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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses., Method: To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression., Results: Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8 + T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8 + T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice., Conclusion: Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC., Competing Interests: Competing interests: EP is co-founder and consultant for Egle-Tx., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Semaphorin-plexin signaling plays a major role in the tumor microenvironment (TME). In particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis; however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triple-negative murine breast carcinoma to elucidate its relevance in cancer progression. We found that primary tumor growth and metastatic dissemination were strongly reduced in PLXNB1-deficient mice, which showed longer survival. PLXNB1 loss in the TME induced a switch in the polarization of tumor-associated macrophages (TAM) toward a pro-inflammatory M1 phenotype and enhanced the infiltration of CD8+ T lymphocytes both in primary tumors and in distant metastases. Moreover, PLXNB1 deficiency promoted a shift in the Th1/Th2 balance of the T-cell population and an antitumor gene signature, with the upregulation of Icos, Perforin-1, Stat3, and Ccl5 in tumor-infiltrating lymphocytes (TILs). We thus tested the translational relevance of TME reprogramming driven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of PLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor growth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by systemic treatment with a specific inhibitor significantly hampered breast cancer growth and enhanced the antitumor activity of the anti-PD-1 treatment in a preclinical model. Altogether, these data indicate that PLXNB1 signaling controls the antitumor immune response in the TME and highlight this receptor as a promising immune therapeutic target for metastatic breast cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objectives: Ascending aorta (AA) dilatation in patients with bicuspid aortic valve (AV) is related both to genetic and haemodynamic factors. The aim of this study is to compare late progression of AA dilatation in bicuspid AV patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve implantation (TAVI)., Methods: Data of 189 consecutive patients who underwent AV replacement for severe bicuspid AV stenosis were prospectively collected. Patients who underwent SAVR were compared to patients who underwent TAVI. Indication to the procedure was validated by the institutional Heart Team. Aortic diameters were evaluated by transthoracic echocardiogram. Differences between preoperative and long-term follow-up AA diameters were compared in the 2 groups., Results: Between January 2015 and December 2021, 143 (76%) patients underwent SAVR and 46 (24%) patients underwent TAVI. At 4.6 (standard deviation 1.7) years follow-up, patients in the TAVI group showed significantly lower survival (P = 0.00013) and event-free survival (P < 0.0001). AA diameter progression was lower in surgical compared to transcatheter patients, 0.95 (0.60, 1.30) vs 1.65 (0.67, 2.63) mm, P = 0.02. AA diameter progression indexed for body surface area and height was lower in the surgical group: 0.72 (0.38, 1.05) vs 1.05 (0.39, 1.71) mm/m2, P = 0.02, and 0.59 (0.36, 0.81) vs 1.11 (0.44, 1.78) mm/m, P = 0.001, respectively. At multivariable linear regression analysis transcatheter procedure, baseline aortic diameter and paravalvular leak were significantly associated with increased postoperative AA dilatation., Conclusions: Bicuspid AV patients who underwent SAVR, showed significantly less long-term AA diameter progression than patients who underwent transcatheter procedure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1-5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.

Purpose: This systematic review aims to investigate the complication rate of endoscopic spine surgeries, stratifying them by technique, district and kind of procedure performed., Methods: This study was conducted according to the PRISMA statement. The literature search was conducted in MEDLINE, CINAHL, EMBASE, Cochrane Register, OTseeker and ScienceDirect database. Types of studies included were observational studies (cohort studies, case-control studies and case series) and randomised or quasi-randomised clinical with human subjects. No restrictions on publication year were applied. Repeated articles, reviews, expert's comments, congress abstracts, technical notes and articles not in English were excluded. Several data were extracted from the articles. In particular, data of perioperative (≤ 3 months) and late (> 3 months) complications were collected and grouped according to: (1) surgical technique [uniportal full-endoscopic spine surgery (UESS) or unilateral biportal endoscopic spine surgery (UBESS)]; (2) spinal district treated [cervical, thoracic or lumbar] and (3) type of procedure [discectomy/decompression or fusion]. Complication analysis was performed in subgroups with at least 100 patients to have clinically meaningful statistical validity., Results: A total of 117 full-text articles were assessed for eligibility. Of the 117 records included, 95 focused their research on UESS (14 LOE V, 33 LOE IV, 43 LOE III and five LOE II) and 23 on UBESS (three LOE V, eight LOE IV, 10 LOE III and two LOE II). A total of 20,020 patients were extracted to investigate the incidence of different perioperative and late complications, 10,405 for UESS and 9615 for UBESS., Conclusion: The present study summarises the complications reported in the literature for spinal endoscopic procedures. On the one hand, the most relevant described were perioperative complications (transient neurological deficit, dural tear and dysesthesia) that are especially meaningful for endoscopic discectomy and decompression. On the other hand, late complications, such as mechanical implant failure, are more common in endoscopic interbody fusion., Level of Evidence: I., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Addressing facial palsy (FP) presents intricate challenges in achieving natural expressions. Although free functional muscle transfers (FFMT) offer effective smile restoration, age impacts their efficacy. The optimal FFMT age range of 5-55 years is limited by physical fitness, which extends beyond age boundaries. Unilateral FP demands vary; younger patients require dynamic solutions like FFMT, whereas older individuals prioritize public appearance due to baseline distortion. The aim of this study is to describe and to assess a new static technique combining deep plane facelift and fascia lata graft for FP treatment. We conducted a prospective pilot study enrolling unilateral FP patients aged >55 and declining FFMT. Exclusions encompassed prior FP surgery, recent injections, uncontrolled diabetes cognitive deficits, and patients unable to quit smoking. To evaluate this technique, the Glasgow Benefit Inventory (GBI), along with two objective scales, the Face- and Neck-Lift Objective Photo-Numerical Assessment Scale and the eFACE scale, were used. Interrater reliability and intrarater reliability were assessed. Fifteen patients (mean age: 60.9 years) underwent the procedure. Both static and dynamic symmetry significantly improved (p < 0.05), including check volume and position, oral commissure, and jawline. Notably, eye closure enhancement was observed. GBI scores also significantly increased (p < 0.05). Interrater reliability and intrarater reliability were minimal (p = 0.12 and p = 0.13). This combined approach offers a static FP treatment option, especially for the elderly or FFMT-ineligible patients. The relatively brief procedure yields immediate and satisfactory results, suggesting its potential value in FP management. Further comprehensive studies are encouraged to validate the technique's long-term efficacy and applicability across larger populations., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)