Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

The role of histology in the diagnosis of spondylodiscitis: correlation with clinical and microbiological findings.

AIMS: The aim of this study was to determine the diagnostic utility of histological analysis in spinal biopsies for spondylodiscitis (SD). PATIENTS AND METHODS: Clinical features, radiology, results of microbiology, histology, and laboratory investigations in 50 suspected SD patients were evaluated. In 29 patients, the final (i.e. treatment-based) diagnosis was pyogenic SD; in seven patients, the final diagnosis was mycobacterial SD. In pyogenic SD, the neutrophil polymorph (NP) infiltrate was scored semi-quantitatively by determining the mean number of NPs per (×400) high-power field (HPF). RESULTS: Of the 29 pyogenic SD patients, 17 had positive microbiology and 21 positive histology (i.e. one or more NPs per HPF on average). All non-SD patients showed less than one NP per HPF. The presence of one or more NPs per HPF had a diagnostic sensitivity of 72.4%, specificity 100%, accuracy 100%, positive predictive value (PPV) 81.0%, and negative predictive value (NPV) 61.9%. Sensitivity, specificity, and accuracy were greater using the criterion of positive histology and/or microbiology than positive histology or microbiology alone. Granulomas were identified histologically in seven mycobacterial SD patients, and positive microbiology was detected in four. CONCLUSION: The diagnosis of pyogenic SD was more often confirmed by positive histology (one or more NPs per HPF on average) than by microbiology, although diagnostic sensitivity was greater when both histology and microbiology were positive. Cite this article: Bone Joint J 2019;101-B:246-252.

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.

Localised foot and ankle amyloid deposition.

BACKGROUND: Localised (transthyretin-associated) amyloid is commonly seen in articular/periarticular tissues of elderly individuals. Whether age-associated, amyloid deposition occurs in foot and ankle (F&A) tissues has not previously been investigated. In this study we assessed the nature and frequency of F&A amyloid deposition and determined whether it is associated with age and/or specific articular/periarticular F&A lesions. METHODS: Histological sections of twenty five normal F&A articular/periarticular tissues (16-71 years) and a range of F&A lesions were stained by Congo Red. The amyloid protein was identified by immunohistochemistry and type of matrix glycosaminoglycans determined by Alcian Blue (critical electrolyte concentration) histochemistry. RESULTS: Amyloid deposits were found in the joint cartilage and capsule of 3/25 normal specimens (57, 62 and 78 years). Amyloid deposits were small, contained transthyretin, and found in areas of matrix degeneration associated with the presence of highly sulphated glycosaminoglycans. In patients older than 47 years, small amyloid deposits were noted in some F&A lesions, including osteoarthritis, Charcot arthropathy, bursa, ganglion, chondrocalcinosis, gout, calcific tendonitis and Achilles tendonitis. CONCLUSION: Small localised amyloid deposits in F&A tissues contain transthyretin and occur in areas of matrix degeneration associated with the presence of highly sulphated glycosaminoglycans; these deposits are age-associated and, although seen more commonly in some F&A lesions, are small and unlikely to be of pathogenic significance.

Survival of Brånemark System Mk III implants and analysis of risk factors associated with implant failure.

The purpose of this study was to retrospectively investigate the outcomes of Brånemark System Mk III TiUnite/Groovy implants placed in patients at Kobe University Hospital. Various risk factors for implant failure, including mechanical coupling, were investigated by univariate and multivariate analysis. The predictive variables investigated included age, sex, smoking habit, general health, history of radiation therapy, application of a dentomaxillary prosthesis, type of prosthesis, use of alveolar bone augmentation, site of implant insertion, mechanical coupling between implants, and the length and diameter of the implants. Of the 907 implants investigated, only 23 were unsuccessful; the overall survival rate was 96.7%. Increased age, radiation therapy, application of a removable prosthesis or dentomaxillary prosthesis, lack of mechanical coupling between implants, and shorter implants (≤8.5mm) were significant risk factors for implant failure according to univariate analysis (P<0.05). Multivariate analysis identified a significant association (P<0.05) between dental implant failure and a lack of mechanical coupling between implants (odds ratio 6.88) and shorter implants (≤8.5mm) (odds ratio 3.43). The findings of this study demonstrated multivariate relationships between various risk factors and dental implant failure.

Visual function 5 years or more after macular translocation surgery for myopic choroidal neovascularisation and age-related macular degeneration.

PURPOSE: To evaluate the changes in the best-corrected visual acuity (BCVA) after 1 year and after ≥ 5 years after macular translocation for age-related macular degeneration (AMD) or myopic choroidal neovascularisation (mCNV). METHODS: The medical records of 61 consecutive patients who underwent macular translocation with 360° retinotomy for AMD (35 eyes) or mCNV (26 eyes) were reviewed. Overall, 40 patients, 17 mCNV and 23 AMD, were followed for at least 5 years. BCVA and area of the Goldmann visual field (VF) measured before, 12 months after surgery, and at the final visit. RESULTS: In the 23 AMD eyes followed for ≥ 5 years, the mean preoperative BCVA was 1.149 ± 0.105 logMAR units, which significantly improved to 0.69 ± 0.06 logMAR units at 1 year (P<0.001). This BCVA was maintained at 0.633 ± 0.083 logMAR units on their final examination. In the 17 eyes with mCNV followed for ≥ 5 years, the mean preoperative BCVA was 1.083 ± 0.119 logMAR units, which was significantly improved to 0.689 ± 0.121 logMAR units at 1 year (P = 0.001). This BCVA was maintained at 0.678 ± 0.142 logMAR units on their final examination. The area of the VF was significantly decreased at 12 months and did not change significantly thereafter. CONCLUSIONS: Our results show that macular translocation surgery significantly improves the BCVA and significantly decreases the VF area of eyes with mCNV or AMD after first 1 year. The BCVA and VF area do not change significantly from the values at 1 year for at least 5 years.

The association of Pro12Ala polymorphism in PPARgamma2 with lower carotid artery IMT in Japanese.

In this study, the association of the Pro12Ala peroxisome proliferator-activated receptor gamma2 (PPARgamma2) polymorphism with atherosclerosis was examined in a Japanese Type 2 diabetic population. PPARgamma has been identified as a key regulator of adipogenesis. Recently, some studies reported that the Pro12Ala polymorphism was associated with resistance to Type 2 diabetes. It is well-known that Type 2 diabetes is closely related with disorder of lipid metabolism as well as impaired glucose homeostasis, resulting in atherosclerosis. We aimed to evaluate the association between carriers of the Pro12Ala PPARgamma2 mutation and clinical profiles concerning atherosclerosis besides plasma glucose and lipid concentrations. Screening for the mutation was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method among 154 Type 2 diabetic patients. The homozygotes of the Pro12 allele were 143 (93%), the heterozygotes of the Pro12 and Ala12 allele were 11 (7%) and the homozygote of the Ala12 allele was not detected. The group with the Ala12 allele had a significantly lower value of carotid artery intima-media thickness (IMT) than that without it, although there was no difference between two groups in sex, age or other clinical variables we examined. The Pro12Ala PPARgamma2 polymorphism may be associated with carotid artery IMT values in Type 2 diabetes mellitus.

[Arch translocation method for an arch aneurysm with open stent grafting using a nephrostomy catheter].

An 81-year-old female found to have an aneurysm in the distal aortic arch was successfully treated with arch translocation method. Under selective cerebral perfusion, a stent graft bound to a nephrostomy balloon catheter with a chainstitch was inserted from the ascending aorta into the descending aorta and its proximal end was sutured together with the distal aortic stump. Then a 4-branched Dacron graft replaced the ascending aorta reconstructing cephalobracheal branches individually. Each proximal end of cephalobracheal branches was ligated. The patient had no neurological deficit except for recurrence nerve palsy that had already existed before the operation. Postoperative angiography revealed complete thrombocclusion of the aneurysm.

Early and long-term results of cardiovascular surgery in octogenarians.

The purpose of this study was to evaluate characteristics and outcomes of octogenarians undergoing cardiovascular surgery with cardiopulmonary bypass in a Japanese population. Thirty-one consecutive patients over 80 years of age underwent coronary artery bypass grafting 19 (61%), combined coronary artery bypass grafting and ventricular septal perforation closure 1 (3%), valve replacement 3 (10%), and prosthetic graft replacement 8 (26%). The early mortality rate was 16.1%. Survival estimates were 74% after 1 year, 74% after 3 year, and 64% after 5 years. Emergency and urgent cases involved 16 (51.6%), and 2 patients (6.5%), respectively. Multivariate analyses revealed that predictors of early mortality was preoperative left ventricular ejection fraction. Predictors of hospital death (within 3 months after surgery) were preoperative renal dysfunction, intraaortic balloon pumping, and age. Predictors of late mortality were chronic lung disease and age. Twenty-one patients expected to have died before surgery were living at home, and 9 (40.9%) patients were completely autonomous. Multivariate analyses revealed diabetes mellitus and a small number of bypass grafts were predictive risk factors for postoperative autonomy. Thus, cardiovascular surgery can be performed in octogenarians under 85 years of age with a favorable long-term outcome, when appropriately applied in selective octogenarians without significant comorbidity. If patients are over 85 years of age or have significant comorbidity, clinical treatment recommendations should be individually tailored while evaluating the risk of having or not having surgery and their life expectancy. QOL of survivors was almost satisfactory and significantly improved compared with a preoperative state.

Regulation of c-Myb activity by tumor suppressor p53.

Heat shock proteins (HSPs) act as chaperones and play important roles during cellular proliferation and apoptosis. Heat shock factors (HSFs) mediate transcriptional induction of HSP genes. Among multiple heat shock transcription factors (HSFs) in vertebrates, HSF3 is specifically activated in unstressed proliferating cells by direct binding to the c-myb proto-oncogene product (c-Myb). Since c-Myb has an important role in cellular proliferation, this regulatory pathway suggests a link between the events of cellular proliferation and the stress response. The c-Myb-induced activation of HSF3 is negatively regulated by the p53 tumor suppressor protein. p53 directly binds to HSF3 and blocks the interaction between c-Myb and HSF3. In addition, p53 stimulates the degradation of c-Myb, which is, at least partly, mediated by induction of Siah in certain types of cells. Thus, c-Myb and p53 regulate the expression of HSPs via HSF3 in opposite ways.

Role of PML and PML-RARalpha in Mad-mediated transcriptional repression.

Fusion of the promyelocytic leukemia (PML) protein to the retinoic acid receptor-alpha (RARalpha) generates the transforming protein of acute promyelocytic leukemias. PML appears to be involved in multiple functions, including apoptosis and transcriptional activation by RAR, whereas PML-RARalpha blocks these functions of PML. However, the mechanisms of leukemogenesis by PML-RARalpha remain elusive. Here we show that PML interacts with multiple corepressors (c-Ski, N-CoR, and mSin3A) and histone deacetylase 1, and that this interaction is required for transcriptional repression mediated by the tumor suppressor Mad. PML-RARalpha has the two corepressor-interacting sites and inhibits Mad-mediated repression, suggesting that aberrant binding of PML-RARalpha to the corepressor complexes may lead to abrogation of the corepressor function. These mechanisms may contribute to events leading to leukemogenesis.

Induction of primer pheromone production by dihydrotestosterone in the male goat.

Castrated goats were treated with dihydrotestosterone (DHT) for four weeks. Skin samples were collected from the head and the rump regions before and after the DHT treatment. The primer pheromone activities of these samples were assessed neurophysiologically by recording electrophysiological manifestations of the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator activity. Pheromone activity was detected in both the head and rump skin samples following the DHT treatment, although the development of sebaceous glands was limited to the head region. Taken together with our previous finding that testosterone treatment results in the appearance of primer pheromone activity in the skin sample of the head region but not of the rump region. these observations suggests that the regional difference of pheromone production would be ascribed to intrinsic expression levels of 5alpha-reductase, an enzyme converting testosterone to DHT.

[A case report of Ebstein's anomaly treated with Hetzer's procedure].

A 27-year-old male who had been diagnosed with Ebstein's anomaly was admitted with uncontrollable congestive heart failure. The echocardiogram revealed severe tricuspid valve incompetence and the electrocardiogram showed atrial fibrillation. He underwent Hetzer's repair procedure for tricuspid valve incompetence and Minzioni's right atrial isolation technique to restore sinus rhythm. His congestive heart failure quickly disappeared and sinus rhythm was restored after operation. He was discharged 3 weeks postoperatively and remains well 22 months after his operation. Hetzer's technique for tricuspid valve repair in Ebstein's anomaly restructures the valve mechanism at the level of the true tricuspid anulus by using the most mobile leaflet for valve closure without plication of the atrialized chamber. We conclude that Hetzer's procedure is an effective operation for Ebstein's anomaly.

New multidrug resistance modulators from Atractylodis Lanceae Rhizoma.

Three new oligoacylated sucroses designated atractysucroses-I, -II, and -III were obtained from Atractylodis Lanceae Rhizoma as multidrug resistance (MDR) modulating substances against human carcinoma cell lines and their chemical structures were characterized as a mixture of acyl groups. Atractysucrose-I modulates MDR in KB-C2 cells as strongly as verapamil. This is the first example of an MDR-modulator classified as a carbohydrate.

Diversity of T cell repertoire shaped by a single peptide ligand is critically affected by its amino acid residue at a T cell receptor contact.

T cell differentiation in the thymus is driven by positive selection through the interaction of alphabeta T cell receptors (TCRs) with self-peptides bound to self-major histocompatibility complex molecules, yet the influence of the peptide sequence on this process remains unknown. To address this issue, we have compared CD4(+) T cell differentiation between two sets of mouse lines in which MHC class II I-A(b) molecules are occupied with either Ealpha chain-derived peptide ((p)Ealpha) or its variant, (p)60K, with one amino acid substitution from leucine to lysine at P5 residue of TCR contacts. Here, we show that despite the comparable expression of I-A(b)-peptide complex in the thymus, this substitution from leucine to lysine affects efficiency of positive selection, resulting in extremely small numbers of CD4(+) T cells to be selected to mature on I-A(b)-(p)60K complex. Furthermore, we show that, although I-A(b)-(p)Ealpha complex selects diverse T cells, T cell repertoire shaped by I-A(b)-(p)60K complex is markedly constrained. Our findings thus suggest that positive selection is both specific and degenerate, depending on the amino acid residues at TCR contacts of the selecting self-peptides.

Regional differences of pheromone production in the sebaceous glands of castrated goats treated with testosterone.

The primer pheromone is responsible for the "male effects" in goats and produced in the sebaceous glands testosterone-dependently. In the present study, the responses of sebaceous glands obtained from the head and rump regions of castrated goats were examined by our bioassay system after testosterone treatment to demonstrate the presence of regional differences in the pheromone production in male goats. The testosterone treatment resulted in the marked development of sebaceous glands and the induction of pheromone bioactivity in the head region of the goats. On the contrary, this treatment brought neither development of the sebaceous glands nor induction of pheromone bioactivity in the rump region. The treatment increased immunoreactivities to androgen receptors (AR) and 5alpha-reductase in the sebaceous glands of both regions, although the activities were more apparent in the head region than the rump region. These findings suggest that the primer pheromone of male goats is produced specifically in the sebaceous glands of the head region due partly to regional differences in the expression of AR and 5alpha-reductase mediating testosterone bioactivities.

Atherosclerotic aneurysm of the intrathoracic segment of the subclavian artery: a case report.

True aneurysms of the intrathoracic segment of the subclavian artery are extremely rare. Atherosclerosis is the most common etiology. The surgical approach and timing of repair remain controversial. We successfully treated a patient with a large proximal subclavian artery aneurysm which was secondary to atherosclerosis. The patient was asymptomatic for 30 years as the aneurysm enlarged. Three-dimensional computed tomography provided the most useful information regarding anatomy of the cervical vasculature. The patient underwent closure of the inlet port of the aneurysm and repair using a 6-mm Dacron bypass graft (Gelsoft , VASCTEK, Scotland) via a minimally invasive surgical approach.

Malassezia pachydermatis isolated from a South American sea lion (Otaria byronia) with dermatitis.

A fungus was isolated from the skin of an Otaria byronia and from the water of the pool in which the animal was kept. It formed creamy colonies with soft texture on Dixon agar and grew well without supplements of long-chain fatty acids. Cells were ovoid to cylindrical in shape, budded from a broad base, and budded and divided at the same location. Thus, the isolate was identified as M. pachydermatis. We compared this very rare isolate from a marine mammal with four strains of M. pachydermatis using the freeze-etching electron-microscopy technique. The cells showed the same characteristic ring-swellings on the protoplasmic membrane on the neck site between the mother and the daughter parts, and the same accumulation of circumvallate bulgings in a small area near the straight sections of spiral grooves as four reference strains. Thus, in terms of morphology and ultrastructure, the isolate could be regarded as a typical M. pachydermatis.