776 = 9.5%), including 40 PFs. Overall, MGPT identified 89 PFs (89/776 = 11.5%). We observed complex results in 21 patients (21/308 = 6.8%) with SGT and in 300 (300/776 = 38.7%) with MGPT. Compared to MGPT, SGT detected a similar percentage of PFs (13.6% vs. 11.5%) but a significantly reduced percentage of complex results (6.8% vs. 38.7%) (p < 0.001). Triple-negative BCs prevailed in BRCA1 carriers, while ER-positive BCs were more prevalent in ATM/CHEK2 carriers. Concerning non-BRCA genes, MGPT detected CNVs in PALB2, representing 20% of PVs in this gene. Conclusions: Although MGPT increases hereditary BC detection, its complexity requires clear guidelines for optimal clinical management and strategies for merging the benefits of SGT and MGPT.

The natural history of ductal carcinoma in situ (DCIS) is highly variable and difficult to predict. Biomarkers are needed to stratify patients with DCIS for adjuvant therapy. We investigated the prognostic and predictive relevance of cell cycle progression (CCP) score in women with DCIS. We measured the expression of 23 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumor samples, and assessed the correlation of a predefined score with histopathologic features and recurrence. The signature was analyzed in a cohort of 909 consecutive DCIS with full histopathological features treated in a single institution. The main outcome measure was ipsilateral breast event (IBE) as first event observed, be it in situ or invasive. Median follow-up time was 8.7 years (IQR 6.5–10.5 years). There were 150 ipsilateral IBEs, 84 (56%) of which were invasive. In the first 5 years of follow-up, the score provided statistically different findings ( p  = 0.009), with IBE rates of 14.7% (95% CI, 10.4–19.7) for the highest quartile of CCP score (Q4) and 8.7% (95% CI, 6.7–11.0) for the lowest quartiles (Q1–3). The prognostic value for IBEs approached significance also in women treated with mastectomy (adjusted hazard ratio [HR] Q4 vs. Q1–3 = 2.60; 95% CI: 0.96–7.08; P  = 0.06). Radiotherapy provided a greater benefit in women with higher CCP score. In addition, Q4 predicted a different risk after tamoxifen depending on menopausal status, with a beneficial trend on IBEs in postmenopausal women (HR 0.30; 95% CI, 0.07–1.39), and an opposite trend in premenopausal women (HR 1.68; 95% CI, 0.38–7.44) ( P -interaction = 0.03). The results of this study provide for the first time the evidence that CCP score is a prognostic marker, which, after additional validation, could have an important role in personalizing the management of DCIS.

Silybin is a flavonolignan extracted from Silybum marianum with chemopreventive activity against various cancers, including breast. This study was designed to develop an HPLC-MS/MS method for the determination of silybin in human plasma, urine and breast tissue in early breast cancer patients undergoing Siliphos® supplementation, an oral silybin-phosphatidylcholine complex. The determination of silybin was carried out by liquid–liquid extraction with methyl-tert-butyl ether (MTBE); total silybin concentration was determined by treating the samples with β–glucuronidase, while for the determination of free silybin, the hydrolytic step was omitted. Naringenin and naproxen were selected as internal standards. The detection of the analyte was carried out by mass spectrometry and by chromatography. The HPLC-MS/MS method was evaluated in terms of selectivity, linearity, limit of quantification, precision and accuracy, and carryover. The method proved to be selective, linear, precise and accurate for the determination of silybin. To the best of our knowledge, this presents the first analytical method with the capacity to quantify the major bioactive components of milk thistle in three different biological matrices with a lower limit of quantification of 0.5 ng/mL for plasma. Silybin phosphatidylcholine, taken orally, can deliver high blood concentrations of silybin, which selectively accumulates in breast tumor tissue.

Polymorphisms of genes involved in estrogen synthesis have been linked to breast cancer risk, prognosis, and treatment response. We investigated the prognostic impact of a deletion spanning the entire UGT2B17 gene (UGT2B17*2) and genetic variants of the aromatase CYP19A1 and estrogen receptor α (ESR1) in 125 postmenopausal women with ER-positive breast cancer enrolled in a randomized pre-surgical trial. The UGT2B17*2 was estimated by copy number variation assays and the CYP19A1 rs10046/rs4646 and ESR1 rs2077647/rs2234693/rs9340799 by TaqMan allelic discrimination assays. Serum exemestane/17-hydroxy exemestane were determined by MS and estrone (E1)/estradiol (E2)/ by GC-MS/MS. The association of genetic polymorphisms with “any event” was assessed by the Cox proportional hazards models adjusted for confounders. The UGT2B17*2 was associated with higher levels of 17-hydroxy exemestane (P = 0.04) and better prognosis (HR = 0.45; 95% CI: 0.20–1.01; P = 0.05) compared with homozygote UGT2B17 wt. The CYP19A1 rs10046 A and rs4646 C alleles were associated with higher estrogen levels: rs10046 AA vs. AG/GG genotypes had median E1 of 35.9 vs. 27.4 pg/mL (P = 0.05) and E2 of 7.57 vs. 3.9 pg/mL (P < 0.004). After a median follow-up of 7 years, women carrying the “low estrogen” alleles rs10046 G and rs4646 A had a better prognosis compared with homozygote wt for both polymorphisms (HR = 0.40; 95% CI: 0.17–0.93; P = 0.03). Our analysis points to an impact of UGT2B17 and CYP19A1 in postmenopausal endocrine responsive breast cancer. Carriers of UGT2B17*2 and CYP19A1 low estrogen variants may have better prognosis, supporting studies addressing the role of these polymorphisms in optimizing endocrine therapy. Trial registration: http://www.isrctn.com/ISRCTN86894592.

Key Clinical Message Posterior glottic lesions resembling granulomas unresponsive to conservative treatment should raise suspicion of a neoplastic condition. Although surgery is rarely recommended for arytenoid granulomas due to their high recurrence rate, histological evaluation is mandatory in cases of uncertain diagnosis. Clinicians should be aware that, although very rare, a laryngeal neuroendocrine tumor occurring in the posterior glottis can mimic the appearance of an idiopathic granuloma, presenting a diagnostic challenge.

Objective Extracorporeal septoplasty (ECS) is a surgical technique used to address severe nasal septal deviations, especially in patients in whom in situ septoplasty (ISS) is insufficient. This systematic review assesses the efficacy, safety, and clinical outcomes of ECS techniques, including conventional and modified ECS methods. Data Sources PRISMA‐compliant systematic search of PubMed, Scopus, Web of Science, and Embase. Methods Studies on ECS techniques were included. Eligibility criteria were established using the PICOTS framework. Study quality was assessed using the Cochrane Risk of Bias 2 tool and the Newcastle‐Ottawa Scale. Functional and aesthetic improvements were primary outcomes, while complication rates represented secondary outcomes. Results Twenty‐two studies (retrospective, prospective, and RCTs) met the inclusion criteria. ECS was associated with significant functional improvement, as assessed by nasal obstruction scores measured by NOSE scores, acoustic rhinometry, and rhinomanometry. Aesthetic results were also satisfactory, with a significant improvement in the nasofrontal angle, nasolabial angle, and the tip projection index, as well as good patients' satisfaction. Complications were rare, with few cases of septal perforation, graft resorption, or residual nasal obstructive symptoms. Evidence strength was limited considering the majority of included studies were retrospective, with inherent bias risks, small sample sizes, and inconsistent follow‐up durations. Conclusions ECS may be a successful and safe method for severe septal deviation correction, providing functional and aesthetic results with a low complication rate. More high‐quality, multicenter RCTs with long‐term follow‐up will be required for a standardization of surgical protocols and outcome measures. Level of Evidence 2. Pooled outcomes of NOSE scores at follow‐up.

(1) Background: to evaluate which factors can reduce the upgrade rate of atypical ductal hyperplasia (ADH) to in situ or invasive carcinoma in patients who underwent vacuum-assisted breast biopsy (VABB) and subsequent surgical excision. (2) Methods: 2955 VABBs were reviewed; 141 patients with a diagnosis of ADH were selected for subsequent surgical excision. The association between patients’ characteristics and the upgrade rate to breast cancer was evaluated in both univariate and multivariate analyses. (3) Results: the upgrade rates to ductal carcinoma in situ (DCIS) and invasive carcinoma (IC) were, respectively, 29.1% and 7.8%. The pooled upgrade rate to DCIS or IC was statistically lower at univariate analysis, considering the following parameters: complete removal of the lesion (p-value < 0.001); BIRADS ≤ 4a (p-value < 0.001); size of the lesion ≤15 mm (p-value: 0.002); age of the patients <50 years (p-value: 0.035). (4) Conclusions: the overall upgrade rate of ADH to DCIS or IC is high and, as already known, surgery should be recommended. However, ADH cases should always be discussed in multidisciplinary meetings: some parameters appear to be related to a lower upgrade rate. Patients presenting these parameters could be strictly followed up to avoid overtreatment.

Surgery is still the standard treatment for breast lesions such as ductal carcinoma (DCIS); however, its survival benefit is minimal, particularly for low-grade DCIS. Surgical complications and related depression status can adversely affect patients' quality of life. Approximately 25% of breast cancer (BC) cases are forms, with DCIS making up 90% of these. Low and intermediate-grade DCIS often grow slowly and do not always progress clinically significant diseases. Identifying non-invasive lesions could help prevent overtreatment. In this context, new diagnostic tools like vacuum-assisted excision (VAE) could enhance the management of these conditions. The prospective VACIS study explores the role of VAE in ensuring the absence of pathology at subsequent surgery and reducing the diagnostic underestimation of breast biopsies for microcalcifications. Patients with suspicious breast microcalcifications up to 15 mm, who are candidates for stereotactic biopsy, will be enrolled and randomised into two groups. The control group will complete the biopsy with typical sampling, aiming to collect some microcalcifications from the target, while the experimental group will focus on the complete removal of the biopsy target (confirmed by mammography on the biopsy table), followed by a second sequence of cleaning samples. Radiograms will confirm lesion removal. Pathologic outcomes at surgery will be compared between the groups, and the percentage of underestimation will be assessed. The sample size is calculated to be 70 patients per group, using statistical tests and multivariate logistic models to detect a significant difference in the absence of pathology. Data collected will include patient age, lesion characteristics, and details of the biopsy, pathology and surgery. Current surgical treatments for low-and sometimes intermediate-grade DCIS offer limited survival benefits and may hurt patients' quality of life due to surgery-related complications and associated depression. These lesions often grow slowly and might not become clinically significant, suggesting a need to avoid overtreatment. Improved diagnostics procedures, such as VAE, could help distinguish non-invasive from potentially invasive lesions, reduce biopsy underestimation, enable personalised management and optimise treatment strategies. This study hypothesises that VAE could be a viable alternative to surgery, capable of removing pathology during the biopsy procedure. Clinicaltrials.gov, identifier NCT05932758.