High-grade transformation of a polymorphous adenocarcinoma of the salivary gland: a case report and review of the literature.

Background: Polymorphous adenocarcinoma (PAC) represents the second most widespread neoplasm of the minor salivary glands. These tumors rarely develop a histological progression from low-grade to high-grade malignancy, named "high-grade transformation" (HGT). Only nine cases are described in literature. Case description: Here, we describe the case of a 76-year-old male patient with a PAC recurrence of the oral floor displaying HGT, and we explore the tumor cytomorphological features, genomic profiling, and the patient's clinical management. The tumor mass was characterized by poorly atypical cellular elements with vesicular nuclei and comedonecrosis foci. The growth pattern was predominantly solid, tubular, and cribriform. The lesion did not show microsatellite instability or targeted molecular alterations. The case was successfully treated with radical surgery followed by radiotherapy. Conclusion: We report for the first time the recurrence of a PAC with HGT arising in the oral floor after 20 years from the primary lesion. These preliminary data and the literature analysis enhance the knowledge of this extremely rare disease.

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.

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches.

Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas.

Adult rhabdomyosarcoma (RMS) represents an uncommon entity with an incidence of less than 3% of all soft tissue sarcomas (STS). Consequently, the natural history and the clinical management of this disease are infrequently reported. In order to fill this gap, we investigated the molecular biology of an adult RMS case series. The expression of epithelial mesenchymal transition-related gene and chemoresistance-related gene panels were evaluated. Moreover, taking advantage of our STS translational model combining patient-derived primary culture and 3D-scaffold, the pharmacological profile of an adult head and neck sclerosing RMS was assessed. Furthermore, NGS, microsatellite instability, and in silico analyses were carried out. RT-PCR identified the upregulation of CDH1, SLUG, MMP9, RAB22a, S100P, and LAPTM4b, representing promising biomarkers for this disease. Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. NGS analysis detected RAB3IP-HMGA2 in frame gene rearrangement and FGFR4 mutation; microsatellite instability analysis did not detect any alteration. In silico analysis confirmed the mutation of FGFR4 as a promising marker for poor prognosis and a potential therapeutic target. We report for the first time the molecular and pharmacological characterization of rare entities of adult head and neck and posterior trunk RMS. These preliminary data could shed light on this poorly understood disease.

"Single-step" resection and cranio-orbital reconstruction for spheno-orbital metastasis with custom made implant. A case report and review of the literature.

INTRODUCTION AND IMPORTANCE: Brain metastasis involving the skull base is a rare complication of malignant tumors. Besides radiotherapy, surgical treatment is a therapeutical option even though it may apply complex technical procedures that may delay complementary therapies. However, in recent days, the innovation of custom-made implants allows treating selected patients with fewer complications and better results. CASE PRESENTATION: We describe a single case of a complex fronto-orbital skull base metastasis requiring skull bone reconstruction that we treated with a single-step surgery and custom-made implant. Our procedure consists of two steps: in the first one, we perform a "virtual" craniotomy on a 3D phantom model previously built on a high-resolution bone CT scan. In the second step, the actual surgical procedure, the patient undergoes the resection and reconstruction of the cranial defect with an implant of PMMA custom-made cranioplasty. A three-month clinical and radiological follow-up is reported, which documented the extent of resection and good aesthetic results. CLINICAL DISCUSSION: In our case, we performed a skull reconstruction of cranio-orbital region with macroscopic gross-total resection of the tumor. Complementary radiotherapy was obtained after one month. Three-month follow-up showed good esthetic results and progression-free disease. A recent review of the literature is provided to discuss different reconstruction techniques. CONCLUSION: "Single-Step" resection and custom-made reconstruction is a relatively new technique that could be helpful not only for benign tumors, which remains its main application but also in selected cases of malignant tumors when immediate reconstruction and faster complementary treatments are needed.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas.

OBJECTIVE: Squamous cell carcinoma (SCC) represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma (OSCC), a tumor associated with different clinical outcomes and linked to human papilloma virus (HPV) status. Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs. The present study proposes a 3-dimensional (3D) biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix (ECM) and cancer cells. METHODS: We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds. We also explored cancer cell adaptation to the 3D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures. RESULTS: HPV-positive and HPV-negative cell lines were successfully grown in the 3D model and displayed different collagen fiber organization. The 3D cultures induced an increased expression of markers related to epithelial-mesenchymal transition (EMT) and to matrix interactions and showed different migration behavior, as confirmed by zebrafish embryo xenografts. The expression of hypoxia-inducible factor 1α (1α) and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area. Furthermore, the 3D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures. CONCLUSIONS: Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs. Moreover, 3D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

Synchronized "One-Step" Resection and Cranio-Orbital Reconstruction for Spheno-Orbital Lesions With Custom Made Implant.

BACKGROUND: In the last few years, skull base tumors involving the fronto-orbital region have been approached with complex, invasive, and time-consuming cranial reconstruction techniques. On the other hand, recent custom-made implants allow easier and faster procedures, with excellent aesthetic results. The authors propose an easy surgical-planned protocol with a synchronized "one-step" resection and reconstruction of these complex lesions, with a preformed poly-methyilmethacrylate (PMMA) cranioplasty. METHODS: Our technique consists of a 2-phases procedure. In the first one, the so-called "virtual" phase, the authors get a tailored 3D-PMMA model based on high-resolution (HR) CT-scans of the patient's skull. Afterward, the authors perform the planned craniotomy on the 3D-PMMA model with the assistance of intraoperative navigation system. Therefore, a further CT-scan of the resected model is performed to develop the final implant. In the second phase, the "surgical phase," a single procedure consisting in a cranial resection and custom reconstruction is performed with the assistance of stealth-navigation. The authors describe 6 cases of complex fronto-orbital-sphenoidal benign tumors that required skull reconstruction. All patients were examined 3 months after surgery through cosmetic (facial and eyes symmetry and globe position) and ophthalmology tests (visual field, visual impairment, and diplopia). Postsurgical HR CT-scans of the head and MRI-scans of the brain documented a total resection of the tumor and an optimal accuracy of skull reconstruction. RESULTS: In all cases, the authors obtained a highly accurate skull reconstruction following cranio-orbital tumor resection, with a less aggressive and faster procedure compared to autologous bone graft. Final cosmetic and functional results were excellent, with good results in cases of presurgical exophthalmos and orbital asymmetry. None of the patients developed implant-related complications. CONCLUSIONS: The "one-step" resection and reconstruction of benign tumors involving the spheno-orbital region with neuronavigation assistance is a technique that allows an accurate tumor removal and a cranial-bone reconstruction within a single surgical procedure, with fewer complications and excellent cosmetic and functional results.

Osteosarcoma of the Jaws: A Literature Review.

Osteosarcoma of the jaws (OSJ) is a relatively rare disease, accounting for between 2% and 10% of all cases of osteosarcoma. It is morphologically and radiologically identical to the trunk and extremity variant, but distinct in several crucial aspects. The lesion is characterized by sarcomatous cells which produce a variable amount of osteoid bone. It arises centrally within the bone and can be subdivided into osteoblastic, chondroblastic and fibroblastic subtype, depending on the predominant cell type. Radiographically, these tumors display a spectrum of bone changes from well-demarcated borders to lytic bone destruction with indefinite margins and variable cortical bone erosion or, in some cases, images of sclerotic bone. Therapeutic options for OSJ include surgery, chemotherapy and radiotherapy, which are employed according to age of the patient, histological classification and localization of the tumor. Today, there is no general consensus in the treatment guidelines for the OSJ though surgery represents the key to the treatment. The main prognostic factor deeply influencing the patient's prognosis remains the complete tumor resection with negative surgical margins. The aim of the present review is to describe state of the art regarding diagnostic and surgical treatment aspects of the primary osteosarcoma of the jaws.

Congenital Ulcerated Lip Hemangioma Treated With a Cleft Lip Technique.

A neonate presented to our clinic for evaluation of unusual congenital cleft lip. The clinical follow-up showed at first an ulceration of the lesion and then a stable result after propanolol systemic therapy. After 18 months of clinical follow-up, surgical treatment was performed, which consisted of double unilimb Z-plasty according to Mulliken's microform cleft lip repair. Knowing the existence of these strange vascular anomalies of the lip will allow us to improve the differential diagnosis and treatment plan.

Mesenchymal stem cells and platelet-rich plasma enhance bone formation in sinus grafting: a histomorphometric study in minipigs.

OBJECTIVES: Autologous, allogenic, and alloplastic materials for sinus augmentation have specific drawbacks, which has stimulated an ongoing search for new materials and tissue-engineering constructs. We investigated whether mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) seeded on a fluorohydroxyapatite (FH) scaffold can improve bone formation and bone-to-implant contact (BIC) in maxillary sinus grafting. MATERIAL AND METHODS: Bilateral sinus augmentation procedures were performed in eight minipigs. MSCs, PRP, and FH scaffold (test site) or FH alone (control site) were grafted in each maxillary sinus. Distal to the osteotomy, one dental implant per sinus was placed in the grafting material through the facial sinus wall. The animals were killed 3 months after grafting, and block sections of the implant sites were harvested and prepared for histomorphometric analysis. RESULTS: After 12 weeks, a significant increase in bone formation occurred in the test sites compared with the control sites (42.51%versus 18.98%; p=0.001). In addition, BIC was significantly greater in the test sites compared with the control sites in the regenerated area (23.71%versus 6.63%; p=0.028). CONCLUSIONS: These findings show that sinus augmentation with MSCs-PRP, combined with FH may enhance bone formation and osseointegration of dental implants compared with FH alone in minipigs.

Mathematical modeling and numerical simulation in maxillofacial virtual surgery.

Computer-based surgery simulation is a rapidly emerging and increasingly important area of research that combines a number of disciplines for the common purpose of improving healthcare. The objective of this article is to provide a virtual surgery tool for accurately planning the aesthetic impact of hard and soft tissue movements in dentoskeletal malocclusions. The approach proposed here allows direct interaction with a completely three-dimensional (3D) computed tomography (CT) model of a solid, highly detailed structure of the head to obtain a realistic prediction of soft tissue behavior. We studied 25 patients who had facial malformations pre- and postoperatively with 3D hard and soft tissue CT studies, and maxillary or mandibular osteotomies were simulated. The postoperative 3D CT and facial outcomes were compared with the simulations. In 80% of the cases studied, the simulation-predicted changes, when compared with the clinical outcomes, were within the tolerance level (2 mm) established by maxillofacial surgeons.

Mathematical modeling and numerical simulation in maxillo-facial virtual surgery (VISU).

Computer-based surgery simulation is a rapidly emerging and increasingly important area of research that combines a number of disciplines for the common purpose of improving healthcare. The objective of this paper is to provide a virtual surgery (VISU) tool for accurately planning the aesthetic impact of hard and soft tissue movements in dento-skeletal malocclusions. The approach proposed here allows direct interaction with a completely three-dimensional (3-D) computed tomography (CT) model of a solid, highly detailed structure of the head to obtain a realistic prediction of soft tissue behavior. We studied 25 patients who had facial malformations pre- and postoperatively with 3-D hard and soft tissue CT studies, and maxillary or mandibular osteotomies were simulated. The postoperative 3-D CT and facial outcomes were compared with the simulations. In 80% of the cases studied, the simulation-predicted changes, when compared with the clinical outcomes, were within the tolerance level (2 mm) established by maxillo-facial surgeons.