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Background: Even if allogeneic stem cell transplantation (allo-SCT) is curative for a minority of patients with multiple myeloma (MM), the patients who have relapsed after allo-SCT can experience long-term survival, suggesting a synergy between anti-myeloma drugs administered after allo-SCT and donor T cells., Objectives: We retrospectively evaluated the outcome of MM patients reported to the "Gruppo Italiano Trapianto Midollo Osseo e Terapia Cellulare" (GITMO) network, who underwent allo-SCTs between 2009 and 2018 in order to identify predictors for long-term outcome in the whole population (242 patients) and for prolonged overall survival (OS) after relapse in the subgroup of relapsed patients (118 patients)., Results: At a median follow-up of 40.9 months after allo-SCT median OS and progression free survival (PFS) of the whole population were respectively 39.4 and 19.0 months from allo-SCT. The cumulative incidence (CI) of non-relapse mortality (NRM) was 10.3 % at one year and 27.6% at five years. Grade 2-4 acute GVHD CI was 19.8% and 5-year CI of moderate or severe chronic GVHD was 31.8%. In the multivariate model older age at transplant (p=0.020), treatment with more than 2 lines of therapy before allo-SCT (p=0.003) and transplant from unrelated or haploidentical donor (p=0.025) were significant factors associated with reduced OS. Relapse after allo-SCT occurred in 118 (59%) patients at a median of 14.3 months (IQR 7.2-26.9). Twenty (17%) received only steroids, radiotherapy or supportive care, 41 (35%) received 1 line, 23 (19%) 2 lines and 34 patients (29%) 3 or 4 lines of salvage treatment. Nine patients were exclusively treated with chemotherapy, 9 received at least one salvage treatment including immunomodulating agents (Imids), 43 patients were treated with at least one rescue therapy including proteasome inhibitors (PIs) and 37 patients received at least one salvage treatment including monoclonal antibodies (33 daratumumab, 1 elotuzumab, 1 isatuximab, 2 belantamab). Median OS of relapsed patients was 38.5 months from allo-SCT and 20.2 months from relapse. In multivariate analysis, OS after relapse was significantly prolonged in patients with a longer time to relapse after allo-SCT (time to relapse 6-24 months p=0.016; time to relapse ≥ 24 months p< 0.001) and in those who had received at least 3 salvage treatment lines (p<0.036) and donor lymphocyte infusions (DLI) (p=0.020)., Conclusions: In our study, patients transplanted in early phases of disease and with HLA identical sibling donors had the best chance of long-term survival. Late relapse after allo-SCT, multiple courses of salvage treatment and the association with DLI could allow long disease control in patients who experienced relapse after allo-SCT., Competing Interests: Declaration of competing interest All the authors declare that there are no potential conflicts of interest regarding the study., (Copyright © 2024. Published by Elsevier Inc.)

In the context of valorizing underutilized crops, this study investigated the starch and protein characteristics of chestnut varieties (Balestrera and Rossera) and their potential for use at 15% and 25% in reformulating gluten-free baked snacks and fresh pasta. Chestnut varieties differ in protein and starch content (Balestrera > Rossera), as well as in amylose, dietary fiber, and lipids (Balestrera < Rossera). Differences in starch and amylose content affected starch gelatinization (Balestrera < Rossera), pasting and retrogradation properties, and water absorption capacity at 90 °C (Balestrera > Rossera). No differences in water and oil absorption capacity and mixing properties were observed, neither in the protein profile nor in the nature of protein aggregates. Both varieties exhibited a good aptitude for producing gluten-free baked snacks and fresh pasta, even at enrichment levels of 25%. Overall, this study could provide valuable information for the development of gluten-free products using sustainable, underutilized crops.

Background: Access to allogeneic haematopoietic stem-cell transplantation (HSCT) remains challenging for older patients (aged >60 years) with acute myeloid leukaemia. We aimed to evaluate the efficacy of venetoclax plus decitabine as first-line therapy and bridge to transplantation in this patient population., Methods: This multicentre, single-arm, phase 2 trial was conducted in 20 Gruppo Italiano Trapianto Midollo Osseo (GITMO) centres in Italy. Patients aged ≥60 and <75 years, with newly diagnosed acute myeloid leukaemia categorised as intermediate or high risk according to 2016 WHO and 2017 European LeukemiaNet, an ECOG performance status of less than 2, and considered fit for allogeneic HSCT were included. Patients received oral venetoclax with a 3-day ramp-up: 100 mg on day 1, 200 mg on day 2, and 400 mg once per day from day 3 of cycle one, and then every 28 days of each cycle (two to four in total). Decitabine was administered intravenously at a dose of 20 mg/m 2 from days 1 to 5 every 28 days. At cycle one, patients were admitted to hospital for a minimum of 24 h, whereas subsequent cycles could be administered on an outpatient basis. Two additional cycles were allowed while waiting for allogeneic HSCT or for those with no response or partial response after cycle two. The primary endpoint was the proportion of patients who had allogeneic HSCT performed during first complete remission, assessed in all patients who received at least one dose of the study medication. This study was registered with ClinicalTrials.gov (NCT04476199, ongoing) and EudraCT (2020-002297-26)., Findings: Between June 1, 2021, and Dec 30, 2022, 93 patients were enrolled and started venetoclax plus decitabine induction (44 [47%] at intermediate risk and 49 [53%] at high risk). The median age was 68·5 (IQR 60·3-74·7). All 93 participants were White, of whom 43 (46%) were female and 50 (54%) were male. The median follow-up was 236 days (IQR 121-506). 64 (69%) of 93 patients reached complete remission and 53 (57%) underwent allogeneic HSCT in complete remission. 53 (83%) of 64 with a complete remission underwent allogeneic HSCT. Five (8%) of 64 patients in complete remission relapsed before transplantation and four died as a consequence. Adverse events (grade ≥3) occurred in 49 (53%) of 93 patients. The most common adverse events were infections (including pneumonia, bacterial sepsis, and SARS-CoV-2 causing seven deaths among 28 [57%] of 49 patients), neutropenia (17 [35%]), thrombocytopenia (two [4%], including one fatal CNS bleeding), and cardiac events (four [8%], including one fatal heart failure). No treatment-related deaths were observed., Interpretation: Venetoclax plus decitabine induction can significantly enhance the feasibility of allogeneic HSCT in older patients with acute myeloid leukaemia who are deemed fit for transplantation., Funding: AbbVie and Johnson & Johnson., Competing Interests: Declaration of interests DR received consulting fees from Medac; honoraria and travel grants from Jazz Pharma, Novartis, MSD, Kite Gilead, and Medac; and has participated in data safety monitoring and advisory board meetings for Novartis, MSD, Kite Gilead, Medac, AbbVie, and Janssen. EB received consulting fees from AbbVie; travel grants from Amgen, Novartis, and AbbVie; and has participated in data safety monitoring and advisory board meetings for Otsuka and Amgen. FO received honoraria from Takeda, Medac, and Kyowa; and travel grants from Roche, Janssen, Kyowa, Takeda, Jazz Pharma, and Medac. RS received a travel grant from Takeda. MaM received honoraria from Novartis, MSD, Astellas Pharma, AbbVie, Takeda, Pfizer, Sanofi, Jazz Pharma, Janssen Cilag, Kite Gilead, Medac, and Bristol Myers Squibb; travel grants from Kite Gilead, Roche, and Janssen Cilag; has participated in data safety monitoring and advisory board meetings for Novartis, Takeda, Kite Gilead, Pfizer, Bristol Myers Squibb, and Janssen Cilag; and served as president of GITMO. CA received honoraria from AbbVie and Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie, Jazz Pharma, and Amgen. GB received travel grants from Janssen Cilag and Amgen. AC received honoraria from AbbVie, Menarini (Stemline), Pfizer, Jazz Pharma, and Servier; a travel grant from Jazz Pharma; and has participated in data safety monitoring and advisory board meetings for AbbVie and Menarini (Stemline). CG received consulting fees from AbbVie, Jazz Pharma, Incyte, Bristol Myers Squibb, and Astellas; and a travel grant from Jazz Pharma. PM received honoraria and travel grants from AbbVie and Johnson & Johnson. LG received honoraria from Novartis, MSD, Gilead, AbbVie, Sanofi, and Bristol Myers Squibb; and travel grants from Janssen and AbbVie. CS received honoraria from Jazz Pharma and Kite Pharma; and a travel grant from Jazz Pharma. VR received travel grants from Neovii, Medac, and Jazz Pharma. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

During ovulation, the apical wall of the preovulatory follicle breaks down to facilitate gamete release. In parallel, the residual follicle wall differentiates into a progesterone-producing corpus luteum. Disruption of ovulation, whether through contraceptive intervention or infertility, has implications for women's health. In this study, we harness the power of an ex vivo ovulation model and machine-learning guided microdissection to identify differences between the ruptured and unruptured sides of the follicle wall. We demonstrate that the unruptured side exhibits clear markers of luteinization after ovulation while the ruptured side exhibits cell death signals. RNA-sequencing of individual follicle sides reveals 2099 differentially expressed genes (DEGs) between follicle sides without ovulation induction, and 1673 DEGs 12 h after induction of ovulation. Our model validates molecular patterns consistent with known ovulation biology even though this process occurs in the absence of the ovarian stroma, vasculature, and immune cells. We further identify previously unappreciated pathways including amino acid transport and Jag-Notch signaling on the ruptured side and glycolysis, metal ion processing, and IL-11 signaling on the unruptured side of the follicle. This study yields key insights into follicle-inherent, spatially-defined pathways that underlie follicle rupture, which may further understanding of ovulation physiology and advance women's health., (© 2024. The Author(s).)

Purpose: To build and validate a combined radiomics and machine learning (ML) approach using B-mode US and SWE images to differentiate benign from malignant solid breast lesions (BLs) and compare its performance with that of an expert radiologist., Methods: Patients with at least one BI-RADS 2-6 BL who performed breast US integrated with SWE were retrospectively included. B-mode US and SWE images were manually segmented to extract radiomics features. A multi-step feature selection process was performed and a predictive model built using the Logistic Regression algorithm. The diagnostic accuracy was evaluated with the AUC and Matthews Correlation Coefficient (MCC) metrics. The performance of the ML classifier was compared to that of an expert radiologist., Results: 427 Bls were included and divided into a training (286 BLs, of which 127 benign and 159 malignant) and a test set (141 BLs, of which 59 benign and 82 malignant). Of 1098 features extracted from B-mode US and SWE images, 13 were finally selected. The ML classifier showed an AUC of 0.768 and 0.746, and an MCC of 0.403 and 0.423 in the training and test sets, respectively. The performance was higher than that of the expert radiologist assessing only B-mode US images, but significantly lower when SWE images were also provided., Conclusion: A ML approach based on B-mode US and SWE images may represent a potential tool in the characterization of BLs. SWE still gives its most relevant contribution in the clinical setting rather than included in a radiomics pipeline., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To date, there are no biomarkers that define a patient subpopulation responsive to bevacizumab (BEV), an effective treatment option for advanced ovarian carcinoma (OC). In the context of the MITO16A/MaNGO OV-2 trial, a Phase IV study of chemotherapy combined with BEV in first-line treatment of advanced OC, we evaluated TP53 mutations by next-generation sequencing and p53 expression by immunohistochemistry (IHC) on 202 and 311 cases, respectively. We further correlated TP53 mutations in terms of type, function, and site, and IHC data with patients' clinicopathological characteristics and survival. TP53 missense mutations of unknown function (named unclassified) represented the majority of variants in our population (44.4%) and were associated with a significantly improved overall survival (OS) both in univariable (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.20-0.92, p = .03) and multivariable analysis (HR = 0.39, 95% CI = 0.18-0.86, p = .02). Concordance between TP53 mutational analysis and IHC was 91%. We observed an HR of 0.70 for OS in patients with p53 IHC overexpression compared to p53 wild-type, which however did not reach statistical significance (p = .31, 95% CI = 0.36-1.38). Our results indicate that the presence of unclassified TP53 mutations has favorable prognostic significance in patients with OC receiving upfront BEV plus chemotherapy. In particular, unclassified missense TP53 mutations characterize a subpopulation of patients with a significant survival advantage, independently of clinicopathological characteristics. Our findings warrant future investigations to confirm the prognostic impact of TP53 mutations in BEV-treated OC patients and deserve to be assessed for their potential predictive role in future randomized clinical studies., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Scope: Inflorescences of the female hop plant (Humulus lupulus L.) contain biologically active compounds, most of which have a bitter taste. Given the rising global obesity rates, there is much increasing interest in bitter taste receptors (TAS2Rs). Intestinal TAS2Rs can have beneficial effects on obesity when activated by bitter agonists. This study aims to investigate the mechanism of action of a hydroalcoholic hop extract in promoting hormone secretion that reduces the sense of hunger at the intestinal level through the interaction with TAS2Rs., Methods and Results: The results demonstrate that the hop extract is a rich source of bitter compounds (mainly α-, β-acids) that stimulate the secretion of anorexigenic peptides (glucagon-like peptide 1 [GLP-1], cholecystokinin [CCK]) in a calcium-dependent manner while reducing levels of hunger-related hormones like ghrelin. This effect is mediated through interaction with TAS2Rs, particularly Tas2r138 and Tas2r120, and through the activation of downstream signaling cascades. Knockdown of these receptors using siRNA transfection and inhibition of Trpm5, Plcβ-2, and other calcium channels significantly reduces the hop-induced calcium response as well as GLP-1 and CCK secretion., Conclusions: This study provides a potential application of H. lupulus extract for the formulation of food supplements with satiating activity capable of preventing or combating obesity., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Purpose: Radiotherapy (RT) plays a crucial role in head and neck (HN) cancer treatment. Nevertheless, it can lead to serious and challenging adverse events such as osteoradionecrosis (ORN). A preclinical rabbit model of irradiated bone and ORN is herein proposed, with the aim to develop a viable model to be exploited for investigating new therapeutic approaches., Methods: Nine New Zealand white rabbits were irradiated using a single beam positioned to the left of the mandible and directed perpendicular to the left mandible. A 10 × 10 mm 2 region of interest (ROI) located below the first molar tooth on the left side was identified and irradiated with 7 Gy each fraction, once every 2 days, for five fractions. Dose distributions demonstrated that the corresponding ROI on the contralateral (right) mandibular side received approximately 5 Gy each fraction, thus bilateral irradiation of the mandible was achieved. ROIs were categorized as ROI H on the left side receiving the high dose and ROI L on the right side receiving the low dose. Rabbits were followed up clinically and imaged monthly. After 4 months, the irradiated bone was excised, and histological examination of ROIs was performed., Results: Radiological signs suggestive for ORN were detected in the entire population (100%) 16 weeks after irradiation on ROI H , which consisted of cortical erosion and loss of trabeculae. ROI L did not show any radiological evidence of bone damage. Histologically, both sides showed comparable signs of injury, with marked reduction in osteocyte count and increase in empty lacunae count., Conclusions: A preclinical double model was successfully developed. The side receiving the higher dose showed radiological and histological signs of bone damage, resulting in an ORN model. Whereas the contralateral side, receiving the lower dose, presented with histological damage only and a normal radiological appearance. This work describes the creation of a double model, an ORN and irradiated bone model, for further study using this animal species., (Head & Neck© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Introduction and Importance: Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue tumor which generally affects people from the second to the fifth decades of life, with the same incidence in both sexes. DFSP can appear as a slow-growing, flesh-colored or erythematous plaque or nodule, often becoming protuberant if untreated., Case Presentation: We report two cases of DFSP. The first case regards a 22-year-old woman with a 1.5-centimeter, mobile nodule of hard-elastic consistency in the left breast initially suspected to be a sebaceous cyst. Ultrasound and MRI suggested benign features, but histopathological examination post-excision confirmed DFSP. The second patient come to our attention is a 54-year-old woman with a 6 mm erythematous lump in the right breast, which reached 22 mm after two years. Mammography and histological examination post-excision confirmed DFSP. Both patients underwent to wide local excision and after four years of follow-up no recurrence or complications are observed., Clinical Discussion: DFSP is a soft tissue sarcoma with low metastatic potential but requires early diagnosis and surgical excision to avoid malignant transformation. There are no standardized guidelines for its diagnosis and treatment. Imaging techniques, including ultrasound, CT, and MRI, are crucial to define tumor extension and planning surgical intervention. Surgical excision with clear margins is the primary treatment, but there are also emerging treatments as Mohs micrographic surgery or Imatinib Mesylate therapy for unresectable cases., Conclusion: Our cases highlight the importance of an accurate diagnostic evaluation and effective surgical management to achieve favorable outcomes., Competing Interests: Conflict of interest statement The authors declare no conflict of interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Oral mucositis (OM) is considered one of the most common side effects of patients undergoing cancer therapy. OM prevention plays a crucial role in the effectiveness of cancer treatment and the patient's quality of life. Different preventive treatments have been proposed in clinical trials, however with inconclusive results., Materials and Methods: A systematic review search was conducted in PubMed, Scopus, Web of Science, and Cochrane Database to answer the PICO question: in cancer patients, do specific topical agents compared to standard treatments or placebo reduce the onset and severity of oral mucositis? The risk of bias was assessed, and a network meta-analysis was conducted., Results: Of 2913 results, 30 randomized clinical trials were considered suitable for inclusion. A total of 2564 patients were analyzed, of which 1284 belonged to the test group and 1280 belonged to the control group. Natural products were the most used, followed mainly by antimicrobial agents, coating agents, and basic oral care measures. Topical sucralfate resulted in the most powerful intervention for the OM prevention (OR = 0.04, 95%C.I. = 0.01-0.25, p-value = 0.001)., Conclusion: Due to its cytoprotective action, low cost, ease of administration, and safety, sucralfate could become a potential ally to prevent the onset of OM during cancer therapy., (© 2024 Wiley Periodicals LLC.)

Purpose: MITO-RT3/RAD (NCT04593381) is a prospective multicenter phase 2 trial designed to assess the effectiveness and safety of stereotactic body radiation therapy (SBRT) in patients who received diagnoses of oligometastatic ovarian cancer. In this report, we provide the results of the trial in the setting of lymph node disease., Methods and Materials: The primary endpoint was the complete response (CR) rate, secondary endpoints included local control (LC), progression-free survival (PFS), overall survival, treatment-free interval, and toxicity rates. The sample size was based on a previous study reporting an average 70.0% CR with SBRT. The study was powered to detect an improvement in the CR rate from 70.0% to 85.0%, with an α error of 0.05 (one-side) and a β error of 0.1., Results: The study met its primary endpoint of a statistically significant improvement in CR. One hundred thirty-five patients with 249 lesions were enrolled across 15 institutions from May 2019 to November 2023. CRs were observed in 194 lesions (77.9%), partial responses in 40 (16.1%), stable disease in 14 (5.6%), and progressive disease in 1 lesion (0.4%). The objective response rate was 94%, with an overall clinical benefit rate of 99.6%. CR lesions exhibited a significantly higher LC rate than partial or not responding lesions (12-month LC: 92.7% vs 63.1%, P < .001). The 12-month actuarial rates for PFS and for overall survival were 36.6% (CR, 38.3% vs not-CR, 18.8%; P, .022) and 97.2% (CR, 97.8% vs not-CR, 93.8%; P, .067), respectively. The 12-month actuarial rate for treatment-free interval was 52.7% (CR, 58.4% vs not-CR, 24.4%; P, .004). CR was substantially associated with higher PFS (P, .036) and treatment-free interval (P, .006) rates in the univariate analysis. Twenty-three patients (17.0%) experienced mild acute toxicity. Late toxicity was reported in 9 patients (6.7%), mostly grade 1., Conclusions: This trial confirms the efficacy of ablative SBRT, with minimal toxicity observed. SBRT offered a high CR rate, promising long-term outcomes, and a significant systemic therapy-free survival period for complete responders., (Copyright © 2024 Elsevier Inc. All rights reserved.)

From a circular bio-economy perspective, biomass valorization requires the implementation of increasingly efficient extraction techniques to ensure the environmental and economic sustainability of biorefining processes. This research focuses on optimizing the specialized metabolite extraction of Turkey oak chips from Quercus cerris L. by applying a 3 levels Full Factorial Design (FFD). The goal is to obtain an extract with the highest antioxidant activity [evaluated by 1,1-diphenyl-2-picryl hydrazyl (DPPH) scavenging activity and ferric reducing antioxidant power (FRAP) assays] and specialized metabolites content [measured as total phenolic content (TPC), total flavonoid content (TFC), condensed tannin content (CTC), and hydrolysable tannins content (THC)]. With this objective, three different variables were investigated and compared: temperature (20 °C, 50 °C, 80 °C), solvents EtOH/H 2 O (0%, 20%, 40%), and time (3 h, 6 h, 24 h), resulting in 27 different extracts. Following the FFD analysis, the optimal extractive conditions were determined to be 80 °C, 40% EtOH/H 2 O, and 19.8 h. Finally, the prediction ability of FFD was compared with that of artificial neural network (ANN) for DPPH scavenging activity, FRAP, and TPC data based on the coefficient of determination (R 2 ), mean absolute error (MAE), and root mean square error (RMSE). The results indicated that ANN predictions were more precise than FFD ones; however, both methods were useful in optimizing the extraction process as they returned comparable optimized extraction parameters.

Purpose: The aim of this observational, retrospective, multicenter study (Epimetheo) was to analyze the activity and the safety of stereotactic body radiation therapy (SBRT) during poly(ADP-ribose)-polymerase inhibitor (PARPi) maintenance in a series of oligometastatic ovarian cancer (OC) patients., Methods and Materials: Patients treated with PARPi in maintenance setting received SBRT if oligometastatic progression occurred. Maintenance treatment was continued until the extensive progression of the disease. The primary endpoints of the study were as follows: next systemic treatment change-free survival (NEST-FS) and acute and late toxicity; the secondary endpoints were as follows: the rate of clinical complete response (CR), the 2-year actuarial local control (LC, progression of disease inside SBRT field) rate on "per lesion" basis, the 2-year actuarial progression-free survival, and 2-year overall survival (OS)., Results: From April 2018 to September 2023, SBRT was used to treat 74 OC patients with a total of 158 lesions (98 lymph nodes and 60 parenchymal lesions) under PARPi maintenance. Olaparib, niraparib, and rucaparib were administered to 41.9%, 48.6%, and 9.5% of patients, respectively. CR, partial response, stable disease, and progressive disease were observed in 115 (72.8%), 32 (20.3%), 9 (5.7%), and 2 lesions (1.3%), respectively. Severe toxicities were reported in less than 3% of patients. The actuarial median NEST-FS was 10 months, with a range of 6.7-13.3 months. The 12- and 24-month actuarial NEST-FS rates were 44.9% and 31.4%, respectively. The 2-year actuarial LC, progression-free survival, and OS were 68.1%, 22.5%, and 77%, respectively with differences in figures between complete and incomplete responders. The achievement of CR was found to be correlated with an improvement in LC and OS., Conclusions: This study reports the activity and the low toxicity profile of SBRT in association with PARPi in oligometastatic OC patients. A rapid, minimally invasive, and cost-effective treatment such as SBRT may be proposed as a means of prolonging NEST-FS and maintaining an effective treatment regimen involving PARPi., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: Primary ciliary dyskinesia (PCD) is a respiratory disorder that impairs mucociliary clearance, leading to decreased lung function. Conventional chest physiotherapy (CCP) is the traditional airway clearance technique (ACT) and is considered a standard treatment for PCD patients. This systematic review investigated whether device supported ACTs are better alternatives for improving lung function and/or quality of life in PCD, compared with CCP., Methods: The OVID Medline, PubMed, CINAHL, and Cochrane databases were searched. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and the Grading of Recommendations, Assessment, Development, and Evaluation approach was used to aggregate the data. This systematic review has been registered on the International Prospective Register of Systematic Reviews website., Results: Of the 389 citations that resulted from our literature search, 2 randomized crossover trials that included a total of 54 patients were analyzed. The certainty of the aggregated study evidence was very low. No difference was identified between device-supported ACTs and CCP in terms of forced vital capacity and forced expiratory volume in 1 second in PCD patients aged 6 to 20 years., Conclusion: Device-supported ACTs could be considered alternative treatment options to replace CCP. High quality research is required to confirm this result.

We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40-65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches., (© 2024. The Author(s).)

Exhausted olive pomace (EOP) represents the principal residue of olive pomace. Several studies have optimized the extraction of specialized metabolites from the EOP of Olea europaea L., but a comparison between different extractive methods has not been made. For this reason, the present investigation aims to compare four different extractive methods by using water and 15% ethanol/water as extractive solvents. Specifically, based on extract antioxidant activity, the methods compared were maceration (MAC), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), and Accelerated Solvent Extraction (ASE). Between these, the UAE and ASE hydroalcoholic EOP extracts were demonstrated to have the highest antioxidant activity. Subsequently, these extracts were investigated for their hypoglycemic and antiradical activity using in vitro cell-free and cell-based assays, respectively. ASE hydroalcoholic EOP extract demonstrated the greatest ability to inhibit the α-amylase enzyme and an in vitro antioxidant activity comparable to N-acetyl cysteine in HepG2 cells. UAE and ASE extracts' phytochemical characterization was also performed, identifying seven phenolic compounds, including 3-hydroxytyrosol, tyrosol, and, for the first time, salidroside. The ASE hydroalcoholic EOP extract was the richest from a phytochemical point of view, thus confirming its major biological activity. Therefore, ASE and 15% ethanol/water may represent the best extractive method for EOP nutraceutical valorization.

With the advancement of artificial intelligence(AI), platforms like ChatGPT have gained traction in different fields, including Medicine. This study aims to evaluate the potential of ChatGPT in addressing questions related to HIV prevention and to assess its accuracy, completeness, and inclusivity. A team consisting of 15 physicians, six members from HIV communities, and three experts in gender and queer studies designed an assessment of ChatGPT. Queries were categorized into five thematic groups: general HIV information, behaviors increasing HIV acquisition risk, HIV and pregnancy, HIV testing, and the prophylaxis use. A team of medical doctors was in charge of developing questions to be submitted to ChatGPT. The other members critically assessed the generated responses regarding level of expertise, accuracy, completeness, and inclusivity. The median accuracy score was 5.5 out of 6, with 88.4% of responses achieving a score ≥ 5. Completeness had a median of 3 out of 3, while the median for inclusivity was 2 out of 3. Some thematic groups, like behaviors associated with HIV transmission and prophylaxis, exhibited higher accuracy, indicating variable performance across different topics. Issues of inclusivity were identified, notably the use of outdated terms and a lack of representation for some communities. ChatGPT demonstrates significant potential in providing accurate information on HIV-related topics. However, while responses were often scientifically accurate, they sometimes lacked the socio-political context and inclusivity essential for effective health communication. This underlines the importance of aligning AI-driven platforms with contemporary health communication strategies and ensuring the balance of accuracy and inclusivity., (© 2024. The Author(s).)

Objective: Agenesis of the maxillary permanent lateral incisors is a condition that requires treatment aimed at improving the esthetics, even at an early age. However, traditional therapeutic protocols are long, invasive and have limitations and contraindications imposed by the age of the patient., Clinical Considerations: Recent developments in restorative dentistry have provided a new approach to this clinical situation, in particular when the deciduous laterals are retained. We report two cases regarding the management of missing lateral incisors using Biologically Active Intrasulcular Restoration (BAIR) technique. The BAIR technique allows us to transform the shape of the deciduous lateral incisor into the permanent, acting both on the dental morphology and proportions, and on the appearance of the soft tissues and the gingival parables., Conclusions: The BAIR technique is a valid approach to cases of agenesis of the maxillary permanent lateral incisors, when the deciduous are retained. It does not require any preparation of the dental tissues, is reversible and minimally invasive. It is applicable to patients of all ages, and results are obtained in a single appointment., Clinical Significance: The BAIR technique allows a biomimetic conservative approach for the rehabilitation of congenitally missing permanent lateral incisors, when the deciduous are retained. It is a non-invasive protocol and effective in successfully restoring esthetics., (© 2024 Wiley Periodicals LLC.)

Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core-shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin-chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration., Competing Interests: The authors declare no conflicts of interest.

Although many college students intend to major in Science, Technology, Engineering, and Mathematics (STEM), dropout from these fields is high, especially among members of historically underrepresented groups, such as women and racial-ethnic minorities. We propose a minimal, yet potentially powerful intervention to broaden participation in STEM: giving positive feedback to students in STEM. Studies 1 and 2 found that giving positive feedback is less normative in math (vs. English) courses, and instructors' feedback-giving practices and students' experiences mirror these norms. However, students who received positive (vs. only objective) feedback on introductory-level college calculus exams showed greater belonging and self-efficacy in math, which predicted better STEM outcomes (i.e., increased interest in STEM and higher final math course grades, respectively, Study 3). These findings were especially strong for racial-ethnic minority students. Giving positive (vs. only objective) feedback is thus a potentially transformative tool that boosts student outcomes, especially for underrepresented groups., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Several novel multiport robotic systems have been developed and introduced in clinical practice after regulatory approval. The objective of this systematic review was to assess the evolution status of novel robotic platforms approved for clinical use in urological surgery according to the IDEAL framework., Methods: A systematic review was conducted using the Medline and Scopus databases according to the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (CRD42024503227). Comparative or noncomparative studies reporting on any urological procedures performed with novel robotic platforms (Hugo RAS; Versius, KangDuo, Senhance, REVO-I, Avatera, Hinotori, Dexter, or Toumai) were selected and included in the analysis., Key Findings and Limitations: Seventy-four eligible studies were included, of which 67 (90.5%) were noncomparative surgical series representing developmental or explorative studies according to the IDEAL criteria. Only one randomised controlled trial (comparing KangDuo vs da Vinci robot-assisted partial nephrectomy) was included. The trial showed comparable perioperative outcomes between the two robotic systems. Four studies assessed clinical outcomes for patients undergoing urological procedures using a REVO-I (1 study), Senhance (2 studies), or Hinotori (1 study) system in comparison to the same procedures performed using a da Vinci system. All studies revealed outcomes comparable to those with the da Vinci system. Limitations include the small sample size in all studies, and assessment of first-generation novel platforms versus the fourth-generation multiarm da Vinci system in most of the comparative studies., Conclusions and Clinical Implications: A few poor-quality studies have compared the use of novel robotic platforms to da Vinci systems in urological surgery and demonstrated comparable results. Most studies can be classified as developmental or explorative, representing the initial steps of clinical research. Large multicentre series are needed to understand whether these novel robots could offer advantages beyond cost reductions over the da Vinci systems., Patient Summary: We reviewed research on new robotic systems for surgery in urology. Several studies have shown the feasibility and safety of these new robots during the most common procedures. Very few studies have assessed clinical outcomes with the new robots in comparison to the reference standard, which is a fourth-generation da Vinci robot. Large multicentre studies are needed to understand whether the new robots could offer advantages other than cost savings over the da Vinci robot., (© 2024 The Authors.)

Background: According to Centers for Medicare and Medicaid Services HHS 2017, when a medical disease suddenly manifests itself with acute symptoms of sufficient intensity (including extreme pain) endangering the patient's health, seriously impairing body functions or bringing an organ or its portion to be seriously dysfunctional, a medical emergency has occurred. Therefore, this study aimed to assess the knowledge, attitude, and perceived confidence in handling medical emergencies among dental students by the means of conducting this investigation., Methods: This is a cross-sectional study conducted among the different hierarchies of dentists of Riyadh using an online survey; 387 dentists from varying clinical levels (9 to 12) were included in this study. The questionnaire used for this study consisted of questions related to demographic data followed by questions including knowledge, attitude, and confidence towards handling medical emergencies in clinics., Results: In this study, male participants represented 64.4% and female subjects represented 35.6% of the total population. Most of the undergraduates were in their 5 th year of dentistry school and accounted for 36.9%, followed by 6 th year 36.2% and 4 th year 26.8%. 67.1% of the undergraduates never encountered any medical emergency during their study, while 32.9% encountered an emergency. Furthermore, 58.4% of the analyzed subjects recorded medical history thoroughly, while priority in an emergency was adrenaline, with a percentage of 45%. For the patient suffering syncope the Trendelenburg position was chosen. Also, the first action choice with unresponsive patients was CPR., Conclusions: In the present study, the findings revealed that the majority of the population never encountered an emergency in their career, but their knowledge about drug priority and patient's position was good. Most of them do not measure vital signs routinely; specifically, females do not usually measure, while males measure when needed. About Basic Life Support (BLS), participants took BLS or were interested in taking it in the future; furthermore, in group population, both have taken it and are interested in further carrying it.

Background: Reconstruction of mandibular bone defects is a surgical challenge, and microvascular reconstruction is the current gold standard. The field of tissue bioengineering has been providing an increasing number of alternative strategies for bone reconstruction. Methods: In this preclinical study, the performance of two bioengineered scaffolds, a hydrogel made of polyethylene glycol-chitosan (HyCh) and a hybrid core-shell combination of poly (L-lactic acid)/poly ( ε -caprolactone) and HyCh (PLA-PCL-HyCh), seeded with different concentrations of human mesenchymal stromal cells (hMSCs), has been explored in non-critical size mandibular defects in a rabbit model. The bone regenerative properties of the bioengineered scaffolds were analyzed by in vivo radiological examinations and ex vivo radiological, histomorphological, and immunohistochemical analyses. Results: The relative density increase (RDI) was significantly more pronounced in defects where a scaffold was placed, particularly if seeded with hMSCs. The immunohistochemical profile showed significantly higher expression of both VEGF-A and osteopontin in defects reconstructed with scaffolds. Native microarchitectural characteristics were not demonstrated in any experimental group. Conclusion: Herein, we demonstrate that bone regeneration can be boosted by scaffold- and seeded scaffold-reconstruction, achieving, respectively, 50% and 70% restoration of presurgical bone density in 120 days, compared to 40% restoration seen in spontaneous regeneration. Although optimization of the regenerative performance is needed, these results will help to establish a baseline reference for future experiments., Competing Interests: Some of the following authors (LS, DR, SP, PN, MF, RG, and JI) declare the present patents, but declare no other financial or non-financial competing interests: LS, DR., SP, PN, MF, RG, JI “Integrated core-shell bioactive structure for the regeneration of bone and osteochondral tissues” licensed to PCT: WO2022009126 (2022); priority IT20200016579 (2020). LS, DR, PG, KD, Salmeron-Sanchez M., Borsani E. “Tridimensional bioactive porous body for bone tissue regeneration and process for its preparation “licensed to ”PCT: WO2022009125 (2022); priority: IT20200016576 (2020). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ferrari, Taboni, Chan, Townson, Gualtieri, Franz, Ruaro, Mathews, Daly, Douglas, Eu, Sahovaler, Muhanna, Ventura, Dey, Pandini, Pasini, Re, Bernardi, Bosio, Mattavelli, Doglietto, Joshi, Gilbert, Nicolai, Viswanathan, Sartore, Russo and Irish.)

Studying hybrid zones that form between morphologically cryptic taxa offers valuable insights into the mechanisms of cryptic speciation and the evolution of reproductive barriers. Although hybrid zones have long been the focus of evolutionary studies, the awareness of cryptic hybrid zones increased recently due to rapidly growing evidence of biological diversity lacking obvious phenotypic differentiation. The characterization of cryptic hybrid zones with genome-wide analysis is in its early stages and offers new perspectives for studying population admixture and thus the impact of gene flow. In this study, we investigate the population genomics of the Myotis nattereri complex in one of its secondary contact zones, where a putative hybrid zone is formed between two of its cryptic lineages. By utilizing a whole-genome shotgun sequencing approach, we aim to characterize this cryptic hybrid zone in detail. Demographic analysis suggests that the cryptic lineages diverged during the Pliocene, c. 3.6 million years ago. Despite this ancient separation, the populations in the contact zone exhibit mitochondrial introgression and a considerable amount of mixing in nuclear genomes. The genomic structure of the populations corresponds to geographic locations and the genomic admixture changes along a geographic gradient. These findings suggest that there is no effective hybridization barrier between both lineages, nevertheless, their population structure is shaped by dispersal barriers. Our findings highlight how such deeply diverged cryptic lineages can still readily hybridize in secondary contact., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Background: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor., Patients and Methods: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab., Results: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002)., Conclusion: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Homologous Recombination Deficiency (HRD) status predicts response to treatment with poly(ADP-ribose) polymerase inhibitors in Ovarian Cancer (OC) patients. The Myriad myChoiceCDx Assay is approved by Food and Drug Agency for the HRD assessment. Here we compared the HRD status obtained by three commercial panels with the results from Myriad reference test., Methods: The HRD analysis was performed on DNA from formalin-fixed and paraffin-embedded tumor samples of 100 untreated OC patients for which Myriad assay results were available, using TruSight Oncology 500 HRD assay (Illumina), Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific) and SOPHiA DDM HRD solution panel (SOPHiA Genetics)., Results: A good overall concordance with the reference method was demonstrated at three different levels: BRCA mutational status (from 94.4 % to 97.7 %), the genomic instability value (from 88.2 % to 95.3 %) and for the HRD status (from 90.4 % to 97.6 %). Moreover, a trend in favour of HRD positive patients for response rate, progression-free survival and overall survival similar to Myriad was observed for all three tests., Discussion: Our data suggest the feasibility of commercial testing for assessing HRD status, with a good concordance with the reference method and association with clinical outcome., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nicola Normanno declares: speaker’s fee and/or advisory boards from MSD, Bayer, Biocartis, Illumina, Incyte, Roche, BMS, Merck, Thermofisher, AstraZeneca, Eli Lilly; financial support to research projects (institutional grants) from Merck, Thermofisher, QIAGEN, Roche, AstraZeneca, Biocartis, Illumina; non-financial interests President of the International Quality Network for Pathology (IQN Path) and Past President of the Italian Cancer Society (SIC). Domenica Lorusso declares: Astrazeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, Oncoinvest, Pharmamar, Roche, Seagen, Sutro, Francesco Perrone declares: institutional grants or contracts from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GSK, Merck; consulting fees from Bayer, Pierre Fabre, Astra Zeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; leadership in scientific society: President of AIOM 2023–2025. Sandro Pignata has received honoraria from Roche, MSD, AZ, GSK, and Novartis. Cristin Roma, Riziero Esposito Abate, Alessandra Sacco, Daniela Califano, Laura Arenare, Francesca Bergantino, Carmela Pisano, Sabrina Chiara Cecere, Giovanni Scambia, Grazia Artioli, Giulia Tasca, Anna Spina, Daniela Russo, Angiolo Gadducci, Carmine De Angelis, Alessandra Bologna, Sergio Marchini and Ettore Domenico Capoluongo have no conflict of interests., (Copyright © 2024. Published by Elsevier Ltd.)

Motivated by the enormous potential of hydrogels in regenerative medicine, new biocompatible gelatin-based hybrid hydrogels were developed through a green process using poly(ethylene glycol) diglycidyl ether as a cross-linking agent, adding carrageenan and chitosan polysaccharides to the network to better mimic the hybrid composition of native extracellular matrix. Overall, the hydrogels show suitable structural stability, high porosity and pore interconnectivity, good swellability, and finally, biocompatibility. Their mechanical behavior, investigated by tensile and compression tests, appears to be characterized by nonlinear elasticity with high compliance values, fast stress-relaxation, and good strain reversibility with no sign of mechanical failure for compressive loading-unloading cycles at relatively high deformation levels of 50%. Degradation tests confirm the hydrogel bioresorbability by gradual hydrolysis, during which the structural integrity of both materials is maintained, while their mechanical behavior becomes more and more compliant. Human Umbilical Cord-derived Mesenchymal Stem Cells (hUC-MSCs) were used to test the hydrogels as potential carriers for cell delivery in tissue engineering. hUC-MSCs cultured inside the hydrogels show a homogenous distribution and maintain their growth and viability for at least 21 days of culture, with an increasing proliferation trend. Hence, this study contributes to a further understanding of the potential use of hybrid hydrogels and hUC-MSCs for a wide range of biomedical applications, particularly in soft tissue engineering.

Objectives: Previous in vitro studies determined the whitening effects of bleaching products on stained resin composite surfaces. This in vitro study aimed to verify the effectiveness of a whitening system on composite resin previously subjected to pigmentation, specifically examining the depth of whitening effectiveness within the material structure., Materials and Methods: A commercially available nano-filled composite resin was used. Specimens were stained using a coffee-based solution and a 10% carbamide peroxide-based gel was employed as the whitening agent. The pigment's penetration and the effect of the bleaching gel were evaluated by measuring color (CieLab values) from the outer edge to the inner part of the specimens. Color measurements were taken at 14 points, starting from 0.1 mm from the external perimeter up to 3.0 mm., Results: Analysis of variance tests showed a statistically significant difference between the Control Group (CG), Pigmentation Group, and Whitening Group. The whitening agent was effective up to 1.5 mm in depth, with Whiteness index (W) values not statistically different from those of CG up to 0.5 mm in depth., Conclusions: Whitening agents on nano-filled resin composite previously pigmented appear effective in restoring the W to values similar to the original, particularly in the superficial layers of the sample., Competing Interests: Conflict of Interest: No potential conflict of interest relevant to this article was reported., (Copyright © 2024. The Korean Academy of Conservative Dentistry.)

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation., (© 2024. The Author(s).)

Breast cancers (BCs) are solid tumors composed of heterogeneous tissues consisting of cancer cells and an ever-changing tumor microenvironment (TME). The TME includes, among other non-cancer cell types, immune cells influencing the immune context of cancer tissues. In particular, the cross talk of immune cells and their interactions with cancer cells dramatically influence BC dissemination, immunoediting, and the outcomes of cancer therapies. Tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) represent prominent immune cell populations of breast TMEs, and they have important roles in cancer immunoescape and dissemination. Therefore, in this article we review the features of TILs, TAMs, and MDSCs in BCs. Moreover, we highlight the mechanisms by which these immune cells remodel the immune TME and lead to breast cancer metastasis.

The conjugation of proteins with polymers offers immense biotechnological potential by creating novel macromolecules. This article presents experimental findings on the structural properties of maltose-binding protein (MBP) conjugated with linear biodegradable polyphosphoester polymers with different molecular weights. We studied isotopic effects on both proteins and polymers. Circular dichroism and fluorescence spectroscopy and small-angle neutron scattering reveal that the conjugation process destabilizes the protein, affecting the secondary more than the tertiary structure, even at room temperature, and that the presence of two domains in the MBP may contribute to its observed instability. Notably, unfolding temperatures differ between native MBP and the conjugates. In particular, this study sheds light on the complex interplay of factors such as the deuteration influencing protein stability and conformational changes in the conjugation processes. The perdeuteration influences the hydrogen bond network and hydrophobic interactions in the case of the MBP protein. The perdeuteration of the protein influences the hydrogen bond network and hydrophobic interactions. This is evident in the decreased thermal stability of deuterated MBP protein, in the conjugate, especially with high-molecular-mass polymers., (© 2024 The Protein Society.)

Background: Mobile phone applications (apps) can potentially enhance patient care as they are easy to use and offer multifunctions. In 2019, 305 orthodontic apps were documented, many of which were patient-focused; however, there was little information on how popular these applications are with orthodontic patients. The main aim of this study was to evaluate how well patients were now aware of orthodontic applications., Methods: A survey asking 700 orthodontic patients about their knowledge of, access to, and use of orthodontic apps to facilitate their treatment resulted in 615 responses., Results: The results showed that a smartphone was owned by 96% of patients. Apple (Apple Inc., Cupertino, CA, USA) was the most used platform, followed by Android (Google LLC, Mountain View, CA, USA). Seventy-five percent of patients have previously used social media to research information, with YouTube (YouTube, San Mateo, CA, USA) being the most popular site. Only 3% of patients knew that applications were available to aid with orthodontic therapy and 12 patients had utilized an app linked to orthodontics. Nevertheless, 88% of patients said they would be open to using an app to supplement their treatment., Conclusions: Although 88% of patients said they would be prepared to use an app to help with orthodontic treatment, there is currently a low level of knowledge of the existence of apps. Given the availability of applications geared toward those patients, it is necessary to evaluate these apps' quality and, when critical, direct patients toward high-quality, efficient apps.

Patterned hair loss (PHL) or androgenetic alopecia is a condition affecting about 50% of people worldwide. Several pharmacological medications have been developed over the years, but few studies have investigated their effectiveness. Therefore, new, safer and more effective strategies are required. Recent investigations showed that Annurca apple extract application could induce keratin production and promote hair growth thanks to the high amount of procyanidin B2 contained in. Hence, this study aimed to investigate the role of an Annurca apple extract in preventing PHL by testing it on human follicle dermal papilla cells (HFDPCs) for the first time. Treatment of HFDPCs with Annurca apple extract counteracted intracellular reactive oxygen species accumulation by increasing the activity of antioxidant enzymes such as superoxide dismutase 2 and catalase. Furthermore, treatment with Annurca apple extract increased β-catenin and fibroblast growth factor 2, which are involved in hair growth stimulation. These data suggest that Annurca apple extract may be a potential therapeutically useful nutraceutical product for preventing or treating hair loss by reducing oxidative stress and inducing the expression of hair growth-related factors., (© 2024 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a rare but potentially fatal complication following allogenic hematopoietic cell transplantation (allo-HCT). Timely identification of SOS/VOD to allow for prompt treatment is critical, but identifying a VOD-predictive biomarker remains challenging. Given the pivotal role of endothelial dysfunction in SOS/VOD pathophysiology, the CECinVOD study prospectively evaluated levels of circulating endothelial cells (CECs) in patients undergoing allo-HCT with a myeloablative conditioning (MAC) regimen to investigate the potential of CEC level in predicting and diagnosing SOS/VOD. A total of 150 patients from 11 Italian bone marrow transplantation units were enrolled. All participants were age >18 years and received a MAC regimen, putting them at elevated risk of developing SOS/VOD. Overall, 6 cases of SOS/VOD (4%) were recorded. CECs were detected using the Food and Drug Administration-approved CellSearch system, an immunomagnetic selection-based platform incorporating ferrofluid nanoparticles and fluorescent-labeled antibodies, and were defined as CD146+, CD105+, DAPI+, or CD45-. Blood samples were collected at the following time points: before (T0) and at the end of conditioning treatment (T1), at neutrophil engraftment (T2), and at 7 to 10 days postengraftment (T3). For patients who developed VOD, additional samples were collected at any suspected or proven VOD onset (T4) and weekly during defibrotide treatment (T5 to T8). A baseline CEC count >17/mL was associated with an elevated risk of SOS/VOD (P = .04), along with bilirubin level >1.5 mg/mL and a haploidentical donor hematopoietic stem cell source. Postconditioning regimen (T1) CEC levels were elevated (P = .02), and levels were further increased at engraftment (P < .0001). Additionally, patients developing SOS/VOD after engraftment, especially those with late-onset SOS/VOD, showed a markedly higher relative increase (>150%) in CEC count. Multivariate analysis supported these findings, along with a high Endothelial Activation and Stress Index (EASIX) score at engraftment (T2). Finally, CEC kinetics corresponded with defibrotide treatment. After the start of therapy (T4), CEC levels showed an initial increase in the first week (T5), followed by a progressive decrease during VOD treatment (T6 and T7) and a return to pre-SOS/VOD onset levels at resolution of the complication. This prospective multicenter study reveals a low incidence of SOS/VOD in high-risk patients compared to historical data, in line with recent reports. The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and its role in in the development of SOS/VOD, suggesting that CEC level can be a valuable biomarker for diagnosing SOS/VOD and identifying patients at greater risk of this complication, especially late-onset SOS/VOD. Furthermore, CEC kinetics may support treatment strategies by providing insight into the optimal timing for discontinuing defibrotide treatment., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Pneumothorax is a rare but serious complication of septic pulmonary embolism (SPE). SPE is a life-threatening disorder wherein infected thrombi bring infarction of the terminal and small caliber parts of the pulmonary vasculature and develop multiple nodular and cavitary lesions. Interventions other than conservative chest tube drainage for pneumothorax due to SPE have rarely been reported. Here, we present a case of bilateral pneumothorax due to SPE treated with intrapleural minocycline pleurodesis., Case Description: A 72-year-old male patient previously diagnosed as esophageal carcinoma developed metachronous bilateral pneumothorax while treated for brain metastases. Based on blood cultures and chest computed tomography images, he was diagnosed with pneumothorax secondary to SPE due to methicillin-susceptible Staphylococcus aureus bacteremia. Bilateral chest tube drainage was instituted. Continuous air leakage was found bilaterally after chest tube placement. He was treated with broad-spectrum antibiotics based on the susceptibility profile and supportive treatment for sepsis. Approximately 3 weeks later, air leakage significantly reduced. We performed intrapleural minocycline pleurodesis bilaterally to prevent the recurrence of pneumothorax; the left side was firstly treated and the right side was treated 2 weeks later. Both chest tubes were successfully removed two days after procedures. Although the patient finally died of brain metastases 1 month after pleurodesis, he never recurred pneumothorax., Conclusions: Intrapleural minocycline pleurodesis may be one of the useful and efficacious options in terms of treating intractable pneumothorax associated with SPE. Intrapleural minocycline pleurodesis could be a consideration for intractable pneumothorax related to SPE., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1923/coif). S.W. received grants from Boehringer Ingelheim and Nippon Kayaku outside the submitted work, and honoraria for lectures from Lily, Chugai Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, Kyowa Kirin, Takeda Pharmaceutical, AstraZeneca, Novartis Pharma, Bristol-Myers, Daiichi Sankyo, Nippon Kayaku, and Celltrion outside the submitted work. The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Background and Objectives : Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (Na 2 SeO 3 ) and to evaluate the expression of SEPP1 as a marker of injury. Materials and Methods : HK-2 cells were pre-incubated with 100 nM Na 2 SeO 3 for 24 h, and then, treated for 24 h with CoCl 2 (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. Results : The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. Conclusions : Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.

Purpose: We present a large real-world multicentric dataset of ovarian, uterine and cervical oligometastatic lesions treated with SBRT exploring efficacy and clinical outcomes. In addition, an exploratory machine learning analysis was performed., Methods: A pooled analysis of gynecological oligometastases in terms of efficacy and clinical outcomes as well an exploratory machine learning model to predict the CR to SBRT were carried out. The CR rate following radiotherapy (RT) was the study main endpoint. The secondary endpoints included the 2-year actuarial LC, DMFS, PFS, and OS., Results: 501 patients from 21 radiation oncology institutions with 846 gynecological metastases were analyzed, mainly ovarian (53.1%) and uterine metastases(32.1%).Multiple fraction radiotherapy was used in 762 metastases(90.1%).The most frequent schedule was 24 Gy in 3 fractions(13.4%). CR was observed in 538(63.7%) lesions. The Machine learning analysis showed a poor ability to find covariates strong enough to predict CR in the whole series. Analyzing them separately, in uterine cancer, if RT dose≥78.3Gy, the CR probability was 75.4%; if volume was <13.7 cc, the CR probability became 85.1%. In ovarian cancer, if the lesion was a lymph node, the CR probability was 71.4%; if volume was <17 cc, the CR probability rose to 78.4%. No covariate predicted the CR for cervical lesions. The overall 2-year actuarial LC was 79.2%, however it was 91.5% for CR and 52.5% for not CR lesions(p < 0.001). The overall 2-year DMFS, PFS and OS rate were 27.3%, 24.8% and 71.0%, with significant differences between CR and not CR., Conclusions: CR was substantially associated to patient outcomes in our series of gynecological cancer oligometastatic lesions. The ability to predict a CR through artificial intelligence could also drive treatment choices in the context of personalized oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The rise of Vancomycin-resistant enterococci (VRE) strains among cellular therapy recipients raises concerns due to increased morbidity, mortality, and hospitalization costs, particularly impacting transplanted patients with diminished survival expectations. Recent research linking lactose to Enterococcus growth and graft-versus-host disease (GVHD) emphasizes the need for data on reducing lactose in the diets of VRE-carrying patients, especially in cellular therapy contexts like CAR-T or allogeneic hematopoietic stem cell transplantation. Responding to elevated VRE positivity rates in rectal swabs among patients in our BMT Unit, a unique nutritional strategy was implemented, introducing lactose-free milk and strictly enforcing lactose-free diets. This approach resulted in a significant reduction in VRE carriers, with a 16% positivity rate in the Lactose Group versus 3.6% in the Lactose-Free Group, as of June 2023. These results indicate the potential efficacy of this innovative nutritional strategy in high-risk departments, such as BMT Units and Intensive Care Units, with implications for reducing isolation strategies and inappropriate antibiotic use in cases of VRE colonization., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms., Experimental Design: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models., Results: We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models., Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments., (©2024 The Authors; Published by the American Association for Cancer Research.)

Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III-IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed., (© 2024. The Author(s).)

Background: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment., Materials and Methods: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR) 3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients., Results: A total of 215 patients in stable MR 3.0 /MR 4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR 3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR 3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03)., Conclusions: The intensification of intermittent TKI therapy is associated with a higher incidence of MR 3.0 loss, but those patients who maintain the MR 3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms., Competing Interests: Disclosures AI: Speaker honoraria – AOP, BMS, GSK, Incyte, Novartis and Pfizer. CB: Speaker's Bureau – Novartis, Incyte and Pfizer AB: Advisory Board and Consultancy - Novartis, Incyte, BMS, Pfizer. GR: Speaker's Bureau and Advisory Boards - Incyte, Novartis and Pfizer. MT: Speaker's Bureau – Novartis, Incyte and BMS. AMR: research funding - AstraZeneca, European Hematology Association, Transcan2-ERANET and Italian Association for Cancer Research (Fondazione AIRC); honoraria - Amgen, Celgene, Janssen and Takeda. All the other Authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The present study aimed to investigate the impact of resveratrol on oral neoplastic parameters through a systematic review and meta-analysis. Resveratrol, a naturally occurring polyphenol, has shown promising potential as a therapeutic agent in various cancer types, including oral neoplasms. Understanding the collective findings from existing studies can shed light on the efficacy and mechanisms of resveratrol in oral cancer management. The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search was performed to identify relevant studies from various databases, registers, websites, and citation searches. The inclusion criteria encompassed in-vivo studies investigating the impact of resveratrol on oral neoplastic parameters in animal models. After screening and assessment, a total of five eligible studies were included in the meta-analysis. The meta-analysis of the selected studies revealed that resveratrol treatment exhibited a potential impact on reducing oral neoplastic proliferation and promoting neoplastic apoptosis. The combined analysis showed a statistically significant decrease in neoplastic parameters with an overall effect size (ES) of 0.85 (95% CI: [0.74, 0.98]). Subgroup analyses were conducted to explore potential variations among different cellular types and exposure compounds, providing further insights into the efficacy of resveratrol in specific contexts. This systematic review and meta-analysis support the potential of resveratrol as a promising therapeutic agent in oral cancer management. The findings indicate that resveratrol may effectively modulate neoplastic proliferation and apoptosis in various cellular types within animal models of oral cancer. However, further well-controlled studies and clinical trials are warranted to validate these observations and elucidate the underlying mechanisms of resveratrol's actions. Resveratrol holds promise as a complementary therapeutic approach in the prevention and treatment of oral neoplastic conditions., (© 2024. The Author(s).)

Background: Moderate hypofractionated radiotherapy is a treatment option for the cure of localized prostate cancer (PCa) patients based on the results of randomized prospective trials, but there is a clinical concern about the relatively short length of follow-up, and real-world results on outcome and toxicity based on cutting-edge techniques are lacking. The objective of this study is to present the long-term results of a large multicentric series., Materials and Methods: We retrospectively evaluated 1325 PCa patients treated with daily volumetric image-guided hypofractionated radiotherapy between 2007 and 2020 in 16 Centers. For survival endpoints, we used Kaplan-Meier survival curves and fitted univariate and multivariable Cox's proportional hazards regression models to study the association between the clinical variables and each survival type., Results: At the end of the follow-up, 11 patients died from PCa. The 15-year values of cancer-specific survival (CSS) and biochemical relapse-free survival (b-RFS) were 98.5% (95%CI 97.3-99.6%) and 85.5% (95%CI 81.9-89.4%), respectively. The multivariate analysis showed that baseline PSA, Gleason score, and the use of androgen deprivation therapy were significant variables for all the outcomes. Acute gastrointestinal (GI) and genitourinary (GU) toxicities of grade ≥ 2 were 7.0% and 16.98%, respectively. The 15-year late grade ≥ 2 GI and GU toxicities were 5% (95%CI 4-6%) and 6% (95%CI 4-8%), respectively., Conclusion: Real-world long-term results of this multicentric study on cutting-edge techniques for the cure of localized PCa demonstrated an excellent biochemical-free survival rate of 85.5% at 15 years, and very low rates of ≥ G3 late GU and GI toxicity (1.6% and 0.9% respectively), strengthening the results of the available published trials., (© 2024. The Author(s).)