A comprehensive luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors.

Breast cancer (BC) is marked by significant genetic, morphological and clinical heterogeneity. To capture this heterogeneity and unravel the molecular mechanisms driving tumor progression and drug resistance, we established a comprehensive patient-derived xenograft (PDX) biobank, focusing particularly on luminal (estrogen receptor, ER+) and young premenopausal patients, for whom PDX models are currently scarce. Across all BC subtypes, our efforts resulted in an overall success rate of 17% (26 established PDX lines out of 151 total attempts), specifically 15% in luminal, 12% in human epidermal growth factor receptor 2 positive (HER2+) and 35% in triple negative BC. These PDX mirrored morphologic and genetic features of BC from which they originated, serving as a reliable tool to investigate drug resistance and test therapeutic strategies. We focused on understanding resistance to CDK4/6 inhibitors (CDK4/6i), which are crucial in the treatment of patients with advanced luminal BC. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumor shrinkage, some tumors might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that these PDXs have become refractory to CDK4/6i, both at biological and molecular levels, displaying significant enrichment in proliferation pathways, such as MTORC1, E2F and MYC. Using organoids derived from these PDX (PDxO), we observed that acquisition of CDK4/6i resistance conferred cross-resistance to endocrine therapy and that targeting MTORC1 was a successful strategy to overcome CDK4/6i resistance. Considered together, these results indicate that our PDX models may serve as robust tools to elucidate the molecular basis of BC disease progression and, by providing the possibility to simultaneously test different therapies on the same tumor, to surmount treatment resistance. While this approach is of course not feasible in the clinic, its exploitation in PDX may expedite the identification and development of more successful therapies for patients with advanced luminal BC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Surgical strategy in treatment of metopic synostosis in a single centre experience: technical note and quantitative analysis of the outcomes.

PURPOSE: Trigonocephaly is the most common craniosynostosis involving orbits. Although some degree of agreement has been reached regarding surgical timing and indications for treatment, there is no consensus regarding the ideal operative technique to guarantee an optimal morphological outcome. The purpose of this study is to describe both strategies and to compare morphological outcomes by means of morphological surface analysis obtained from three-dimensional (3D) stereophotogrammetry, with two different techniques. METHODS: We retrospectively investigated 43 patients with metopic synostosis surgically treated between 2004 and 2020. Two different techniques were applied, addressed as technique A and B. Ten patients undergone postoperative 3d stereophotogrammetry were enrolled, and cephalometric measurements were taken and compared to a cohort of unaffected patients matched by age and gender. RESULTS: Comparison of the groups demonstrated a hypercorrection of the metopic angle of the second technique, associated with a slightly lower correction of the interfrontoparietal diameter. The metopic angle showed to be significantly undercorrected with the first method. CONCLUSIONS: Alternated barrel staving technique appears to be a quick and satisfactory method in cranial remodelling for metopic synostosis. It guarantees an optimal aesthetic result in the first years after surgery.

The Accuracy of Computer-Assisted Surgical Planning in Predicting Soft Tissue Responses After Le Fort I Osteotomy: Retrospective Analysis.

PURPOSE: Mismatch between preoperative planning and surgical outcome in maxillofacial surgery relate to on-table replication of presurgical planning and predictive algorithm inaccuracy: software error was hereby decoupled from planning inaccuracy to assess a commercial software. The hypothesis was that soft tissue prediction error would be minimized if the surgical procedure was replicated precisely as planned and is independent of the extent of bone repositioning. MATERIALS AND METHODS: Cone-beam computed tomography scans of 16 Le Fort I osteotomy patients were collected at Boston Children's Hospital. Preoperative and postoperative models of bone and soft tissue were constructed and the maxilla repositioning was replicated. Each model was subdivided into 6 regions: mouth, nose, eyes, and cheeks. Soft tissue prediction (performed using Proplan CMF-Materialise) for each patient was compared with the relative postoperative reconstruction and error was determined. P <0.05 was considered significant. RESULTS: Le Fort I segment repositioning was replicated within 0.70±0.18 mm. The highest prediction error was found in the mouth (1.49±0.77 mm) followed by the cheeks (0.98±0.34 mm), nose (0.86±0.23 mm), and eyes (0.76±0.32). Prediction error on cheeks correlated significantly with mouth ( r =0.63, P < 0.01) and nose ( r =0.67, P < 0.01). Mouth prediction error correlated with total advancement ( r =0.52, P =0.04). CONCLUSIONS: ProPlan CMF is a useful outcome prediction tool; however, accuracy decreases with the extent of maxillary advancement even when errors in surgical replication are minimized.

A 3-Dimensional Evaluation of Bone Density in Alveolar Cleft Grafting Methods: Bone Substitutes Versus Autologous Bone.

INTRODUCTION: Secondary alveolar cleft repair using autologous bone graft is currently the gold standard in treating residual alveolar clefts. Despite its effectiveness, this technique is still burdened by several withdrawals, mostly related to donor site morbidity. To decrease disadvantages for patients, numerous attempts in the literature regarding bone substitutes have been described. The aim of this study is to compare the viability of bovine-based replacement bone material with respect of autologous bone graft in alveolar cleft reconstruction, through 3-dimensional alveolar cleft segmentation and bone density evaluation from preoperative and postoperative cone-beam computed tomography. PATIENTS AND METHODS: A retrospective cohort study of 10 patients who underwent surgical procedure for alveolar cleft grafting at Sant'Orsola Malpighi University Hospital of Bologna from December 2012 to December 2016 was undertaken. Five patients received autologous bone graft and 5 a bovine bone substitute graft. Preoperative and immediate postoperative orthopanoramic x-rays were recorded. Cone-beam computed tomography scans have recorded both pre and postoperatively. Volumetric evaluation on 3-dimensional cone-beam computed tomography images was performed. RESULTS: Alveolar clefts repaired using substitute bovine bone/biological membrane scaffold had a mean fill of 69.00% of total cleft volume, while this figure was of 67.07% with autologous bone grafting. The immediate postoperative course and subsequent discharge were uneventful for both groups, with a difference in timing. The cost of substitute bovine bone was offset by cost savings associated with a reduction in operative and postoperative and hospitalization time. CONCLUSIONS: Bone substitutes showed to be a promising solution in alveolar cleft grafting.

Development and validation of the quality-of-life adolescent cleft questionnaire in patients with cleft lip and palate.

Only a few reports in the literature have described the use of specific instruments for assessing the quality of life in adolescents and young adults with cleft lip and palate (CLP). This condition markedly affects their lifestyle, even after surgical treatment. In the present study, we aimed to develop a quality-of-life assessment tool specifically designed for such patients with CLP. Our multidisciplinary team created a questionnaire focused on the physical, psychological, and social satisfaction of adolescents and young adults with CLP, which was adapted from 3 dimensions of the 36-item Short-Form Health Survey. The questionnaire was administered to a randomized sample of 40 adolescents and young adults (aged 16-24 years) with CLP who had completed treatment protocols and 40 (aged 16-24 years) who were not affected by CLP. The statistical results stated that the questionnaire had good reliability and validity; the Cronbach α coefficient was found to be 0.944. Moreover, factorial analysis confirmed the presence of 3 subscales that were the fundamental components of this questionnaire, which is consistent with the areas theoretically proposed and from which the items were designed and selected. Thus, we validated our novel questionnaire that was administered in the present study and proved its consistency. However, further investigations on a larger population would be useful to confirm these findings.

Giuseppe Dagnini (1866-1928): Discoverer of the Trigemino-Cardiac Reflex and Practical Implications in Neurosurgery and Other Medical Specialties.

The authors present the life and art of Giuseppe Dagnini, a renowned Italian physician who was born in Bologna in 1866. He was the chief of the Maggiore Hospital in Bologna and authored valuable scientific works on the trigemino-cardiac reflex which is still applied in modern clinical practice. Dr. Dagnini firstly described the reflex in 1908 postulating that stimulation of one of the 3 branches of the trigeminal nerve triggers the afferent pathway in lowering heart rate. The authors also provide a modern outlook on the clinical implications of the TCR in neurosurgery, neuroanesthesia, and other medical specialties.

The Ability to Look Beyond: The Treatment of Peripheral Arterial Disease.

This paper offers a practical overview of the contemporary management of patients with peripheral arterial disease presenting intermittent claudication (IC), including clinical and instrumental diagnosis, risk factors modification, medical management, and evidence-based revascularization indications and techniques. Decision making represents a crucial element in the management of the patient with IC; for this, we think a review of this type could be very useful, especially for non-vascular specialists.

Soft tissue prediction in orthognathic surgery: Improving accuracy by means of anatomical details.

Three-dimensional virtual simulation of orthognathic surgery is now a well-established method in maxillo-facial surgery. The commercial software packages are still burdened by a consistent imprecision on soft tissue predictions. In this study, the authors produced an anatomically detailed patient specific numerical model for simulation of soft tissue changes in orthognathic surgery. Eight patients were prospectively enrolled. Each patient underwent CBCT and planar x-rays prior to surgery and in addition received an MRI scan. Postoperative soft-tissue change was simulated using Finite Element Modeling (FEM) relying on a patient-specific 3D models generated combining data from preoperative CBCT (hard tissue) scans and MRI scans (muscles and skin). An initial simulation was performed assuming that all the muscles and the other soft tissue had the same material properties (Homogeneous Model). This model was compared with the postoperative CBCT 3D simulation for validation purpose. Design of experiments (DoE) was used to assess the effect of the presence of the muscles considered and of their variation in stiffness. The effect of single muscles was evaluated in specific areas of the midface. The quantitative distance error between the homogeneous model and actual patient surfaces for the midface area was 0.55 mm, standard deviation 2.9 mm. In our experience, including muscles in the numerical simulation of orthognathic surgery, brought an improvement in the quality of the simulation obtained.

Preclinical Application of Augmented Reality in Pediatric Craniofacial Surgery: An Accuracy Study.

BACKGROUND: Augmented reality (AR) allows the overlapping and integration of virtual information with the real environment. The camera of the AR device reads the object and integrates the virtual data. It has been widely applied to medical and surgical sciences in recent years and has the potential to enhance intraoperative navigation. MATERIALS AND METHODS: In this study, the authors aim to assess the accuracy of AR guidance when using the commercial HoloLens 2 head-mounted display (HMD) in pediatric craniofacial surgery. The Authors selected fronto-orbital remodeling (FOR) as the procedure to test (specifically, frontal osteotomy and nasal osteotomy were considered). Six people (three surgeons and three engineers) were recruited to perform the osteotomies on a 3D printed stereolithographic model under the guidance of AR. By means of calibrated CAD/CAM cutting guides with different grooves, the authors measured the accuracy of the osteotomies that were performed. We tested accuracy levels of ±1.5 mm, ±1 mm, and ±0.5 mm. RESULTS: With the HoloLens 2, the majority of the individuals involved were able to successfully trace the trajectories of the frontal and nasal osteotomies with an accuracy level of ±1.5 mm. Additionally, 80% were able to achieve an accuracy level of ±1 mm when performing a nasal osteotomy, and 52% were able to achieve an accuracy level of ±1 mm when performing a frontal osteotomy, while 61% were able to achieve an accuracy level of ±0.5 mm when performing a nasal osteotomy, and 33% were able to achieve an accuracy level of ±0.5 mm when performing a frontal osteotomy. CONCLUSIONS: despite this being an in vitro study, the authors reported encouraging results for the prospective use of AR on actual patients.

Sural Nerve Vertical Cross-Face Graft for Lacrimal Gland Neurotization to Improve Tear Secretion in Neurodeprivative Dry Eye.

PURPOSE: No specific interventions have been reported for the treatment of severe neurodeprivative dry eye disease owing to facial nerve palsy. We describe herein the feasibility of a novel surgical procedure to reinnervate the lacrimal gland and report the preliminary outcomes of the first series of patients who were treated accordingly. METHODS: Prospective interventional case series including consecutive patients affected by facial palsy with absolute deficiency of tear secretion who underwent lacrimal gland neurotization. A sural nerve vertical cross-face graft was used to connect the lacrimal gland with the parasympathetic branch of the lingual nerve directed to the contralateral submandibular gland. RESULTS: Lacrimal neurotization was performed uneventfully in 10 patients (4 M, 6 F; mean age 47.1 ± 17.1 years). In all cases, the procedure was combined with facial reanimation, while corneal neurotization was performed in 4 cases. One year postoperatively, mean values of a Schirmer test increased significantly compared with baseline values (7.56 ± 7.84 vs. 0 ± 0 mm/5 min; P = 0.02), while the mean daily number of instillation of tear substitutes decreased significantly (21.8 ± 4.5 vs. 7.1 ± 2.2; P = 0.009). Overall, all patients were satisfied with surgery (very satisfied: n = 7 and satisfied: n = 2). No major postoperative complications occurred. CONCLUSIONS: Vertical cross-face using a sural nerve graft to connect the lacrimal gland with the contralateral submandibular gland is a novel technique for treating patients with facial nerve palsy and severe neurodeprivative dry eye disease. This surgery both performed alone and combined with corneal neurotization is able to improve tear secretion and decrease the need for frequent instillations of tear substitutes.

Changes in hospital admissions for facial fractures during and after COVID 19 pandemic: national multicentric epidemiological analysis on 2938 patients.

PURPOSE: The objective of this multicenter study was to examine the differences in maxillo-facial fractures epidemiology across the various phases of the SARS-CoV-2 pandemic. METHODS: This is a retrospective study on patients who underwent surgery for facial bone fractures in 18 maxillo-facial surgery departments in Italy, spanning from June 23, 2019, to February 23, 2022. Based on the admission date, the data were classified into four chronological periods reflecting distinct periods of restrictions in Italy: pre-pandemic, first wave, partial restrictions, and post-pandemic. Epidemiological differences across the groups were analysed. RESULTS: The study included 2938 patients. A statistically significant difference in hospitalization causes was detected between the pre-pandemic and first wave groups (p = 0.005) and between the pre-pandemic and partial restriction groups (p = 0.002). The differences between the pre- and post-pandemic groups were instead not significant (p = 0.106). Compared to the pre-pandemic period, the number of patients of African origin was significantly higher during the first wave and the post-pandemic period. No statistically significant differences were found across the periods concerning gender, age, fracture type, treatment approach, and hospital stay duration CONCLUSIONS: The COVID-19 pandemic brought about significant changes in fracture epidemiology, influenced by the restrictive measures enforced by the government in Italy. Upon the pandemic's conclusion, the fracture epidemiology returned to the patterns observed in the pre-pandemic period.

Finite element method for the design of implants for temporal hollowing.

Temporal indentations are the most impacting craniofacial complication after coronal flap dissection. It is mainly due to a temporal fat pad or temporalis muscle dissection. Because of the great improvements achieved recently in CAD-CAM-aided surgery and the possibility of performing accurate pre-surgical virtual planning, it is now possible to correct it with a customised virtual approach. Furthermore, advancements in material science have allowed surgeons to rely on biocompatible materials like PEEK (showing a low complication and recurrence rate) for the manufacturing of patient-specific implants. We hereby describe our experience on a case of secondary and corrective surgery after a fronto-orbital remodelling, in which we used PEEK implants designed by CAD and optimized by finite element modelling.

PSI-Guided Mandible-First Orthognathic Surgery: Maxillo-Mandibular Position Accuracy and Vertical Dimension Adjustability.

In orthognathic surgery, patient-specific osteosynthesis implants (PSIs) represent a novel approach for the reproduction of the virtual surgical planning on the patient. The aim of this study is to analyse the quality of maxillo-mandibular positioning using a hybrid mandible-first mandibular-PSI-guided procedure on twenty-two patients while the upper maxilla was fixed using manually bent stock titanium miniplates. The virtual surgical plan was used to design PSIs and positioning guides, which were then 3D printed using biocompatible materials. A Cone Beam Computed Tomography (CBCT) scan was performed one month after surgery and postoperative facial skeletal models were segmented for comparison against the surgical plan. A three-dimensional cephalometric analysis was carried out on both planned and obtained anatomies. A Spearman correlation matrix was computed on the calculated discrepancies in order to achieve a more comprehensive description of maxillo-mandibular displacement. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned maxillo-mandibular positioning reproduction, while maintaining a degree of flexibility to allow for aesthetics-based verticality correction in a pitch range between -5.31 and +1.79 mm. Such a correction did not significantly affect the achievement of planned frontal symmetry.

Hybrid treatment of fibroadipose vascular anomaly: A case report.

BACKGROUND: First identified in 2014, fibroadipose vascular anomaly (FAVA) is a very rare type of venous and lymphatic malformation. Marked by tough fibrofatty tissue in the extremities overtaking portions of the muscles, it is associated with constant pain and contracture of the affected extremity. There is a paucity of literature, and no guidelines on treatment procedure are available. This case highlights the role of hybrid treatment with primary ethanol percutaneous ethanol embolization and additional surgery for radicality in excision of FAVA lesions. CASE SUMMARY: A 9-year-old girl with FAVA underwent the hybrid treatment. The achievements of complete excision, clinical response, and patient satisfaction in long-term follow-up were assessed. Following the hybrid treatment, the patient experienced significant improvement in pain. Concurrent symptoms of physical limitation, leg swelling, and skin hyperesthesia also improved. The clinical benefit, supported by postoperative physiotherapy, was well stabilized at 6-month follow-up, resulting in complete patient satisfaction at 12- and 36-month follow-ups. No major complications were encountered. CONCLUSION: Ethanol embolization plus surgery is a safe, effective, and long-term hybrid treatment of symptomatic FAVA lesions.

A population-specific material model for sagittal craniosynostosis to predict surgical shape outcomes.

Sagittal craniosynostosis consists of premature fusion (ossification) of the sagittal suture during infancy, resulting in head deformity and brain growth restriction. Spring-assisted cranioplasty (SAC) entails skull incisions to free the fused suture and insertion of two springs (metallic distractors) to promote cranial reshaping. Although safe and effective, SAC outcomes remain uncertain. We aimed hereby to obtain and validate a skull material model for SAC outcome prediction. Computed tomography data relative to 18 patients were processed to simulate surgical cuts and spring location. A rescaling model for age matching was created using retrospective data and validated. Design of experiments was used to assess the effect of different material property parameters on the model output. Subsequent material optimization-using retrospective clinical spring measurements-was performed for nine patients. A population-derived material model was obtained and applied to the whole population. Results showed that bone Young's modulus and relaxation modulus had the largest effect on the model predictions: the use of the population-derived material model had a negligible effect on improving the prediction of on-table opening while significantly improved the prediction of spring kinematics at follow-up. The model was validated using on-table 3D scans for nine patients: the predicted head shape approximated within 2 mm the 3D scan model in 80% of the surface points, in 8 out of 9 patients. The accuracy and reliability of the developed computational model of SAC were increased using population data: this tool is now ready for prospective clinical application.

Validation of a patient-specific system for mandible-first bimaxillary surgery: ramus and implant positioning precision assessment and guide design comparison.

In orthognathic surgery, the use of patient-specific osteosynthesis devices is a novel approach used to transfer the virtual surgical plan to the patient. The aim of this study is to analyse the quality of mandibular anatomy reproduction using a mandible-first mandibular-PSI guided procedure on 22 patients. Three different positioning guide designs were compared in terms of osteosynthesis plate positioning and mandibular anatomical outcome. PSIs and positioning guides were designed according to virtual surgical plan and 3D printed using biocompatible materials. A CBCT scan was performed 1 month after surgery and postoperative mandibular models were segmented for comparison against the surgical plan. A precision comparison was carried out among the three groups. Correlations between obtained rami and plates discrepancies and between planned rami displacements and obtained rami discrepancies were calculated. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned mandibular anatomy reproduction. Different guide designs did not differ in mandibular outcome precision. Plate positional discrepancies influenced the corresponding ramus position, mainly in roll angle and vertical translation. Ramus planned displacement was found to be a further potential source of inaccuracy, possibly due to osteosynthesis surface interference.

[Persistence of protection induced by hepatitis B vaccine.]. / Persistenza della protezione indotta dal vaccino anti-epatite B.

Universal mass vaccination against hepatitis B virus in infants and adolescents, together with targeted prophylaxis for risk groups, is recommended since almost twenty years all over the world to prevent infection and related diseases. Safety and effectiveness of the vaccine have been clearly demonstrated while unambiguous data about long term protection and need of booster administration are not yet available, especially for high risk subjects like health care workers and dialysis patients. By means of new vaccines and new adjuvants better results could be obtained in a next future.

Design and manufacturing of a patient-specific nasal implant for congenital arhinia: Case report.

Arhinia (congenital absence of the nose) is a congenital rare disease, which has been reported in less than 60 cases in the literature. It consists of the absence of external nose, nasal cavities and olfactory apparatus and is generally associated with midline defects, microphthalmia, blepharophimosis and hypotelorism. Aesthetic problems as well as associated functional anomalies can potentially impact on the development and interpersonal relationships of the child at a later stage in life. Arhinia requires extensive management in early life in order to ensure airway patency and protection by means of tracheostomy, and to allow adequate pharyngeal and feeding function to the child. Aesthetic issues are managed with reconstructive surgery or an external prosthesis. There is no previous description in Literature of internal prosthetic devices used to sequentially shape soft tissues in complex reconstruction. We present an example of design and manufacturing of a bespoke nose implant produced by means of 3D printing and directly assessed on-table by means of 3D surface scanning.

Syndromic Craniosynostosis: Complexities of Clinical Care.

Patients with syndromic craniosynostosis have a molecularly identified genetic cause for the premature closure of their cranial sutures and associated facial and extra-cranial features. Their clinical complexity demands comprehensive management by an extensive multidisciplinary team. This review aims to marry genotypic and phenotypic knowledge with clinical presentation and management of the craniofacial syndromes presenting most frequently to the craniofacial unit at Great Ormond Street Hospital for Children NHS Foundation Trust.