Incidence of maxillary sinusitis and oro-antral fistulae in bisphosphonate-related osteonecrosis of the jaw

ObjectiveBisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious side-effect of bisphosphonate therapy. In the majority of cases BRONJ occurs in the mandible. As a consequence a detailed investigation of BRONJ of the maxilla and in particular of involvement of the maxillary sinus has largely so far been neglected. The aim of this study was to analyse the frequency of maxillary sinusitis and oro-antral fistulae in BRONJ of the maxilla.Subjects and methodsA retrospective multicentre analysis was carried out in three Departments of Oral and Maxillofacial Surgery focussing on patients suffering from BRONJ in the maxilla. The role of involvement of the maxillary sinus, in particular sinusitis and oro-antral fistula, was analysed.ResultsOut of a total of 170 patients suffering from BRONJ 53 cases (31.2%) with involvement of the maxilla were identified. At least one sign of maxillary sinusitis was present in 43.6% (23/53) and an oro-antral fistula in the course of the disease was detected in 35.8% (19/53) of those patients. The mean length of time of bisphosphonate intake was 36.16 ± 16.32 months. Zoledronate was most frequently associated (60.4%) with symptoms, followed by the combination of Zoledronate/Ibandronate (13.2%), and Zoledronate/Pamidronate or Pamidronate alone (both 7.5%).ConclusionMaxillary sinusitis and oro-antral fistulae are associated with a BRONJ manifestation in the upper jaw in approximately 44%. The involvement of the maxillary sinus should be given special attention and three-dimensional imaging modalities might be necessary, not only to evaluate the extent of necrosis, but also to exclude involvement of the maxillary sinus.     

The effect of current used bone substitution materials and platelet-rich plasma on periosteal cells by ectopic site implantation: An in-vivo pilot study

The aim of this study was to investigate de novo bone formation following ectopic site implantation of bone substitutes covered by periosteum, with and without the application of autologous platelet-rich plasma (PRP). Twenty-four weeks after subcutaneous implantation of various bone substitutes (bovine hydroxyapatite (bHAP), phycogenic hydroxyapatite (pHAP), and bioglass (BG)) in 35 mini-pigs, bone regeneration rates were compared microradiographically and histologically. Without PRP, bHAP showed a mean de novo bone formation of 32.41% ± 29.99, in contrast to the other substitute materials where no mineralization could be detected. In combination with PRP, in the bHAP (63.61% ± 12.98; p ± 0.03) and pHAP (34.37 ± 29.38; p = 0.015) group, significantly higher de novo bone formation was ascertained than without PRP. No ossification could be detected in the BG group. In conclusion, bHAP and pHAP bone substitutes in combination with PRP showed a significant positive effect on periosteal cells by de novo bone formation after ectopic, subcutaneous, low-vascular site implantation.     

Current trends and future perspectives of bone substitute materials – From space holders to innovative biomaterials

An autologous bone graft is still the ideal material for the repair of craniofacial defects, but its availability is limited and harvesting can be associated with complications. Bone replacement materials as an alternative have a long history of success. With increasing technological advances the spectrum of grafting materials has broadened to allografts, xenografts, and synthetic materials, providing material specific advantages. A large number of bone-graft substitutes are available including allograft bone preparations such as demineralized bone matrix and calcium-based materials. More and more replacement materials consist of one or more components: an osteoconductive matrix, which supports the ingrowth of new bone; and osteoinductive proteins, which sustain mitogenesis of undifferentiated cells; and osteogenic cells (osteoblasts or osteoblast precursors), which are capable of forming bone in the proper environment. All substitutes can either replace autologous bone or expand an existing amount of autologous bone graft.Because an understanding of the properties of each material enables individual treatment concepts this review presents an overview of the principles of bone replacement, the types of graft materials available, and considers future perspectives. Bone substitutes are undergoing a change from a simple replacement material to an individually created composite biomaterial with osteoinductive properties to enable enhanced defect bridging.     

Early release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation

This article presents a treatment strategy for early release of interalveolar synechiae, aiming to facilitate early oral feeding and prevent temporomandibular joint ankylosis.The treatment results of 2 patients with van der Woude syndrome were retrospectively studied. Both patients underwent early surgical release of interalveolar synechiae under general anesthesia through fiberscopic nasal intubation. The 2 patients were treated at the ages of 6 and 14 days, respectively. The interincisival distances increased from 5 and 6 mm preoperatively to 11 and 10 mm immediately after surgery. This was increased further to 25 and 20 mm at long-term follow-up (6 and 24 months).In conclusion, synechiae between the upper and lower jaws can be safely treated at a very early age under general anesthesia with fiberscopic nasotracheal intubation. The purpose of early intervention in these cases is to facilitate oral feeding and prevent temporomandibular joint ankylosis.     

Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors

Chronic myeloid leukemia in chronic phase (CML-CP) is induced by BCR-ABL1 oncogenic tyrosine kinase. Tyrosine kinase inhibitors eliminate the bulk of CML-CP cells, but fail to eradicate leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) displaying innate and acquired resistance, respectively. These cells may accumulate genomic instability, leading to disease relapse and/or malignant progression to a fatal blast phase. In the present study, we show that Rac2 GTPase alters mitochondrial membrane potential and electron flow through the mitochondrial respiratory chain complex III (MRC-cIII), thereby generating high levels of reactive oxygen species (ROS) in CML-CP LSCs and primitive LPCs. MRC-cIII-generated ROS promote oxidative DNA damage to trigger genomic instability, resulting in an accumulation of chromosomal aberrations and tyrosine kinase inhibitor-resistant BCR-ABL1 mutants. JAK2(V617F) and FLT3(ITD)-positive polycythemia vera cells and acute myeloid leukemia cells also produce ROS via MRC-cIII. In the present study, inhibition of Rac2 by genetic deletion or a small-molecule inhibitor and down-regulation of mitochondrial ROS by disruption of MRC-cIII, expression of mitochondria-targeted catalase, or addition of ROS-scavenging mitochondria-targeted peptide aptamer reduced genomic instability. We postulate that the Rac2-MRC-cIII pathway triggers ROS-mediated genomic instability in LSCs and primitive LPCs, which could be targeted to prevent the relapse and malignant progression of CML.     

Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment

The interactions between hematopoietic cells and the bone marrow (BM) microenvironment play a critical role in normal and malignant hematopoiesis and drug resistance. These interactions within the BM niche are unique and could be important for developing new therapies. Here, we describe the development of extramedullary bone and bone marrow using human mesenchymal stromal cells and endothelial colony-forming cells implanted subcutaneously into immunodeficient mice. We demonstrate the engraftment of human normal and leukemic cells engraft into the human extramedullary bone marrow. When normal hematopoietic cells are engrafted into the model, only discrete areas of the BM are hypoxic, whereas leukemia engraftment results in widespread severe hypoxia, just as recently reported by us in human leukemias. Importantly, the hematopoietic cell engraftment could be altered by genetical manipulation of the bone marrow microenvironment: Extramedullary bone marrow in which hypoxia-inducible factor 1α was knocked down in mesenchymal stromal cells by lentiviral transfer of short hairpin RNA showed significant reduction (50% ± 6%; P = .0006) in human leukemic cell engraftment. These results highlight the potential of a novel in vivo model of human BM microenvironment that can be genetically modified. The model could be useful for the study of leukemia biology and for the development of novel therapeutic modalities aimed at modifying the hematopoietic microenvironment.     

Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.