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.

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.

A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ?

Root amputation, extraction of a single tooth, bone loss or severe tooth mobility, and an unclosed wound were significantly associated with increased risk of developing medication-related osteonecrosis of the jaw (MRONJ). We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. INTRODUCTION: Osteonecrosis of the jaws can occur following tooth extraction in patients receiving bisphosphonate drugs. Various strategies for minimizing the risk of MRONJ have been advanced, but no studies have comprehensively analyzed the efficacy of factors such as primary wound closure, demographics, and drug holidays in reducing its incidence. The purpose of this study was to retrospectively investigate the relationships between these various risk factors after tooth extraction in patients receiving oral bisphosphonate therapy. METHODS: Risk factors for MRONJ after tooth extraction were evaluated using univariate and multivariate analysis. All patients were investigated with regard to demographics; type and duration of oral bisphosphonate use; whether they underwent a discontinuation of oral bisphosphonates before tooth extraction (drug holiday), and the duration of such discontinuation; and whether any additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 6.64), extraction of a single tooth (OR = 3.70), bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were significantly associated with increased risk of developing MRONJ. CONCLUSIONS: We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. We find no evidence supporting the efficacy of a pre-extraction short-term drug holiday from oral bisphosphonates in reducing the risk of MRONJ.

Preoperative prediction for regaining ambulatory ability in paretic non-ambulatory patients with metastatic spinal cord compression.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To analyze the predictive factors for postoperative ambulatory recovery in paretic non-ambulatory patients with metastatic spinal cord compression (MSCC). SETTING: Japan. METHODS: Eighty-two consecutive patients (74.4% men; mean age, 66.2 years) who could not walk before surgery due to cervical or thoracic MSCC and underwent posterior decompressive surgery between 2003 and 2014 were included. Patients were divided into two groups according to ambulatory status at 6 weeks after surgery: recovery (group R) and non-recovery (group NR). To evaluate the speed of progression of motor deficits, we assessed the period from onset of neurological symptoms to gait inability (T1). RESULTS: Fifty patients (61.0%) regained the ability to walk (group R). The period of T1 demonstrated a positive correlation with probability of ambulatory recovery (P=0.00; Kendall's tau-b=0.38), and a receiver operating characteristic curve analysis showed that the cutoff value of T1 was 5 days (area under the curve=0.72; P=0.001). In multivariate analysis, <6 days of T1 was one of the independent risk factors for failing to regain ambulatory ability (odds ratio, 8.74; P=0.00). CONCLUSIONS: The speed of progression of motor deficits can independently and powerfully predict the chance of postoperative ambulatory recovery as well as previously identified predictors. Since information about the speed of progression can be obtained easily by interviewing patients or family members, even if the patient is in an urgent state, our results will be helpful in clinical decision-making.

Evaluation of masticatory function after maxillectomy using a colour-changing chewing gum.

The purpose of this study was to identify the risk factors associated with the masticatory dysfunction after maxillectomy using a colour-changing chewing gum. Thirty-nine patients who underwent maxillectomy between January 2002 and May 2010 in the Department of Kobe University Hospital were recruited for this study. There were 20 male and 19 female subjects, with a median age of 73·3 years (range of 44-90) at the time of surgery. The intra-oral conditions after maxillectomy were classified by HS classification, and the masticatory function was evaluated by a colour-changing chewing gum and the results of a modified Sato's questionnaire. The scores of the colour-changing gum were closely correlated with the scores of the modified Sato's questionnaire (r = 0·661, P < 0·01). A logistic regression analysis with the outcome variable of the gum test <4 demonstrated that significant predictors for the masticatory dysfunction were the number of anchor teeth ≤2 and a soft palate defect. A colour-changing gum was found to be useful for evaluating the post-operative masticatory function, and it was important to conserve the anchor teeth and the soft palate to avoid masticatory dysfunction.

Evaluating the masticatory function after mandibulectomy with colour-changing chewing gum.

The aim of this study was to clarify the usefulness of colour-changing gum in evaluating masticatory performance after mandibulectomy. Thirty-nine patients who underwent mandibulectomy between 1982 and 2010 at Kobe University Hospital were recruited in this study. There were 21 male and 18 female subjects with a mean age of 64·7 years (range: 12-89 years) at the time of surgery. The participants included six patients who underwent marginal mandibulectomy, 21 patients who underwent segmental mandibulectomy and 12 patients who underwent hemimandibulectomy. The masticatory function was evaluated using colour-changing chewing gum, gummy jelly and a modified Sato's questionnaire. In all cases, the data were obtained more than 3 months after completing the patient's final prosthesis. The colour-changing gum scores correlated with both the gummy jelly scores (r = 0·634, P < 0·001) and the total scores of the modified Sato's questionnaire (r = 0·537, P < 0·001). In conclusion, colour-changing gum is a useful item for evaluating masticatory performance after mandibulectomy.

COVID-19 transmission in dental and oral/maxillofacial surgical practice during pandemic: questionnaire survey in 51 university hospitals in Japan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a major public health problem. Dental procedures that generate aerosols are considered to impose a high risk of infection; therefore, dental professionals, such as dentists and dental hygienists, may be at high risk of viral transmission. However, few studies have reported COVID-19 clusters in dental care settings. AIM: To investigate whether dental and oral/maxillofacial procedures are associated with the occurrence of COVID-19 clusters and measures taken to prevent nosocomial infection in dental clinics. METHODS: An online questionnaire survey on clinical activities (administrative control), infection control measures (environmental/engineering control, personal protective equipment, etc.), and confirmed or probable COVID-19 cases among patients and clinical staff was administered to the faculties of the dental and oral/maxillofacial surgical departments of university hospitals. FINDINGS: Fifty-one faculty members completed the questionnaire. All members were engaged in the treatment of dental and oral surgical outpatients and actively implemented standard precautions. Fourteen faculty members treated patients with COVID-19, but no infections transmitted from the patients to the medical staff were observed. In seven facilities, patients were found to have the infection after treatment (medical staff came in close contact), but there was no transmission from patients to medical staff. Four facilities had medical staff with infections, but none of them exhibited disease transmission from staff to patients. CONCLUSION: COVID-19 clusters are unlikely to occur in dental and oral surgical care settings if appropriate protective measures are implemented.

Pharmacokinetics of cyclosporine A at a high-peak concentration of twice-daily infusion and oral administration in allogeneic haematopoietic stem cell transplantation.

WHAT IS KNOWN AND OBJECTIVE: The most appropriate immunosuppressive strategy with calcineurin inhibitors for the prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) has not yet been established. To estimate the safety and efficacy of a new strategy, we investigated the pharmacokinetics of cyclosporine A (CyA) delivered by twice-daily infusion and oral administration maintained with a peak level above 1000 ng/mL to keep 24 h area under the concentration-time curve (AUC0-24) higher than 10 000 ng·h/mL in 12 patients. METHODS: Cyclosporine A was started as a twice-daily infusion at 1·5 mg/kg and then orally administered at twice the infusion dose to maintain the trough blood concentration between 200 and 500 ng/mL, and with a peak level above 1000 ng/mL. Serial blood samples were collected at 0, 1, 2, 3, 5, 8 and 12 h after CyA dosing (C0, C1, C2, C3, C5, C8 and C12) on days 14-21 after transplantation and on days 7-14 after switching to oral administration, and the AUC was calculated. RESULTS: In all patients, the AUC0-24 for both twice-daily infusion and oral administration was higher than 10 000 ng·h/mL. Two close relationships were observed between AUC0-12 and the C3 for infusion and between AUC0-12 and the C8 for oral administration. None of the patients had grades 3-4 aGVHD or other serious complications. WHAT IS NEW AND CONCLUSION: This strategy was well tolerated, and the C3 for twice-daily infusion and the C8 for oral administration were the optimal points for monitoring of CyA concentration in the early phase of transplantation.

Multisystem Inflammatory Syndrome in Children (MIS-C) with COVID-19: Insights from simultaneous familial Kawasaki Disease cases.

Recently, an increasing number of SARS-CoV-2 patients with COVID-19 syndrome, which overlaps with Kawasaki Disease (KD), have been reported, supporting the suggestion that infection is one of the triggers of KD. We summarized the reports of simultaneous familial KD cases to better understand the etiopathogenesis of both KD and Multisystem Inflammatory Syndrome in Children (MIS-C) related to COVID-19. Here we discuss the etiology of these syndromes from the point of view of infection and genetic susceptibility.

Antineutrophil cytoplasmic antibody-associated vasculitis with oculomotor nerve palsy.

We report a patient with antineutrophil cytoplasmic antibody-associated vasculitis with oculomotor nerve palsy. The patient presented with a high fever, diplopia, blepharoptosis and impairment of ocular movement of the left eye except for lateral gaze. Multiple erythematous and livedoid lesions were observed on the forehead, both cheeks and both legs. Laboratory examination showed positive results for myeloperoxidase antineutrophil cytoplasmic antibodies. Skin biopsy revealed leucocytoclastic vasculitis of the small arteries in the lower dermis. The patient was successfully treated with systemic corticosteroids.

Cytokine profile during the clinical course of toxic shock syndrome.

Toxic shock syndrome (TSS) is an acute febrile disease with multiple organ involvement caused by massive and rapid release of cytokines induced by staphylococcal exotoxins. However, the precise cytokine profile is still undefined in clinical cases. We measured serum cytokine concentrations in a patient who developed TSS after a caesarean section. Measurements were taken on admission and several times during the course of the disease. Methicillin-resistant Staphylococcus aureus producing TSS toxin-1 and staphylococcal enterotoxin C was detected in the lochia and venous blood. Serum interleukin (IL)-6 level was markedly increased on admission, and IL-10, tumour necrosis factor-alpha, and interferon-gamma levels were also raised. These cytokine levels rapidly returned to normal levels. In contrast, IL-1beta and IL-2 were below the analytical sensitivity threshold throughout the course. Our data and other previous case reports indicate that a marked increase in IL-6 concentration could be a clinical marker of TSS onset.

Acute heart failure associated with human parvovirus B19 infection.

We report a patient with acute heart failure due to human parvovirus B19 infection. The patient was a 36-year-old man with polyarthralgia, fatigue and swelling of his upper eyelids and all four limbs. These symptoms disappeared, but 5 days after the first consultation, the patient presented with severe exertional dyspnoea, chest pain and swelling of his whole body. Erythema was observed on the skin of hands, fingers and abdomen. Pleural and pericardial effusion, ascites and hepatosplenomegaly were detected. Laboratory examination showed positive results for anti-human parvovirus B19 IgM and B19 DNA in the serum. A diagnosis of acute heart failure by pericarditis caused by B19 was made. This case report suggests that B19 should be considered as a cause of acute heart failure through acute pericarditis.

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.

First Report of Pepper yellow leaf curl Indonesia virus in Ageratum conyzoides in Indonesia.

Ageratum conyzoides L. plants affected with yellow vein disease were collected from Magelang, Bandung, and Purwokerto locations in Indonesia during 2001. A. conyzoides is a naturally occurring weed that is found in and around fields of cultivated pepper (Capsicum annuum L.) and tomato (Lycopersicon esculentum L.). It is frequently found with symptoms of yellow vein disease and the abundance of whiteflies on the affected plants suggested the possible involvement of a geminivirus. Total nucleic acids were extracted from nine samples collected from these locations of A. conyzoides-affected plants exhibiting yellow vein disease and amplified using PCR with geminivirus DNA-A-specific designed primers (virion-sense primer 5'-GAGCTCTTAGCCGCCTGAATGTTC-3'; complementary-sense primer 5'-GAGCTCGTCAGATGTTAAGACCTAC-3') (1). A PCR-amplified product of approximately 2.7 kbp was obtained from each sample. Five independent sequences were cloned and sequenced from each sample. Sequence analysis showed that five of nine samples were Ageratum yellow vein virus (one each from Bandung and Purwokerto and three from Magelang) and the remaining four samples (two samples each from Bandung and Purwokerto) were a strain of Pepper yellow leaf curl Indonesia virus (PepYLCIDV). Full-length DNA-A of PepYLCIDV from systemic A. coniziodes was amplified using PCR with additional primers designed at only one restriction site (BamHI) (5'-GGATCCGCTTGTTCATCCTTTTCCAG-3'/5'-GGATCCCACATCTTTGGTTAGTGGAGGGTG-3') and cloned. Three independent clones obtained were sequenced and analyzed. The sequence of a full-length DNA-A component was determined (2,760 bases, GenBank Accession No. AB267838). PCR using degenerate primers (DNABLC1: 5'-GTVAATGGRGTDCACTTCTG-3'; DNABLC2: 5'-RGTDCACTTCTGYARGATGC-3', DNABLV2: 5'-GAGTAGTAGTGBAKGTTGCA-3') of begomovirus DNA-B component (2), five independent clones were obtained and sequenced. Primers designed to amplify a full-length B component were constructed around a unique restriction site (BamHI) (5'-GGATCCCCTCATTCCTTTTGCGGAG-3'/5'-GGATCCACAGAGGAAAACTCGCAAGGC-3'). A PCR product was obtained from A. conyzoides samples and three independent clones were sequenced and analyzed. A full-length sequence of a begomovirus B component was determined (2,746 bases, GenBank Accession No. AB267839). Five open reading frames (ORF) were found in DNA-A and two in DNA-B. The DNA-A and DNA-B had a common region (CR) (74% nucleotide sequence identity) that comprised approximately 160 nucleotides. The DNA-A and DNA-B had an identical 31-base stem loop region in the CR. In addition, DNA-A and DNA-B had the highest nucleotide sequence identity (93%) with those of PepYLCIDV (GenBank Accession Nos. AB267834 and AB267835), suggesting it is a strain of PepYLCIDV, which is widely prevalent in Indonesia. To our knowledge, this is the first report of PepYLCIDV isolated from A. conyzoides plants affected with yellow vein disease. References: (1) R. W. Briddon and P. G. Markham. Mol. Biotechnol. 1:202, 1994. (2) S. K. Green et al. Plant Dis. 85:1286, 2001.

Role of Hageman factor/kallikrein-kinin system in pseudomonal elastase-induced shock model.

The role of the Hageman factor dependent pathway in pseudomonal elastase-induced shock was investigated in guinea pigs. Presence of a bradykinin B2 receptor antagonist [D-Arg0,Hyp3,Thi5,8,D-Phe7]-bradykinin (200 nM) in the circulation prevented shock caused by an intrajugular injection of pseudomonal elastase (0.8 mg/kg body weight). During the lethal shock caused by elastase (1.2 mg/kg), a significant consumption of components of the Hageman factor/kallikrein-kinin system was observed such as 45.7 +/- 2.20% consumption of Hageman factor, 100 +/- 0% of prekallikrein, and 85.1 +/- 2.50 of high-molecular-weight kininogen. More striking evidence for the participation of this system was demonstrated in depletion experiments with monospecific F(ab')2 antibodies against the components of the system. After depletion of any one of the components, guinea pigs exhibited unresponsiveness to the same lethal dose of pseudomonal elastase in regard to the cardio-respiratory alterations. In vitro, pseudomonal elastase (60 micrograms/ml) possessed a capacity to generate substantial amount of bradykinin in undiluted plasmas of humans (300.0 +/- 32.16 ng/ml) as well as guinea pigs (460.2 +/- 20.67 ng/ml) at 37 degrees C but not in those deficient in Hageman factor or prekallikrein. These results strongly suggested a pathological role of elastase in pseudomonal sepsis through activation of the Hageman factor dependent pathway.

Activation of human plasma prekallikrein by Pseudomonas aeruginosa elastase in vitro.

Human plasma prekallikrein, precursor of the bradykinin-generating enzyme, was activated in a purified system under a near physiological condition (pH 7.8, ionic strength I = 0.14, 37 degrees C) by Pseudomonas aeruginosa elastase which is a tissue-destructive metalloproteinase. Compared with that, Pseudomonas aeruginosa alkaline proteinase poorly activated it with a rate as low as less than one-twentieth of that of elastase. The activation by elastase was blocked with a specific inhibitor of elastase, HONHCOCH(CH2C6H5)CO-Ala-Gly-NH2 (10 microM). Generation of kallikrein-like amidolytic activity was also observed in plasma deficient in Hageman factor by treatment with elastase, but was not in plasma deficient in prekallikrein. The kallikrein-like activity generated in Hageman factor deficient plasma as well as the generation process itself was indeed inhibited by anti-human prekallikrein goat antibody. These results suggest that the pathological activation of the kallikrein-kinin system might occur under certain clinical conditions in pseudomonal infections.

Pseudomonas aeruginosa alkaline proteinase might share a biological function with plasmin.

Pseudomonas aeruginosa alkaline proteinase, which is a zinc-dependent bacterial endopeptidase, preferentially hydrolyzed Boc-Val-Leu-Lys-methylcoumarylamide (MCA) which was originally designed as a specific substrate of plasmin, a plasma serine proteinase. The hydrolytic capacity was resistant to tosyl-lysine chloromethylketone at a concentration as high as 1 mM, but was blocked by a treatment with metal chelator such as o-phenanthroline at the concentration of 5 mM. Kinetic parameters of the amidolytic reaction were Km = 21 microM, kcat = 0.067 s-1 and kcat/Km = 3190 M-1 s-1. A synthetic peptide inhibitor which bore a possible ligand for zinc atom at the carboxy terminal was designed. This inhibitor, Ac-Val-Leu-Lys-4-mercaptoanilide, blocked the amidolytic activity of the pseudomonal alkaline proteinase in a competitive manner with the dissociation constant (Ki) value of 24 microM. The results imply that P. aeruginosa alkaline proteinase must be an unusual zinc-dependent 'C (COOH)-type' endopeptidase, which hydrolyzes the peptide bond of certain amino acid residues at the carboxyl group side by specific recognition, like serine- and cysteine-proteinases. In comparison, P. aeruginosa elastase which is a typical 'N (NH2)-type' metalloproteinase did not hydrolyze all of the commercially available peptide-MCA substrates tested at the present study. P. aeruginosa alkaline proteinase also hydrolyzed natural substrates of plasmin, such as fibrin and fibrinogen, with similar specific activities to plasmin. The susceptible subunits of fibrinogen were the A-alpha and B-beta ones, in this order. P. aeruginosa alkaline proteinase also exhibited an anti-coagulant activity in human plasma attributed to the direct fibrinogenolytic function. Such potential anti-coagulant capacity of the P. aeruginosa alkaline proteinase might explain, at least partly, the most characteristic pathologic feature of the P. aeruginosa septicemia, hemorrhagic lesions with lacking thrombi (Fetzer, A.E. et al. (1967) Am. Rev. Respirat. Dis. 96, 1121-1130).