Treatment of medication-related osteonecrosis of the jaw with cell therapy.

Introduction: Medication-related osteonecrosis of the jaw (MRONJ) poses a significant challenge considering the absence of a "gold standard" treatment. Cell-based therapy and tissue engineering offer promising therapeutic alternatives. This study aimed to harness the regenerative properties of adipose-tissue stromal vascular fraction (AT-SVF) and leukocyte-platelet-rich fibrin (L-PRF) for MRONJ treatment. AT-SVF contains mesenchymal stromal cells (MSC) and endothelial progenitor cells (EPC), which promote bone formation, while the L-PRF scaffold can serve as a three-dimensional scaffold for the AT-SVF and support tissue healing through growth factor release. Materials and methods: The protocol involved applying autologous AT-SVF within an L-PRF matrix following surgical debridement. Age, gender, body mass index, comorbidities, underlying oncological condition, prescribed antiresorptive treatment: BP or DMB, antiresorptive treatment duration, antiresorptive treatment potential discontinuation, number of MRONJ lesion, MRONJ location, MRONJ stage, MRONJ trigger factor were assessed for each patient. Patients underwent the procedure and were monitored for a minimum of 6 months based on clinical, biological and medical imaging criteria. Results: Nine patients, with a total of ten MRONJ lesions, participated in the study. Six patients were female, and three were male, with a mean age of 68 ± 8 years. Four patients had multiple myeloma (MM), three had metastatic breast cancer, and two had metastatic prostate cancer. Seven MRONJ cases were classified as stage II, and three were classified as stage III. Soft tissue completely healed within a month after treatment in nine cases, with no clinical improvement observed in the remaining case. During follow-up, no sign of MRONJ recurrence was observed. Tridimensional medical imaging revealed bone healing 6 months after the surgical procedure. Immunophenotyping confirmed the presence of MSC and EPC in the AT-SVF: 12,6 ± 4,5% CD31+, 20.5 ± 7,8% CD34+, 34,4 ± 7,3% CD146+ and 54,6 ± 7,4% CD45+. Conclusion: This prospective study introduces a potential new treatment approach for MRONJ using autologous AT-SVF within an L-PRF scaffold. Our results are encouraging and suggest the need for further investigation with a larger patient cohort to better understand the underlying mechanisms.

Antibiotic Use in Patients Undergoing Complex Clean-Contaminated Head and Neck Surgery: A Prospective Study.

Aims and Objectives: Oncological surgery of the upper aerodigestive tract is a complex procedure and often includes neck dissection and flap reconstruction. It can be complicated by severe surgical site infection (SSI) leading to flap necrosis, delayed wound healing, and increasing mortality and morbidity. The purpose of this study is to perform a systematic descriptive analysis and to evaluate the effect of our adapted antibiotic regimen strategy on postoperative outcomes. Materials and Methods: A prospective cohort analysis of 47 patients undergoing major clean-contaminated head and neck surgery was conducted at the Cervicomaxillofacial Surgery Department (Saint-Pierre Hospital), between 2019 and 2022. The patients were divided into two groups: group I, which received a short-term postoperative antibiotic regimen for 24 h, and group II, which received a more extended postoperative antibiotic course for more than 24 h. Antibioprophylaxy amoxicillin and clavulanate were administered intravenously 30-60 min before making the incision. The antibiotic regimen was continued after surgery. The prognostic significance of the antibiotic regimen on postoperative outcomes, including clinical signs of infection and biological markers such as white blood cells count, and C-reactive protein levels was evaluated using univariate analysis. Results: Eighteen patients developed SSIs. All of these infections were grade 2 and were treated with antibiotics. After univariate analysis, only a history of hypothyroidism seems to be a predictor of SSI (P = 0.038). No significant difference was found in terms of onset and hospital stay when we compared the patients who received antibiotics for 24 h or more. Moreover, the rate of multidrug-resistant bacteria was not different in both groups. Conclusions: Our results suggest that postoperative antibiotics for more than 24 h do not confer benefit in terms of SSI. Oncological patients undergoing complex clean-contaminated head and neck surgery are often suffering from infectious complications and, despite the absence of guidelines, practicians should consider these findings in their decision-making.

Preventive and Therapeutic Effect of Metformin in Head and Neck Cancer: A Concise Review.

BACKGROUND: Head and neck cancer (HNC) is a complex affection. Nowadays, conventional treatments are associated with many side effects, reducing the patient's quality of life. Recent studies suggest that metformin, a first-line treatment for diabetes, could decrease cancer incidence and improve cancer-related survival rates. METHODS: This systematic review summarizes important data from studies evaluating metformin's contribution to preventing and treating HNC. RESULTS: The results suggest a protective effect of metformin in HNC. However, no consensus has been found on its therapeutic effects. Metformin seems to confer an improved cancer-related survival rate in a diabetic population, but compared to a non-diabetic population, the review could not identify any advantages. Nevertheless, no studies presented a negative impact. CONCLUSION: In conclusion, the results of this systematic review suggest that HNC patients may benefit from metformin. Indeed, it would reduce the HNC incidence. However, more studies are required to evaluate the effect on cancer-related survival rates.

Extracellular Vesicles Derived from Human Umbilical Cord Mesenchymal Stromal Cells as an Efficient Nanocarrier to Deliver siRNA or Drug to Pancreatic Cancer Cells.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Treatment of PDAC remains a major challenge. This study aims to evaluate, in vitro, the use of human umbilical cord mesenchymal stromal cell (UC-MSC)-derived EVs to specifically target pancreatic cancer cells. EVs were isolated from the FBS-free supernatants of the cultured UC-MSCs by ultracentrifugation and characterized by several methods. EVs were loaded with scramble or KRASG12D-targeting siRNA by electroporation. The effects of control and loaded EVs on different cell types were evaluated by assessing cell proliferation, viability, apoptosis and migration. Later, the ability of EVs to function as a drug delivery system for doxorubicin (DOXO), a chemotherapeutic drug, was also evaluated. Loaded EVs exhibited different kinetic rates of uptake by three cell lines, namely, BxPC-3 cells (pancreatic cancer cell line expressing KRASwt), LS180 cells (colorectal cell line expressing KRASG12D) and PANC-1 cells (pancreatic cell line expressing KRASG12D). A significant decrease in the relative expression of the KRASG12D gene after incubation with KRAS siRNA EVs was observed by real-time PCR. KRASG12D siRNA EVs significantly reduced the proliferation, viability and migration of the KRASG12D cell lines compared to scramble siRNA EVs. An endogenous EV production method was applied to obtain DOXO-loaded EVs. Briefly, UC-MSCs were treated with DOXO. After 24 h, UC-MSCs released DOXO-loaded EVs. DOXO-loaded EVs were rapidly taken up by PANC-1 cells and induced apoptotic cell death more efficiently than free DOXO. In conclusion, the use of UC-MSC-derived EVs as a drug delivery system for siRNAs or drugs could be a promising approach for the targeted treatment of PDAC.

Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles as Natural Nanocarriers: Concise Review.

Intercellular communication, through direct and indirect cell contact, is mandatory in multicellular organisms. These last years, the microenvironment, and in particular, transfer by extracellular vesicles (EVs), has emerged as a new communication mechanism. Different biological fluids and cell types are common sources of EVs. EVs play different roles, acting as signalosomes, biomarkers, and therapeutic agents. As therapeutic agents, MSC-derived EVs display numerous advantages: they are biocompatible, non-immunogenic, and stable in circulation, and they are able to cross biological barriers. Furthermore, EVs have a great potential for drug delivery. Different EV isolation protocols and loading methods have been tested and compared. Published and ongoing clinical trials, and numerous preclinical studies indicate that EVs are safe and well tolerated. Moreover, the latest studies suggest their applications as nanocarriers. The current review will describe the potential for MSC-derived EVs as drug delivery systems (DDS) in disease treatment, and their advantages. Thereafter, we will outline the different EV isolation methods and loading techniques, and analyze relevant preclinical studies. Finally, we will describe ongoing and published clinical studies. These elements will outline the benefits of MSC-derived EV DDS over several aspects.

An Unusual Case of Primary Hyperparathyroidism: Case Report of a Bifocal Intrathyroidal Parathyroid Carcinoma.

Intrathyroidal parathyroid carcinoma is an extremely rare cause of primary hyperparathyroidism. We reported a 51-year old woman who presented symptoms of hypercalcemia. 99mTc sestamibi single-photon emission computed tomography/computed tomography (CT) revealed a large hypermetabolic nodule in the left thyroid lobe suggestive of hyperfunctioning parathyroid tissue. 11C-methionine positron emission tomography/computed tomography (PET/CT) and 18F-fluorocholine PET/CT confirmed the nodule in the left thyroid lobe and also revealed a hypermetabolic activity on the posterior surface of the lower left pole. The patient underwent a total thyroidectomy and parathyroidectomy, and a diagnosis of bifocal intrathyroidal parathyroid carcinoma was confirmed. We present the first reported case of bifocal intrathyroidal carcinoma and discuss the discordant imaging results.

Contribution of Antiangiogenic Agents to the Risk of Medication-related Osteonecrosis of the Jaw in Combination with Antiresorptive Agents: Preliminary Results in a Comparative Prospective Report of 59 Oncologic Cases.

Aim: The aim of this preliminary study was to evaluate in an oncological population the association risk of antiangiogenic (AA) agents to antiresorptive (AR) agents on the incidence and the severity of medication-related osteonecrosis of the jaw (MRONJ). Materials and Methods: In this prospective study, we reviewed the medical records and clinical variables of 59 consecutive oncologic patients who developed MRONJ. For all patients, we retrieved the following variables: age, gender, alcohol and tobacco use, type of cancer, use of corticosteroids for >3 months, history of diabetes, MRONJ staging, combination of AR and AA agents, dental history (surgery, prosthesis) or spontaneous, site of MRONJ, delay between AR and AA first intake, and MRONJ development. Patients were divided into two groups according to drugs therapy they underwent: group 1 (G1) including patients treated with AR agents alone and group 2 (G2) including patients receiving antiresorptive-antiangiogenic drugs (AR+AA). The degree and the therapeutical success were defined as primary outcomes and the number, the localization, and the delay in onset of the lesions as secondary outcomes. In order to identify predictive factors of osteonecrosis-free interval time, univariate and multivariate Cox regression was performed. Statistical tests were carried out using the IBM® SPSS® Statistics software. All reported P-values are two-tailed and were considered to be significant when less than 0.05. Results: Among the 47 patients who received AR agent alone (group 1), the mean treatment duration before diagnosis of MRONJ was 39.2 months. In the second group (n = 12), patients developed MRONJ with a comparable mean time of 55 months (P = 0.16). According to the staging of MRONJ at the time of diagnosis, no significant difference (P = 0.736) was observed between the two groups. Moreover, the treatment applied was not statistically different in both the groups and was successful in 36.17% of the patients in group 1 and 58.33% of the patients in group 2. No statistically difference was reported in both the groups (P = 0.16). After statistical analysis, no significant difference in terms of MRONJ localization (P = 0.13) was observed. Finally, the incidence of spontaneous MRONJ was comparable in both the groups. Statistical analysis revealed that total time of treatment was the only factor associated with poor osteonecrosis-free interval time (hazard ratio 0.99; P = 0.001). Interestingly, the combination of an AA and AR agent was not a significant predictor factor of the interval time before the diagnosis of osteonecrosis. Additionally, corticosteroid use, diabetes mellitus, and dental consultation before treatment were not statistically related to poorer osteonecrosis-free interval time rates. Conclusion: In our preliminary study, neither the mean treatment time duration before the diagnosis of MRONJ nor the dose delivered was different in both the groups (AR vs. AR+AA). Moreover, no significant difference was observed between both the groups regarding the localization and the staging of MRONJ at the time of diagnosis. Interestingly, our results demonstrated that the risk of spontaneous MRONJ is statistically comparable in the AR and AR-AA groups. Additionally, the addition of an AA agent did not influence the treatment applied in the two groups of patients.

Suburethral implantation of autologous regenerative cells for female stress urinary incontinence management: Results of a pilot study.

OBJECTIVES: To assess the feasibility and the safety of treating female stress urinary incontinence (SUI) with suburethral implantation of a mixture of the stromal vascular fraction from adipose tissue and leukocyte-and platelet-rich-fibrin. METHODS: Patients with SUI were treated with a mixture of stromal vascular fraction and leukocyte-and platelet-rich fibrin. The stromal vascular fraction was obtained from enzymatic digestion of autologous adipose-tissue and added to an leukocyte-and platelet-rich-fibrin membrane. The mixture was transvaginally implanted into the suburethral area. A fraction of the Stromal vascular fraction sample was used for cellular characterization. Patients were followed for 9 months. Every 3 months, the patients were clinically evaluated with a cough- stress test and a validated-questionnaire. An MRI was performed preoperatively and 3 months after the procedure to assess tissue changes. RESULTS: Ten patients received the surgical procedure. The validated-questionnaire revealed a subjective SUI improvement in nine patients 3 months after the operation and in seven patients 9 months after the operation. Eight, six, and four patients achieved a negative cough-stress test 3, 6 and 9 months post-injection, respectively. Flow cytometric analysis of stromal vascular fraction cell phenotypes revealed predominantly mesenchymal and endothelial cell heterogeneity. In total, we injected 0,18 × 106 to 13,6 × 106 cells. No adverse events were observed peri- or postoperatively. CONCLUSION: These preliminary results suggest that the suburethral implantation of a combination of SVF and l-PRF is a feasible and safe modality for treating female SUI. However, evidence is lacking and further research are needed to clarify the respective roles of SVF and l-PRF in female SUI treatment.

Neutrophil-to-lymphocyte ratio as a prognostic marker for head and neck cancer with lung metastasis: a retrospective study.

PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) is the most widely biomarker used to assess the inflammatory system in various solid cancers. An elevated NLR has been reported to be associated with worse outcomes in head and neck squamous cell cancers (HNSCC). However, questions remain about the prognostic value of these findings in HNSCC patients with lung metastasis. This study aims to quantify the prognostic impact of NLR on HNSCC patients with lung metastasis. METHODS: A retrospective chart review of 169 HNSCC patients was performed at the Otorhinolaryngology and the Stomatology and Maxillofacial Surgery Department (Saint-Pierre Hospital), between 2000 and 2017. All patients were divided into two subgroups. Patients who developed lung involvement were assigned to the lung-metastasis-group (LM-group) in contrast to no-lung-metastasis-group patients (NLM-group). The prognostic significance of NLR was evaluated using multivariable analysis adjusting for overall-survival (OS) and lung-metastasis-free-survival (LMFS). RESULTS: 95 patients were enrolled in the NLM-group while 74 were in the LM-group. Multivariable analysis highlights that patients with a higher NLR value had shortened OS in the NLM subgroup (HR 1.3; p = 0.024). However, this association was not found in the LM subgroup. When considering both subgroups, an elevated NLR was reported as a prognostic factor of poor LMFS (HR 1.65; p = 0.047). CONCLUSION: Our data revealed that pretreatment NLR is an independent prognostic factor of mortality and lung metastasis development. However, the prognostic value of NLR is not confirmed in patients who suffered from lung metastasis. Physicians should integrate these findings in their treatment algorithm approach.

Prognostic Significance of a Scoring System Combining p16, Smoking, and Drinking Status in a Series of 131 Patients with Oropharyngeal Cancers.

BACKGROUND: Tobacco and alcohol are two main risk factors associated with head and neck squamous cell carcinoma (HNSCC). Studies showed that human papillomavirus (HPV) plays a role in the etiology of this cancer. HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients present in general a better response to conventional therapy and better overall survival (OS). However, OSCC is a heterogeneous disease regarding treatment. This study aimed to identify more effective prognostic factors associated with a poor clinical outcome for OSCC patients to improve treatment selection. MATERIALS AND METHODS: OSCC patients diagnosed between 2007 and 2017, in two Belgian hospitals, were included. Demographic and clinicopathologic data were extracted from medical records. HPV status was determined through p16 immunohistochemistry. Univariable and multivariable Cox proportional hazard regression analyses allowed to identify variables prognostic for OS and recurrence-free survival (RFS). Kaplan-Meier survival curves have been assessed for survival. RESULTS: The study included 131 patients. Statistics showed that monotherapies were significantly associated with a shorter OS; p16 overexpression was significantly associated with a weak consumption of tobacco or alcohol, and a high p16 expression was significantly associated with both longer RFS and OS. The study validated that tobacco and alcohol consumption were significantly correlated with poorer RFS and poorer OS. Only p16 expression trended to be significant for RFS when compared to smoking and drinking habits, while p16 upregulation and alcohol use were both vital for OS indicating that p16 is an independent and significant prognostic factor in OSCC patients. Finally, a scoring system combining p16, tobacco, and alcohol status was defined and was significantly associated with longer RFS and longer OS for nonsmoker and nondrinker p16-positive OSCC patients. CONCLUSIONS: This study confirmed that the overexpression of the p16 protein could be viewed as a factor of good prognosis for RFS and OS of OSCC patients. The prognostic significance of a scoring system combining p16 expression, smoking, and drinking status was evaluated and concluded to be a more effective tool to determine therapeutic orientations based on the risk factors for better treatment relevance and survival.

Cross-Talk Between Mesenchymal Stromal Cells (MSCs) and Endothelial Progenitor Cells (EPCs) in Bone Regeneration.

Bone regeneration is a complex, well-orchestrated process based on the interactions between osteogenesis and angiogenesis, observed in both physiological and pathological situations. However, specific conditions (e.g., bone regeneration in large quantity, immunocompromised regenerative process) require additional support. Tissue engineering offers novel strategies. Bone regeneration requires a cell source, a matrix, growth factors and mechanical stimulation. Regenerative cells, endowed with proliferation and differentiation capacities, aim to recover, maintain, and improve bone functions. Vascularization is mandatory for bone formation, skeletal development, and different osseointegration processes. The latter delivers nutrients, growth factors, oxygen, minerals, etc. The development of mesenchymal stromal cells (MSCs) and endothelial progenitor cells (EPCs) cocultures has shown synergy between the two cell populations. The phenomena of osteogenesis and angiogenesis are intimately intertwined. Thus, cells of the endothelial line indirectly foster osteogenesis, and conversely, MSCs promote angiogenesis through different interaction mechanisms. In addition, various studies have highlighted the importance of the microenvironment via the release of extracellular vesicles (EVs). These EVs stimulate bone regeneration and angiogenesis. In this review, we describe (1) the phenomenon of bone regeneration by different sources of MSCs. We assess (2) the input of EPCs in coculture in bone regeneration and describe their contribution to the osteogenic potential of MSCs. We discuss (3) the interaction mechanisms between MSCs and EPCs in the context of osteogenesis: direct or indirect contact, production of growth factors, and the importance of the microenvironment via the release of EVs.

Survival and treatment outcome of head and neck cancer patients with pulmonary oligometastases.

OBJECTIVES: The purpose of this study was to determine the outcome of head and neck squamous cell carcinoma (HNSCC) patients developing lung metastasis. DESIGN: Retrospective study. PARTICIPANTS: HNSCC patients with lung metastasis treated between 2001 and 2018 were included. MEAN OUTCOMES MEASURES: Statistical analyses described the relationship between patient survival, treatment efficacy and pulmonary metastasis occurrence. RESULTS: One hundred HNSCC patients were included in the study. The median overall survival (OS) was 21 months. The median recurrence-free survival (RFS) was seven months. Patient survival with only lung metastases was significantly longer compared to patients with lung metastases and lymph nodes involvement or other metastases. Moreover, patients with a single metastasis had longer post-RFS and OS than patients with multiple metastases. The local control of metastasis was better when patients presented only lung metastases, and it was more effective in single metastasis. The surgery allowed better metastases local control than supportive care or radio and/or chemotherapy. In case of specific therapy, pulmonary resection was associated with a longer post-RFS and a longer OS compared to supportive care or radio and/or chemotherapy. CONCLUSIONS: We confirmed, in the current study, the significant survival benefit for HNSCC patients treated by surgery for their pulmonary metastasis. While treatment of multiple metastases required palliative chemotherapy or best supportive care in most of the cases, specific surgical treatment in selected HNSCC patients should be considered.

Laryngopharyngeal reflux, gastroesophageal reflux and dental disorders: A systematic review.

OBJECTIVES: To investigate the role of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in the development of dental disorders. METHODS: The first outcome was review of the role of reflux in the development of dental disorders in adults. The second outcome was review of the potential pathophysiological mechanisms underlying the association between reflux and dental disorders. Three investigators screened publications for eligibility and exclusion based on predetermined criteria through a literature search conducted on PubMed, Cochrane Library, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: From 386 publications, 24 studies were kept for analysis. Objective approaches were used in 16 studies to confirm GERD diagnosis. Pharyngeal reflux episodes (LPR) were considered in 2 studies. No study considered nonacid reflux. The study results supported a higher prevalence of dental erosion and caries in reflux patients compared with healthy individuals. Patients with dental erosion have a higher prevalence of reflux than controls. The pathophysiological mechanisms would involve changes in the saliva physiology. No study investigated the microbiota modifications related to reflux although the findings are supporting the critical role of microbiota change in the development of dental disorders. There is an important heterogeneity between studies about diagnostic methods and clinical outcome evaluation. CONCLUSION: The involvement of reflux in the development of dental disorders is not formally demonstrated and requires future investigations considering pharyngeal acid and nonacid reflux episodes and in particular their potential impact on oral microbiota.

Application of the Canadian C-Spine rule and nexus low criteria and results of cervical spine radiography in emergency condition.

INTRODUCTION: The Canadian C Spine Rule (CCR) and the National Emergency X-Radiography Utilization Study (Nexus) low criteria are well accepted as guide to help physician in case of cervical blunt trauma. METHODS: We aimed to evaluate retrospectively the application of these recommendations in our emergency department. Secondly we analyzed the quality of cervical spine radiography (CSR) in an emergency setting. RESULTS: 281 patients with cervical blunt trauma were analyzed retrospectively. The CCR and the NEXUS rules were respected in 91.2% and 96.8% of cases respectively. No lesions were found in 96.4% of patient. A lesion was present in 1.1% of patient and suspected in 2.5% of patient. The quality of CSR was adequate in only 37.7% of patient. The poor quality of CSR was due either to the lack of C7 vertebrae visualization in 64.6% or other lower vertebrae in 28%. Other causes included the absence of open mouth view (8%), the absence C1 vertebrae visualization (3.4%), artifact in 2.3% and the absence of lateral view in 0.6% of patient. CONCLUSION: CCR and NEXUS are widely used in our emergency department. The high rate of inadequate CSR reinforces the debate about it's utility in emergency condition.