Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Treatment modalities and risk factors associated with refractory neurosensory disturbances of the inferior alveolar nerve following oral surgery: a multicentre retrospective study.

Little research has been conducted into hypoesthesia, and no studies have elucidated the risk factors for refractory hypoesthesia and compared treatment modalities. The purpose of this multicentre retrospective cohort study was to investigate the relationships between various risk factors, treatment modalities, and refractory hypoesthesia. Risk factors for refractory hypoesthesia after oral surgery were evaluated using univariate and multivariate analysis. To minimize the selection bias associated with a retrospective data analysis, a propensity score analysis was performed between the medication and non-medication groups (65 sites in each group). Moderate or severe hypoesthesia (odds ratio 13.42) and no or late administration of ATP/vitamin B12 (odds ratio 2.28) were significantly associated with refractory hypoesthesia. In the propensity score analysis, the incidence rate of refractory hypoesthesia in the medication group was lower than that in the non-medication group (P<0.001). This study demonstrated the multivariate relationships between various risk factors, treatment modalities, and refractory hypoesthesia. Moderate or severe hypoesthesia and no or late administration of ATP/vitamin B12 were significantly associated with refractory hypoesthesia. Therefore, clinicians should consider these risk factors and initiate early oral administration of ATP/vitamin B12 in cases of hypoesthesia.

Growth of human cultured cells exposed to a non-homogeneous static magnetic field generated by Sm-Co magnets.

A static magnetic field, with a strong spatial gradient, was established on the surface of cell culture dishes by use of a gilded iron needle set vertically above an Sm-Co magnet. The calculated magnetic flux density was more than 1.5 T at the center of the needle tip, and the products of the flux density and its gradient were about 200 and 60 T2/m at distances of 0.1 and 0.3 mm, respectively, from the center. The DNA content, DNA synthesis and labeling index of cultured cells located within 0.1 mm from the center of the needle, and the growth rate of cells located within 0.3 mm from the center, were measured. HeLa cells grew at a normal rate for 96 h in the magnetic field and showed no significant change in shape, detectable by scanning electron microscopy. The growth of HeLa cells was not influenced by exposure to the magnetic field. Similarly, exposure for 48 h to the magnetic field had no effect on growth of normal human gingival fibroblasts (Gin-1). The DNA content, assayed by microfluorometry of the nuclei of both types of cells stained by the Feulgen reaction, was not significantly different from that of controls. Moreover, exposure to the magnetic field had no effect on DNA synthesis or the labeling index of HeLa cells assayed by autoradiography of incorporated [3H]thymidine. It is concluded that a non-homogeneous magnetic field of the intensity and the gradient used in this study does not significantly influence the growth of HeLa cells or Gin-1 cells.

Effects of seven months' exposure to a static 0.2 T magnetic field on growth and glycolytic activity of human gingival fibroblasts.

Human gingival fibroblasts in confluent cultures were continuously exposed to a static 0.2 T magnetic field for 6 or 8 months. Culture flasks were not changed during the exposure, but culture medium was renewed. After dilution and mixing of the cultures surviving intact, field-exposed and sham-exposed cultures received further field- or sham-exposure on Sm-Co blocks. Rate of cell proliferation, histogram of the nuclear DNA content, rates of lactate production and glucose consumption and the ATP content were determined and cell morphology was investigated by both light- and electron-microscopy. Results show no marked differences between exposed and control cells.

Cytomedical therapy for IgG1 plasmacytosis in human interleukin-6 transgenic mice using hybridoma cells microencapsulated in alginate-poly(L)lysine-alginate membrane.

Cytomedical therapy for human interleukin-6 transgenic mice (hIL-6 Tgm) was implemented by the intraperitoneal injection of alginate-poly(L)lysine-alginate (APA) membranes microencapsulating SK2 hybridoma cells (APA-SK2 cells) which secrete anti-hIL-6 monoclonal antibodies (SK2 mAb). IgG1 plasmacytosis in the hIL-6 Tgm was suppressed by a single injection of APA-SK2 cells, and the survival time of these mice was remarkably prolonged. The viable cell number and the SK2 mAb-secretion of APA-SK2 cells increased for at least one month both under culture conditions and in allogeneic recipients (in vivo). Moreover, SK2 mAb which were secreted from APA-SK2 cells injected into allogeneic recipients was detected in serum at high concentrations; 3-5 mg/ml from day 14 to day 50 post-injection. In contrast, the injection of free SK2 cells had no therapeutic effect on hIL-6 Tgm. These results strongly suggest that APA membranes microencapsulating cells which were modified to secrete molecules useful for the treatment of a disorder were effective as an in vivo long-term delivery system of bioactive molecules, as 'cytomedicine'.

Force-induced osteoclast apoptosis in vivo is accompanied by elevation in transforming growth factor beta and osteoprotegerin expression.

The mechanism controlling the disappearance of osteoclasts from bone surfaces after bone resorption in vivo is largely unknown. This is because there is no suitable experimental system to trace the final fate of osteoclasts. Here, we used an experimental model of tooth movement in rats to show that preexisting osteoclasts disappeared from the bone surface through apoptosis during a force-induced rapid shift from bone resorption to formation. On the distal alveolar bone surface of the maxillary molar in growing rats, many mature osteoclasts were present. When light tensional force was applied to the bone surface through an orthodontic appliance, these preexisting osteoclasts gradually disappeared. One day after the application of force, about 24% of the osteoclasts exhibited apoptotic morphology and the proportion of apoptotic cells was increased to 41% by day 2, then decreased afterward. These changes were undetectable on the control distal alveolar bone surface, which is free from tensional force. As shown by in situ hybridization, a marked increase in transforming growth factor beta1 (TGF-beta1) and osteoprotegerin (OPG) messenger RNA (mRNA) was observed in the stretched cells on the tensioned distal bone surface, simultaneously with the loss of osteoclasts. Both of these factors are known to have a negative effect on osteoclast recruitment and survival. As early as 2 days after force application, some of these stretched cells were identified as cuboidal osteoblasts showing intense signals for both factors. Our data suggest there may be a sequential link in tensional force applied on the bone lining cells, up-regulation of TGF-beta1/OPG, and disappearance of osteoclasts.

Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble polymer in the treatment of choroidal neovascularization.

PURPOSE: The conjugation of drugs with water-soluble polymers such as poly(vinyl alcohol) (PVA) tends to prolong the half-life of drugs and facilitate the accumulation of drugs in tissues involving neovascularization. The purpose of this study was to evaluate the effect of TNP-470-PVA conjugate on the proliferation of endothelial cells in vitro and on experimental choroidal neovascularization (CNV) in vivo. METHODS: TNP-470 was conjugated in PVA by a dimethylaminopyridine-catalyzed reaction. The effects of TNP-470-PVA and free TNP-470 on the proliferation of human umbilical vein endothelial cells (HUVECs) and bovine retinal pigment epithelial cells (BRPECs) were evaluated by the tetrazolium-based colorimetric assay (XTT assay). Experimental CNV was induced by subretinal injection of gelatin microspheres containing basic fibroblast growth factor, into rabbits. Thirty rabbits were intravenously treated either with TNP-470-PVA (n = 8), free TNP470 (n = 5), free PVA (n = 5), or saline (n = 12) daily for 3 days, 2 weeks after implantation of gelatin microspheres. Fluorescein angiography was performed to detect the area with CNV, and the evaluation was made by computerized measurement of digital images. These eyes were also examined histologically. To observe the accumulation of conjugate, 3 rabbits with CNV received rhodamine B isothiocyanate-binding PVA (RITC-PVA), and the lesion was studied 24 hours later by fluorescein microscopy. RESULTS: The TNP-470-PVA inhibited the growth of HUVECs, similar to that of free TNP-470. The BRPECs were less sensitive to TNP-470-PVA than were the HUVECs. TNP-470-PVA significantly inhibited the progression of CNV in rabbits (P = 0.001). Histologic studies at 4 weeks after treatment demonstrated that the degree of vascular formation and the number of vascular endothelial cells in the subretinal membrane of the eyes treated with TNP-470-PVA were less than those of the control eyes. RITC-PVA remained in the area with CNV 24 hours after administration. CONCLUSIONS: These results suggest that TNP-470-PVA inhibited the proliferation of HUVECs more sensitively than that of BRPECs, and the targeted delivery of TNP-470-PVA may have potential as a treatment modality for CNV.

Properties of Ca(2+)-dependent K+ channels of human gingival fibroblasts.

Cells in the oral cavity are normally exposed to different temperatures. Ion transport systems are influenced by temperature in other tissues: In particular, changes in intracellular K+ ion can affect cell growth and synthesis of macromolecules. The purpose of this investigation was to identify K+ channels in human gingival fibroblast cells and analyze the effect of temperature on their K+ conduction properties. Ca(2+)-dependent K+ channels with a large conductance (125 pS in symmetrical K(+)-rich solutions) were identified in human gingival fibroblasts and studied by the patch-clamp technique. The open probability of the channels varied with membrane potential between +40 and -100 mV. When the bath temperature was decreased from 40 to 4 degrees C, channel conductance was reduced, but the mean open time of the channels was increased. The activation energies for the conductance and the reciprocal of the mean open time were estimated to be 9.1 and 22.9 kJ/mol, respectively. These values are lower than those reported for these and other types of channels in cells from other tissues. The open probability of the channels was nearly constant in the temperature range studied. These results suggest that the properties of Ca(2+)-dependent K+ channels of gingival fibroblasts remain relatively unchanged when the cells are exposed to a wide range of temperatures.

Oral and maxillofacial reconstruction using the free rectus abdominis myocutaneous flap. Various modifications for reconstruction sites.

The rectus abdominis myocutaneous flap consists of the skin paddle, anterior rectus sheath, rectus muscle and deep inferior epigastric artery and veins. Of these four components, the skin paddle, rectus sheath and rectus muscle could all be adjusted appropriately for reconstruction sites. Only one or two large perforators in the paraumbilical region could easily supply the large abdominal wall. The bulkiness of the rectus abdominis flap is reduced by removal of subcutaneous fat and rectus muscle. These possibilities can provide many modification of the flap for various reconstruction sites. 16 cases were reconstructed primarily and secondarily using this flap after oral and maxillofacial tumour ablation. The results of these cases indicated a very favourable and reliable vascularity. The rectus abdominis myocutaneous flap was considered to be one of the most suitable flaps for oral and maxillofacial reconstruction. Various modifications for different reconstruction sites are mainly discussed.

Peripheral facial palsy after sagittal split ramus osteotomy for setback of the mandible. A case report.

The case of a 21-year-old man who underwent sagittal split setback osteotomy is described. He experienced facial nerve palsy 2 days after his surgery. However, after physical therapy and the administration of vitamins, he regained normal function within 3 months. The literature related to postoperative facial nerve paralysis is briefly reviewed.

The effect of gap arthroplasty on temporomandibular joint ankylosis: an experimental study.

The aim of this study was to demonstrate the functional and anatomical changes after gap arthroplasty release of unilateral temporomandibular joint (TMJ) ankylosis. Five adult sheep weighing an average of 57 kg were used. All right joints were operated. Ankylosis was induced in the right TMJ by articular damage, disk removal and placement of a bone graft plus immobilization wire. At 3 months the gap arthroplasty were performed. All TMJs were examined functionally, radiologically, macroscopically and histologically. Functionally, the range of jaw movements decreased following induction of ankylosis (P<0.0001), increased immediately on release but was reduced again at 3 months after release (the vertical movement, no statistically significant difference; the right movement, P<0.001; the left movement, P<0.0001). Histologically, all operated joints showed fibrous adhesions across the gap, and further, the articular surface was irregular with osteophytes and with bony islands in the gap. This appearance is more consistent with a fibrous reankylosis than a functioning pseudo joint. This study shows that the gap arthroplasty for TMJ ankylosis did not restore the TMJ functionally and histologically to the preexisting state.

The role of the disk in sheep temporomandibular joint ankylosis.

OBJECTIVE: The purpose of this study was to determine the role of the disk in intraarticular ankylosis of the temporomandibular joint. STUDY DESIGN: Twelve adult sheep were divided into 2 groups. In group 1, removal of the temporal and condylar articular surfaces was performed on the right temporomandibular joint and the disk was maintained; in group 2, removal of the articular surfaces and diskectomy were performed on the right temporomandibular joint. One sheep from each group was killed just after surgery and 5 sheep from each group were killed at 3 months. The joints were examined radiologically, macroscopically, and histologically. The range of jaw movements was recorded preoperatively and at sacrifice. RESULTS: Each of 2 sheep in group 2 had lost 4% of their body weight by 3 months; all of the other sheep maintained or increased their weight. The range of jaw motion to the right was significantly lower in group 2 than in group 1 (P<.01). In group 1, fibrous repair of the articular surface and regeneration of the condylar head was seen. In group 2, each of the joints showed a total fibrous ankylosis with some calcification. There was a statistically significant difference in radiologic score between the groups (P<.0001). Histologic scores for group 1 demonstrated significantly lower scores on the degree of ankylosis scale and degree of calcification scale (P<.0001). CONCLUSIONS: This study showed that the presence of the disk prevented the development of fibrous intraarticular ankylosis of the temporomandibular joint.

Craniofacial skeletal abnormalities in anomalous calves with clefts of the face.

Thirteen anomalous calves with clefts of the face were morphologically examined, and craniofacial skeletons were studied in detail. According to the type and site of the cleft, four groups could be distinguished: median cleft lip and jaw (CLJ); median cleft lip, jaw, and palate (CLJP); lateral CLJ; and cleft palate (CP), including unilateral and bilateral type. Craniofacial skeletal abnormalities were observed in several bones at the roof, wall, and floor of the nasal cavity and at the boundary portion between the nasal and cranial cavities. Fissure formation at the cranial sutures, partial absence of the nasal process of the incisive bone, and opening of the bony palate were characteristic changes in median CLJ and CLJP, lateral CLJ, and CP, respectively. Furthermore, various associated changes were recognized in the median and paramedian skeletal elements of the face and other organs. The morphological changes of craniofacial skeletons with various types of clefts of the face depended on the site and degree of the cleft formation and reflected developmental errors of the facial embryonic segments. These changes would suggest disorders of the correlated development of facial processes and of other fetal organs of the face. For these conditions, etiologically hereditary cases were negative.

Arthroscopic management of temporomandibular closed lock.

Sixty-three consecutive patients with painful closed lock involving 83 temporomandibular joints were treated by surgery and followed up for at least 24 months. Prior to surgical treatment all had imaging to demonstrate that the cause of their painful jaw locking was an anterior displaced disc without reduction. All patients had received at least three months non-surgical treatment without response. The arthroscopic surgery consisted of release of adhesions, manipulation and placement of 25 mg hyaluronic acid into the joint space. No significant surgical complications occurred. Postoperative treatment involved physical therapy and stabilization splints. At 24 months after surgery 57 patients (90.5 per cent) had no pain and month opening had improved from preoperative 27.2 +/- 5.4 mm to 44.4 +/- 4.1 mm (p < 0.001). This study shows that arthroscopic surgery with continuing non-surgical therapy is a highly effective treatment for painful closed lock.

Pull-through technique of scapular osteocutaneous flap to decrease frequency of positioning change.

During reconstructions of the head and neck regions with a scapular or a scapular osteocutaneous flap, it is usually necessary to reposition the patient twice and prepare the operating field three times for removal of tumor, harvesting the flap, and reconstruction. This is one of the main disadvantages of the scapular flap. We have used the pull-through technique to reduce the number of changes in position that are required. In addition, the ischaemic time of the flap is also substantially reduced. The flap is first raised and then tunneled through the axilla to lie passively on the chest while the tumor is excised. These procedures have been followed in 13 cases of scapular and scapular osteocutaneous flap with no problems.

Synovial chondromatosis of the temporomandibular joint.

We report two cases of temporomandibular joint (TMJ) synovial chondromatosis, one of which was in the early stage and treated arthroscopically. The second was more advanced and recurred after removal of the free bodies, and so required condylectomy and synovectomy.

Arthroscopic surgery of the temporomandibular joint: comparison of two successful techniques.

We have compared two techniques of arthroscopic surgery for advanced internal derangement of the temporomandibular joint (TMJ). Patients with stage III or above TMJ internal derangement, who had not responded to three months of non-surgical treatment, were prospectively and randomly assigned to one of two types of treatment. One group had arthroscopic lysis and lavage (ALL) and the other had ALL plus arthroscopic anterolateral capsular release (AALCR). All patients were assessed preoperatively, and at 1, 3, 6, and 12 months postoperatively. Thirty-five patients (41 joints) had ALL and 66 patients (73 joints) had AALCR. The only significant difference was at 1 month, when the ALL group could not open their mouths as far as the AALCR group (P < 0.01). Both groups had significantly less pain in the joint and better jaw opening one year postoperatively. The stage of disease did not affect the outcome. Both ALL and AALCR gave good results in the management of advanced internal derangement of the TMJ. Unless early wide mouth-opening is required, the less invasive procedure of lysis and lavage should be chosen.

Regeneration of the mandibular condyle after unilateral condylectomy and myotomy of the masseter in lambs.

We investigated the degree of regeneration of the mandibular condyle after unilateral condylectomy and myotomy of the masseter in growing lambs. Four 10-week-old lambs had unilateral condylectomy and myotomy of the superficial layer of the masseter on the right side, and were killed 3 months later. The joints were examined radiologically and histologically. All joints showed poor regeneration of the condylar head. In the medial plane there was partial condylar and articular cartilage reformation, but in the lateral plane there was neither condylar nor cartilaginous reformation. The articular cartilage of the temporal bone was thicker in the medial plane and the disc was thicker in the central plane, than in unoperated joints. We conclude that unilateral condylectomy and myotomy of the masseter in the growing period results in poor regeneration of the condyle.

Effect of partial immobilization on reconstruction of ankylosis of the temporomandibular joint with an autogenous costochondral graft:an experimental study in sheep.

The purpose of this study was to show the effect of partial immobilization of a costochondral graft reconstruction of an ankylosed temporomandibular joint (TMJ) in five adult sheep. Ankylosis was induced in all right TMJs. At three months, a graft was inserted and partially immobilized. Three months after the second operation, four sheep were killed by an overdose with pentothal. One sheep was killed at one month because of infection. Functionally, the body weight, which decreases with ankylosis, did not recover after insertion of the graft and the range of jaw movements got worse. Histologically, the grafts were well attached to the mandibular rami in three of four joints. In one joint, the graft showed signs of resorption and a foreign body reaction. We conclude that, if the reconstructed joint is partially immobilized, then there will be a degree of reankylosis. There was also a high failure rate.

Effect of limited jaw motion on ankylosis of the temporomandibular joint in sheep.

The purpose of this study was to investigate the effect of limited movement of the jaw on ankylosis of the temporomandibular joint (TMJ). Eighteen adult sheep were divided into two groups. In Group 1, the temporal and condylar articular surfaces were removed together with the disc on the right. In Group 2, we did the same procedures but in addition the jaw movements were limited by a wire. One sheep was killed just after the operation, four at one month, and four at three months, in each group. The range of jaw movements preoperatively and at the time of death were recorded. The joints were examined radiologically, macroscopically, and histologically. We used a scoring system to assess the radiological changes and histological extent of ankylosis. At one month, the joint spaces were filled with fibrous tissue, but a small joint space existed in all four joints in Group 1. In Group 2, there was full ankylosis in two joints and partial ankylosis in two joints. At three months, similar ankylotic changes were seen in both groups. The histological score for ankylosis at one month showed that those in Group 2 were significantly more ankylosed than in Group 1 (P<0.01). The range of jaw movements was more limited at one month in Group 2, both vertically and to the left, and was significantly decreased in both groups (P<0.01) at three months. Limitation of jaw motion hastens the progress of TMJ ankylosis.