High-dose cytarabine plus gemtuzumab ozogamicin as consolidation therapy in patients with favorable- or intermediate-risk acute myeloid leukemia.

Previous prospective randomized trials have investigated the efficacy of gemtuzumab ozogamicin in the frontline treatment of acute myeloid leukemia (AML). We evaluated the efficacy of high-dose cytarabine with GO as consolidation therapy in 20 patients with favorable- or intermediate-risk AML in first complete remission. They included six patients with wild-type nucleophosmin (NPM1) core binding factor (CBF), ten with NPM1-mutated non-CBF, and four with wild-type NPM1 non-CBF. The median follow-up for the entire cohort was 62.0 months. The three-year overall survival (OS) and relapse-free survival (RFS) rates were 72.2% and 77.8%, respectively. OS and RFS were significantly higher for NPM1-mutated non-CBF AML than for wild-type NPM1 non-CBF AML (p = 0.001). We also examined the CD33 single-nucleotide polymorphism (SNP) rs12459419, which has been reported to influence the therapeutic efficacy of GO and CD33 expression. The CD33 expression ratio was higher in CD33 SNP C/C than in C/T (83.1% vs. 49.8%, p = 0.035), but 3-year OS and RFS did not differ significantly. These results suggest that consolidation therapy with high-dose cytarabine plus GO is highly effective in transplant-ineligible elderly patients and may be a reasonable treatment, especially for NPM1-mutated AML.

Risk factors for the development of medication-related osteonecrosis of the jaw and effects of tooth extraction with local infection.

Background/purpose: Tooth extraction has been avoided in patients receiving antiresorptive agent (ARA) therapy. This study aimed to investigate dental findings associated with medication-related osteonecrosis of the jaw (MRONJ) development in patients. Materials and methods: First, in patients treated with high-dose ARAs, the relationship between dental findings and MRONJ development was examined. Next, in patients with MRONJ undergoing surgery, the relationship between dental findings and MRONJ occurring at a site distant from the initial site was examined. Results: MRONJ occurred in 13 of 172 patients (80 of 3725 teeth) during observation. Multiple tooth loss, periodontal ligament space enlargement, alveolar bone loss, periapical osteosclerosis, and local infection symptoms were associated with MRONJ development. Tooth extraction significantly reduced MRONJ development. Regarding other-site recurrence, new MRONJ developed at other sites in 54 of 357 patients with MRONJ (171 of 5038 teeth). Multiple tooth loss, apical lesions, periodontal ligament space enlargement, and periapical osteosclerosis were significantly associated with MRONJ development. In patients with malignant tumors, tooth extraction significantly reduced the subsequent incidence of MRONJ, while in patients with osteoporosis, there was no difference in the incidence of MRONJ between patients with and without tooth extraction. Conclusion: MRONJ was more likely to develop from teeth with local infections. Extraction of teeth with local infection in patients with malignancy may be more effective than tooth preservation in preventing MRONJ.

Effect of oral function and postoperative eating patterns on salivary bacterial counts in gastrointestinal tract surgery patients: A preliminary study.

Background/purpose: Perioperative oral care is widely provided to prevent postoperative pneumonia and surgical site infections in patients undergoing surgery under general anesthesia. However, there is a lack of clarity regarding the kind of oral care that should be provided for different patients. The purpose of this study was to clarify the factors that influence the increase in salivary bacterial counts before and after gastrointestinal surgery to identify patients with a particular need for oral care. Materials and methods: Twenty patients undergoing gastrointestinal surgery were examined before surgery for denture use, number of remaining teeth, regular dental care, Oral Hygiene Index-Simplfied tongue coating, tongue pressure, bite pressure, masticatory efficiency, and dry mouth. Saliva samples were collected before surgery, in the fasting period after surgery, and in the oral feeding period. Total bacterial counts were determined by real-time PCR, and factors associated with bacterial counts were investigated. Results: Patients with decreased oral functions, such as tongue pressure, bite pressure, and masticatory efficiency, tended to have higher salivary bacterial counts in the preoperative, fasting, and oral feeding periods. Regarding the pre- and postoperative changes, salivary bacterial counts increased in the fasting period compared to the pre-operative period and returned to preoperative values in the oral feeding period. Conclusion: Perioperative oral care is important for patients with reduced oral function because the number of bacteria in saliva tends to be higher in such patients. As the number of bacteria in saliva increases during the fasting period, oral care is important, and oral feeding should be restarted as soon as possible.

Efficacy and safety of molecularly targeted agents and immune checkpoint inhibitors for unresectable or recurrent/metastatic oral cancer in Japan.

Background/purpose: For unresectable recurrent/metastatic head and neck cancer, pembrolizumab alone or pembrolizumab combined with cisplatin and 5-fluorouracil is the first-line therapy, depending on the PD-L1 combined positive score (CPS). However, this is based on clinical studies of head and neck cancer, and few similar studies have been conducted on oral cancer alone. This study aimed to investigate the current status of pharmacotherapy for unresectable, recurrent, or metastatic oral cancer. Materials and methods: Patients with unresectable or recurrent/metastatic oral cancer who received cetuximab, nivolumab, or pembrolizumab as first-line treatment were reviewed. Overall survival (OS), progression-free survival (PFS), PFS 2 (PFS2), overall response rate (ORR), disease control rate (DCR), and immune-related adverse events were obtained from medical records. Results: A total of 155 patients were enrolled from six hospitals. The ORR in the nivolumab, pembrolizumab, and cetuximab groups was 17.2 %, 4.2 %, and 21.6 %, respectively, and the DCR was 37.9 %, 41.7 %, and 58.8 %, respectively. Median OS in nivolumab, pembrolizumab, and cetuximab groups was 10.3, 9.5, and 11.1 months, respectively. No significant differences were observed in survival among the three groups. The small number of cases and the retrospective nature of the study precluded the determination of the more effective first-line treatment among the three drugs. Conclusion: The current statuses of nivolumab, pembrolizumab, and cetuximab in unresectable recurrent metastatic oral cancer was reported.

Bone resection methods in medication-related osteonecrosis of the jaw in the mandible: An investigation of 206 patients undergoing surgical treatment.

Background /purpose: The standard treatment for medication-related osteonecrosis of the jaw (MRONJ) is surgery. However, reports on the appropriate extent of bone resection are few. We aimed to examine the relationship between the extent of bone resection and postoperative outcomes in patients with mandibular MRONJ. Materials and methods: The clinical and imaging findings and treatment outcomes of 206 patients (258 surgeries) with mandibular MRONJ undergoing surgery were reviewed. Imaging findings were evaluated using computed tomography (CT) to sequestrum, osteolysis, periosteal reaction, and mixed-type osteosclerosis, and determine the extent of resection. In some cases, samples were taken from within the bone, and real-time polymerase chain reaction was used to confirm the presence of bacteria and fungi. Results: The three-year cumulative cure rate was 81.7%. Patients with malignant tumors showing no osteolysis and undergoing sequestrum removal or marginal mandibulectomy had significantly worse prognosis than those with osteoporosis showing osteolysis and undergoing segmental mandibulectomy. Furthermore, patients with residual osteolysis, periosteal reactions, and mixed-type osteosclerosis on CT were more likely to develop recurrence. Eleven patients showed no osteolysis on CT images. Patients with cancer administered with high-dose denosumab had significantly poorer prognosis. Bacteria and fungi were also detected in samples obtained from gap-type periosteal reaction and mixed-type osteosclerosis. Conclusion: Surgery for MRONJ requires resection of the infected bone. Aside from the osteolysis area, the gap-/irregular-type periosteal reaction and mixed-type osteosclerosis must also be included in the resection area. Methods for determining the extent of bone resection in MRONJ without osteolysis are a future challenge.

Differences Between Medication-Related Osteonecrosis of the Jaw Caused by Bisphosphonates and Denosumab: Histological, Molecular Biological, and Clinical Studies.

Purpose Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents such as bisphosphonates (BPs) and denosumab (DMB). We investigated whether a difference exists between BP- and DMB-related osteonecrosis of the jaw (ONJ). Patients and methods Histological images of 30 patients with BP-related ONJ and 13 patients with DMB-related ONJ were observed using hematoxylin-eosin and cathepsin K staining. Moreover, bone metabolism markers in the blood and bone mineral density were measured in 18 patients with BP-related ONJ and five patients with DMB-related ONJ. Furthermore, we conducted a quantitative analysis of local bone metabolism-related genes using surgical specimens through real-time reverse transcription polymerase chain reaction. Additionally, a retrospective study of 298 patients with MRONJ examined the differences in the characteristics of BP- and DMB-related ONJ and the factors associated with treatment outcomes. Results Histological examination revealed that patients treated with DMB had more severe osteoclast suppression than those treated with BP. No significant difference was observed in blood-bone metabolism markers between the two drugs; however, the suppression of local bone metabolism-related genes was stronger in patients treated with DMB. Clinical studies indicate that DMB-related ONJ is more frequently observed without osteolysis. Conclusion BP-associated ONJ and DMB-associated ONJ were shown to differ slightly. Clinical studies indicate that osteolysis is often unclear in DMB-related ONJ, and methods of bone resection during surgery need to be established.

CRISPR/Cas9 gene editing clarifies the role of CD33 SNP rs12459419 in gemtuzumab ozogamicin-mediated cytotoxicity.

The single-nucleotide polymorphism (SNP) rs12459419 is located at the intron/exon junction of CD33 exon2. When exon2 is skipped by this CD33 SNP, the full-length CD33 (CD33FL) is converted to a short CD33 isoform (CD33D2). Since gemtuzumab ozogamicin (GO) only recognizes CD33FL, the CD33 SNP may affect the clinical efficacy of GO. To elucidate the significance of CD33 SNP on GO reactivity, we leveraged the CRISPR/Cas9 genome-editing system to create OCI-AML3 cell lines with specifically modified CD33 SNPs. Levels of CD33 D2 mRNA were significantly higher in the T/T clone (p < 0.001), but CD33D2 protein was not detectable in any clones. There was no significant difference in CD33FL mRNA expression across edited clones, and CD33FL protein expression was lowest in T/T clones, followed by T/C and C/C. Cytotoxicity assays revealed that the IC50 of GO was significantly lower in T/C and C/C clones than in the T/T clone (p < 0.001). Our study demonstrated a difference in GO-induced cytotoxicity in CD33 SNP-edited clones, clearly indicating that at least one CD33 SNP allele, rs12459419 C, is important for sensitivity to GO.

Interventional Prospective Studies on Xerostomia in Patients Undergoing Palliative and End-of-Life Care: A Scoping Review.

Patients undergoing palliative care often develop debilitating oral conditions, including xerostomia. These conditions may significantly impact patients' quality of life. Despite the high prevalence and adverse impact of xerostomia, effective management strategies remain unclear. This scoping review was performed to elucidate effective interventions for xerostomia in patients undergoing palliative and end-of-life care. A comprehensive search strategy was employed to identify relevant studies up to August 2023. Full-text primary articles focusing on xerostomia in patients receiving palliative care were included in the review. Eleven articles were selected for analysis, and data were extracted by six reviewers. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among the 11 studies, interventions ranged from oral care to saliva substitutes and methods to stimulate saliva secretion. The primary method of assessing xerostomia was the performance of subjective evaluations using visual analog scale scores or numerical rating scale scores. Various interventions including oral care regimens, topical treatments, and mixed efficacy outcomes were reported. Notably, only one study directly measured the saliva volume, highlighting a reliance on subjective endpoints in most studies. Although no definitive conclusions can be drawn regarding the most effective intervention, oral care was a preferred option for managing xerostomia in patients undergoing palliative care. Additionally, adjunctive treatments such as ice cubes, saline, and moisturizers showed promise but require further investigation. Objective measures should be incorporated into future intervention trials to complement subjective assessments and provide a comprehensive evaluation of xerostomia management strategies in this patient population.

Prognostic value of a mandibular canal staging system for primary lesions in patients with lower gingival squamous cell carcinoma: a multicenter, retrospective study.

BACKGROUND: The Union for International Cancer Control and American Joint Committee on Cancer tumor staging system is used globally for treatment planning. As it may be insufficient for tumor staging of lower gingival carcinomas, we proposed the mandibular canal tumor staging system. In this study, we aimed to compare the two systems for such tumor staging and to identify prognostic markers. METHODS: This multicenter, retrospective study included patients with lower gingival squamous cell carcinoma who underwent radical surgery during 2001-2018. We compared survival rates (Kaplan-Meier estimator) and patient stratification according to the two systems. RESULTS: The proposed system yielded more balanced patient stratification than the existing system. Progression in the tumor grade according to the proposed system was associated with a poorer prognosis. The 5-year overall and disease-specific survival rates for the entire cohort were 74.9% and 81.8%, respectively. Independent factors affecting overall survival were tumor stage according to the proposed system, excision margins, and number of positive nodes, whereas those affecting disease-specific survival were excision margins and number of positive nodes. CONCLUSIONS: Subsite-specific tumor classification should be used for patients with oral cancer, and our results suggest that mandibular canal tumor classification may be effective for patients with lower gingival carcinoma.

Correlation of ex vivo and in vivo ammonia production with L-asparaginase biological activity in adults with lymphoid malignancies.

Silent inactivation of L-asparaginase (L-Asp) represents rapid clearance of L-Asp by anti-L-Asp IgG antibodies without clinical symptoms. Measurement of L-Asp activity is the gold standard for diagnosis of silent inactivation, but this test is not commercially available in Japan as of 2023. We evaluated ex vivo and in vivo ammonia production in relation to L-Asp activity. Blood samples from ten adult patients treated with L-Asp were collected to measure ammonia levels and L-Asp activity before the first dose and 24 h after the last dose of L-Asp, during each cycle of treatment. Plasma ammonia levels were analyzed immediately and 1 h after incubation at room temperature, and ex vivo ammonia production was defined as the increase in ammonia concentration. Ex vivo ammonia production correlated with L-Asp activity (R2 = 0.741), and ammonia levels measured immediately after blood collection were moderately correlated with L-Asp activity (R2 = 0.709). One patient with extranodal NK/T-cell lymphoma showed an increase in ammonia levels during the first cycle, but no increase in ammonia levels or L-Asp activity after L-Asp administration during the second cycle. Both ex vivo and in vivo ammonia production and surrogate markers are used for L-Asp biological activity.

Risk factors for dental findings of the development of medication-related osteonecrosis of the jaw: Investigation of 3734 teeth in cancer patients receiving high dose antiresorptive agents.

Background/purpose: Local infection is a risk factor for medication-related osteonecrosis of the jaw (MRONJ), along with invasive dental treatment of the bone; the tooth that is the source of infection should be extracted prior to the administration of bone resorption inhibitors. However, which teeth should be extracted remains unclear. This study aimed to determine the relationship between dental findings prior to high-dose antiresorptive agent (ARA) administration and the subsequent development of MRONJ. Materials and methods: Patients with cancer who were scheduled to receive high-dose ARAs and referred to our hospital between 2011 and 2020 were included in this retrospective study. Apical lesions, enlargement of the periodontal space, thickening of the lamina dura, alveolar bone resorption of >1/3, periapical osteosclerosis, and local infection symptoms in each tooth were investigated using medical records and panoramic radiographs. Results: A total of 172 patients, 329 jaws, and 3734 teeth were registered. MRONJ developed in 68 teeth in 33 jaws of 32 patients. In tooth-by-tooth analysis, fewer teeth (P < 0.001), apical lesions (P < 0.001), periapical osteosclerosis (P < 0.001), local infection symptoms (P = 0.002), and one or more dental findings (P < 0.001) were significant factors for MRONJ development. In jaw-by-jaw analysis, old age, local infection symptoms, and number of radiographic abnormalities per tooth were significant. In patient-by-patient analysis, patients with diabetes and those with fewer teeth developed MRONJ. Conclusion: Patients with fewer teeth, apical lesions, periapical osteosclerosis, and local infection were more likely to develop MRONJ. Therefore, these teeth should be treated as much as possible before ARA administration.

Restricted Diffusion in the Bilateral Subcortical Motor Areas Associated with Status Epilepticus in an Infant with Kawasaki Disease.

Status epilepticus (SE) often causes neuronal death in the cerebrum and consequent long-term sequelae. Acute encephalopathy with biphasic seizures and late reduced diffusion is clinically characterized by SE associated with fever and seizure clusters that occur 3-9 days after symptom onset. MRI reveals reduced diffusion in the frontal or frontoparietal subcortical white matter, with sparing of the perirolandic region following seizure clusters. Kawasaki disease (KD) is an acute self-limited vasculitis secondary to activation of the immune system; KD is rarely complicated by acute encephalopathy. We report the case of a male infant who developed SE associated with KD and showed late reduced diffusion in the subcortical white matter beneath the bilateral motor cortices (primary motor, premotor and supplementary motor areas) and the right frontal cortex. The patient had characteristic neurological sequelae in the chronic phase, including clumsiness of fingers and forearms, impaired discrimination of tactile sensation and position sense on digits in his hands and feet, corresponding to the lesions with reduced diffusion at the acute phase.

Extranodal Extension and Epithelial Cell Adhesion Molecule Over-expression in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Concomitant chemoradiotherapy (CCRT) with cisplatin is commonly administered after neck dissection in patients with oral squamous cell carcinoma (OSCC) showing extranodal extension (ENE). This study investigated whether the efficacy of CCRT differed depending on the degree of ENE and whether the expression of epithelial cell adhesion molecule (EpCAM) was associated with prognosis. PATIENTS AND METHODS: Patients with OSCC who underwent neck dissection and had histologically proven neck metastasis (pN+) were investigated retrospectively. ENE was divided into ENE minor (ENEmi; <2 mm) and ENE major (ENEma; ≥2 mm). The expression of EpCAM was also immunohistochemically examined using tissues obtained during neck dissection. RESULTS: One hundred and seventy pN+ cases [ENE(-), n=89; ENEmi, n=23; ENEma, n=58] were included. Multivariate analysis revealed that advanced T stage and ENEma were significantly correlated with poor prognosis. The 5-year disease-specific survival rates in ENE(-), ENEmi, and ENEma groups were 73.7%, 75.5%, and 28.0% respectively. An add-on effect of postoperative CCRT was not seen in the ENEmi group; however, postoperative CCRT improved the survival of patients in the ENEma group. In the ENEma group, the prognosis was significantly worse in EpCAM-positive patients than in EpCAM-negative patients. CONCLUSION: Postoperative CCRT may improve prognosis in ENEma cases. EpCAM expression may be a poor prognostic factor in ENEma cases. On the other hand, postoperative CCRT did not have a significant effect on prognosis in ENEmi cases. Among them, although there was no significant difference in the survival rate, postoperative CCRT could be omitted in ENEmi/EpCAM(-) cases.

Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study.

PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).

A novel method for determining viable bacteria from a mixture of dead and viable bacteria: Delayed real-time PCR (DR-PCR) method.

Aspiration pneumonia can occur in perioperative and older patients, and various oral care methods have been used to prevent it. To validate the effective oral care methods, measuring bacterial counts before and after oral care is necessary. However, isolating and quantifying viable bacteria from those that are inactivated by agents used in oral care is not possible. In this study, we developed a novel method, Delayed real-time PCR (DR-PCR), that can quantify only viable bacteria from mixed samples of viable and dead bacteria. This method takes advantage of the fact that dead bacteria do not grow but viable bacteria do. When the samples were incubated in a liquid medium for 4 hours, the higher the percentage of viable bacteria, the higher the rate of increase in the number of bacteria. This method showed that povidone­iodine mouthwashing reduced the number of viable bacteria to approximately 1/4 of that before mouthwashing. Although DR-PCR is slightly more time consuming than real-time PCR, it is effective for studying changes in bacterial counts before and after oral care.

Three Signs to Help Detect Sjögren's Syndrome: Incidental Findings on Magnetic Resonance Imaging and Computed Tomography.

This study aimed to retrospectively investigate the prevalence of Sjögren's syndrome (SS) among patients with ranulas, parotid cysts, or parotid calcifications; identify the characteristic magnetic resonance imaging (MRI) or computed tomography (CT) findings of the lesions associated with SS; and compare the SS disease stages among SS patients with the three lesion types. A total of 228 patients with the lesions were classified into SS, possible SS, and non-SS groups. The prevalence of SS among patients with ranulas, parotid cysts, or parotid calcifications was 16%, 24%, and 40%, and the rates of either SS or possible SS were 25%, 41%, and 64%, respectively. SS was associated with (i) ranulas: ≤17 mm; (ii) parotid cysts: bilateral and multiple; and (iii) parotid calcifications: in females, bilateral, multiple, parenchymal, and no coexisting calcifications in other tissues. SS patients with ranulas were significantly younger and had lower submandibular gland stage scores on MRI/CT than those with other lesions. Additionally, in 58% and 15% of SS patients with ranulas and parotid calcifications, respectively, detection of the lesions led to the diagnosis of primary SS. Therefore, recognizing the prevalence of SS among patients with these lesions and the findings associated with SS can help detect undiagnosed SS.

EFFICACY AND SAFETY OF A DEXAMETHASONE-BASED MOUTHWASH TO PREVENT CHEMOTHERAPY-INDUCED STOMATITIS IN WOMEN WITH BREAST CANCER: A MULTICENTRE, OPEN-LABEL, RANDOMISED PHASE 2 STUDY.

PURPOSE: No standard approach other than oral care is available for preventing chemotherapy-induced stomatitis in patients with breast cancer. In this randomized, controlled phase 2 trial, we aimed to assess the efficacy and safety of a dexamethasone-based mouthwash in preventing chemotherapy-induced stomatitis in patients with early breast cancer. BASIC PROCEDURES: Patients with breast cancer scheduled for epirubicin and cyclophosphamide (EC) or docetaxel and cyclophosphamide (TC) therapy were selected and allocated in a 1:1 ratio to the intervention and control groups. The intervention group received chemotherapy, oral care, and a dexamethasone-based mouthwash, whereas the control group received chemotherapy and oral care. The primary endpoint was the incidence of stomatitis. This was a phase 2 study, and the significance level for the analysis of the primary endpoint was set a priori at 0.2. MAIN FINDINGS: Data pertaining to 58 patients in the control group and 59 patients in the intervention group were analyzed. Stomatitis incidence was 55% and 38% in the control and intervention groups, respectively (risk ratio, 0.68; 80% confidence interval, 0.52-0.88; P = .052). Stomatitis severity was lower in the intervention group than in the control group (P = .03). The proportion of patients who adhered to the mouthwash regimen was 87% (interquartile range, 67.8%-95.3%). No severe oral infections were observed. PRINCIPAL CONCLUSIONS: The dexamethasone-based mouthwash safely reduced stomatitis incidence and severity in patients receiving chemotherapy for early breast cancer. Phase 3 clinical trials are warranted for validating our results.

Comparison of the 8th edition of TNM staging of oral cancer with the 7th edition and its prognostic significance using clinical depth of invasion and extranodal extension.

OBJECTIVES: The 8th edition of the International Union Against Cancer Control/American Joint Committee on Cancer Staging System introduced depth of invasion (DOI) and extranodal extension (ENE) into the staging of oral cavity cancer. We evaluated the prognostic ability of this new staging system compared with the 7th edition using clinical DOI (cDOI) and clinical ENE (cENE). MATERIALS AND METHODS: We retrospectively reviewed and restaged 2,118 patients with oral squamous cell carcinoma treated between 2001 and 2018 using cDOI and cENE. Overall and disease-specific survival were used as endpoints to compare the prognostic outcomes of the 7th and 8th editions using Harrell's concordance index (C-index). RESULTS: In total, 305 (14.4 %) cases were upstaged in the T category, 85 (4.0 %) cases were upstaged in the N category, and 280 (13.2 %) cases were upstaged in the overall TNM stage. The introduction of the cDOI increased the C-index and hazard ratio (HR) for each T category. The introduction of cENE increased the N3b category of 85 cases, bringing the total to 94 cases, thereby widening the differences between each N category. In the 8th edition, the C-index and HR for overall TNM stage increased, and the discrimination between stage groups improved. CONCLUSIONS: The 8th edition of the TNM clinical staging system using cDOI and cENE predominantly identified patients with a high mortality rate, thus improving the ability to discriminate and prognosticate oral cancer.

C/ebpα represses the oncogenic Runx3-Myc axis in p53-deficient osteosarcoma development.

Osteosarcoma (OS) is characterized by TP53 mutations in humans. In mice, loss of p53 triggers OS development, and osteoprogenitor-specific p53-deleted mice are widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms underlying the initiation or progression of OS following or parallel to p53 inactivation remain largely unknown. Here, we examined the role of transcription factors involved in adipogenesis (adipo-TFs) in p53-deficient OS and identified a novel tumor suppressive molecular mechanism mediated by C/ebpα. C/ebpα specifically interacts with Runx3, a p53 deficiency-dependent oncogene, and, in the same manner as p53, decreases the activity of the oncogenic axis of OS, Runx3-Myc, by inhibiting Runx3 DNA binding. The identification of a novel molecular role for C/ebpα in p53-deficient osteosarcomagenesis underscores the importance of the Runx-Myc oncogenic axis as a therapeutic target for OS.

Levilactobacillus brevis with High Production of Putrescine Isolated from Blue Cheese and Its Application.

Polyamine intake has been reported to help extend the lifespan of animals. Fermented foods contain high concentrations of polyamines, produced by fermenting bacteria. Therefore, the bacteria, isolated from fermented foods that produce large amounts of polyamines, are potentially used as a source of polyamines for humans. In this study, the strain Levilactobacillus brevis FB215, which has the ability to accumulate approximately 200 µM of putrescine in the culture supernatant, was isolated from fermented foods, specifically the Blue Stilton cheese. Furthermore, L. brevis FB215 synthesized putrescine from agmatine and ornithine, which are known polyamine precursors. When cultured in the extract of Sakekasu, a byproduct obtained during the brewing of Japanese rice wine containing high levels of both agmatine and ornithine, L. brevis FB215 grew to OD600 = 1.7 after 83 h of cultivation and accumulated high concentrations (~1 mM) of putrescine in the culture supernatant. The fermentation product also did not contain histamine or tyramine. The Sakekasu-derived ingredient fermented by the food-derived lactic acid bacteria developed in this study could contribute to increasing polyamine intake in humans.