Pharmacist-led multi-faceted intervention in an antimicrobial stewardship programme at a dental university hospital in Japan.

BACKGROUND: Antimicrobials are commonly prescribed in dentistry. However, inappropriate antimicrobial prescriptions are common in this field. Optimizing antimicrobial prescriptions in dentistry requires an effective strategy for modifying prescribing behaviour. AIM: To assess the efficacy of pharmacist-led multi-faceted intervention for the proportion of monthly antimicrobial prescriptions in each drug group per 100 oral antimicrobial prescriptions. METHODS: A before-after trial was performed at a university hospital outpatient dental clinic. A pharmacist-led, multi-faceted intervention, including immediate and direct feedback to the prescribers, an explanation of the rules of antimicrobial prescriptions for patients with penicillin allergy, tutorials for dentistry students, and a review of hospital-approved antimicrobials, was implemented from April 2017 to March 2022. Antimicrobials were classified into eight groups, namely, penicillins, first- and second-generation cephalosporins, third-generation cephalosporins, fluoroquinolones, macrolides, clindamycin, carbapenem, and others. FINDINGS: In total, there were 2,643,988 visits to the outpatient dental clinic during the study period. The monthly mean proportion of prescriptions for penicillins increased from 45.6 to 84.1 per 100 oral antimicrobial prescriptions (P<0.001) while that of third-generation cephalosporins decreased from 43.0 to 7.3 (P<0.001) from the pre-intervention to the intervention period. Moreover, the monthly mean proportion of fluoroquinolones, macrolides, and carbapenems decreased from 11.2 to 7.44 (P<0.001). CONCLUSION: The intervention modified dentists' antimicrobial prescribing behaviours, leading to an immediate increase in the number of monthly prescriptions for penicillins and a simultaneous decrease in the number of monthly prescriptions for third-generation cephalosporins and other broad-spectrum, oral antimicrobials.

A Targeted Genetic Association Study of the Rare Type of Osteomyelitis.

Chronic nonbacterial osteomyelitis is a rare bone disorder that can be found in the jaw. It is often associated with systemic conditions, including autoimmune deficiencies. However, little is known about how the genetic and immunologic background of patients influences the disease. Here, we focus on human leukocyte antigen (HLA), killer cell immunoglobulin-like receptors (KIRs), and their specific combinations that have been difficult to analyze owing to their high diversity. We employed a recently developed technology of simultaneous typing of HLA alleles and KIR haplotype and investigated alleles of the 35 HLA loci and KIR haplotypes composed of centromeric and telomeric motifs in 18 cases and 18 controls for discovery and 472 independent controls for validation. We identified an amino acid substitution of threonine at position 94 of HLA-C in combination with the telomeric KIR genotype of haplotype tA01/tB01 that had significantly higher frequency (>20%) in the case population than in both control populations. Multiple logistic regression analysis based on a dominant model with adjustments for age and sex revealed and validated its statistical significance and high predictive accuracy (C-statistic ≥0.85). Structure-based analysis revealed that the combination of the amino acid change in HLA-C and the telomeric genotype tA01/tB01 could be associated with lower stability of HLA-C. This is the first case-control study of a rare disease that employed the latest sequencing technology enabling simultaneous typing and investigated amino acid polymorphisms at HLA loci in combination with KIR haplotype.

Small size of metastatic lymph nodes with extracapsular spread greatly impacts treatment outcomes in oral squamous cell carcinoma patients.

Extracapsular spread (ECS) of metastatic lymph nodes from oral carcinoma is the most significant prognostic predictor of a poor treatment outcome. However, only a few reports on prognostic factors in ECS-positive cases have been investigated. To address this problem, a detailed examination of ECS pathology was conducted to determine the prognostic factors of oral squamous cell carcinoma (OSCC) with ECS of metastatic lymph nodes. This study involved 63 OSCC patients with at least one pathologically metastatic node with ECS. Among the 229 metastatic lymph nodes, 149 exhibited ECS. Univariate analysis revealed that a poor outcome and recurrence were significantly associated with the number of ECS-positive nodes, density of ECS, and the minor axis of the smallest ECS-positive node. However, multivariate analysis identified only small size of ECS-positive nodes as a significant and independent factor predicting recurrence and a poor outcome. Thus, small size of ECS-positive nodes is the most important prognostic indicator for OSCC with ECS in metastatic lymph nodes. The classification of ECS status using the minor axis of ECS-positive nodes may be useful for further prediction of a poorer prognosis in OSCC cases. Standardization of ECS diagnosis and multicenter prospective studies will be required to confirm and refine these findings.

First signs of late-presenting cervical lymph node metastasis in oral cancers during follow-up.

One of the most important prognostic factors in oral squamous cell carcinoma (OSCC) is the presence of lymph node metastasis. Therefore, the early detection of late-presenting cervical lymph node metastasis is important. Although many studies have assessed diagnostic modalities for detecting metastatic cervical lymph nodes, no study has evaluated the process, especially first signs, for detecting late-presenting cervical lymph node metastasis. A retrospective analysis comparing methods for detecting the first signs of late-presenting lymph node metastasis was performed. A total of 65 OSCC patients were assessed. These patients were identified retrospectively as having presented late metastasis during follow-up after initial treatment with curative intent. The findings of four detection methods were analyzed: palpation, ultrasonography, computed tomography, and subjective symptoms. The numbers of cases identified by each method were as follows: palpation, 31 (47.7%); ultrasonography, 17 (26.1%); computed tomography, 12 (18.5%); and subjective symptoms, 5 (7.7%). Palpation played a major role in the discovery of late-presenting lymph node metastasis. In contrast, metastatic lymph nodes were detected by other methods in about half of the cases. The results suggest a possible stratification of the various methods used for metastatic lymph node detection, depending on the characteristics of individual cases.

Analysis of the factors affecting the formation of the microbiome associated with chronic osteomyelitis of the jaw.

Chronic osteomyelitis of the jaw (COMJ) is one of the most intractable diseases among head and neck infections. Antimicrobial agents are routinely administered for COMJ without sufficient bacterial information, resulting in frequent treatment failures. To improve our knowledge of the bacterial aetiology of COMJ and to assist in the development of effective treatments, we performed a comprehensive analysis of the microbiome. Sixteen patients with four clinical types of COMJ (four with suppurative osteomyelitis, three with osteoradionecrosis of the jaw, four with primary chronic osteomyelitis, and five with bisphosphonate-related osteonecrosis of the jaw) were enrolled in this study. Bone samples were subjected to bacterial community comparisons by 16S rRNA gene pyrosequencing. As a result, we clarified that COMJ was caused by a far greater range of bacterial species (12 phyla and 163 genera) than previously reported. Moreover, the bacterial structures in COMJ changed dramatically with disease stage and the condition of the affected bone. Multiple correlation analyses revealed that sequestration and bone exposure could affect the community structure. On the basis of these factors, we reclassified COMJ into three clinical stages: I, inflamed or sclerotic bone without exposure; II, sequestrum without exposure; and III, exposed sequestrum. In stage II, the bacterial diversity was significantly lower, and the anaerobe genera Fusobacterium, Tannerella (formerly Bacteroides) and Porphyromonas were more abundant, than observed during other stages. Because these bacteria habitually reside in any clinical stage, they were considered to constitute the core microbiome of COMJ. Targeting these bacteria should lead to the development of effective preventive measures and cures.

Human oral squamous cell carcinoma cell lines promote angiogenesis via expression of vascular endothelial growth factor and upregulation of KDR/flk-1 expression in endothelial cells.

Angiogenesis is an important phenomenon for the growth and metastasis of solid tumors. The present study examined the characterization of angiogenic factors produced by human oral squamous cell carcinoma (oral SCC) cell lines established from lymph node metastatic tumors and primary tumor in different patients. The conditioned medium of HSC3 with the strongest metastatic ability among the examined lines enhanced a tube-forming activity of bovine carotid artery endothelial (BAE) cells in collagen gel cultures. The treatment of HSC3 with anti-vascular endothelial growth factor (VEGF) antibody or anti-basic fibroblast growth factor (bFGF) antibody, either alone or in combination, attenuated the activity of urokinase-type plasminogen activator (uPA) in the endothelial cells stimulated by the conditioned medium of HSC3. In contrast, neither anti-interleukin-8 (IL-8) antibody nor anti-hepatocyte growth factor (HGF beta) antibody affected uPA activity in the endothelial cells. Among these HSC cell lines, HSC3 secreted VEGF with the highest (1.92 +/- 0.24 ng/10(6) cells/24 h) level and bFGF. The level of bFGF secreted by HSC3 was lower than that secreted by BAE cells. Other oral SCC cell lines secreted lower levels of VEGF and undetectable levels of bFGF. By reverse transcriptase-polymerase chain reaction analysis of mRNA the production of VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206 in these cell lines was able to be detected. Moreover, the conditioned medium of HSC3 enhanced the tyrosine phosphorylation and expression of kinase insert domain-containing receptor (KDR/flk-1) in the endothelial cells. These results suggest that oral SCC promotes angiogenesis via expression of VEGF and upregulation of their receptor KDR/flk-1 expression in endothelial cells.