Comparative analysis of sorafenib and lenvatinib on HepG2 cells and human umbilical vein endothelial cells: Involvement of transforming growth factor-ß signaling in their molecular effects.

AIM: This study aimed to compare the effects of the molecular targeted drugs, sorafenib and lenvatinib, on the survival, invasion, and angiogenesis of hepatocellular carcinoma cells. Additionally, we investigated the involvement of transforming growth factor beta (TGF-ß) signaling in their molecular mechanisms. METHODS: To investigate the effects of sorafenib and lenvatinib, we conducted cell viability, invasion, and angiogenesis assays, as well as western blotting analyses. RESULTS: In human hepatocellular carcinoma cells (HepG2), sorafenib demonstrated potent inhibitory effects on cell proliferation, but induced cell invasion similar to TGF-ß. In contrast, lenvatinib showed weaker cytotoxicity compared with sorafenib, but suppressed cell invasion induced by TGF-ß. The actions of these two molecular targeted drugs were suggested to involve the regulation of the TGFßR2/ERK pathway. Moreover, in human umbilical vein endothelial cells, Sorafenib showed weaker cytotoxicity and enhanced the effects of TGF-ß on angiogenesis. Conversely, lenvatinib showed potent cytotoxic abilities and suppressed angiogenesis induced by TGF-ß. The actions of these two molecular targeted drugs were suggested to involve the regulation of the crosstalk between TGF-ß signaling and vascular endothelial growth factor signaling. CONCLUSIONS: Our findings indicate that both sorafenib and lenvatinib possess anticancer abilities by inducing the cytotoxicity of hepatocellular carcinoma cells. Furthermore, they show opposing effects on TGF-ß-induced cell invasion and angiogenesis, thereby enhancing the understanding of the multifaceted functions of molecular targeted drugs in treating hepatocellular carcinoma.

Risk factors of medication-related osteonecrosis of the jaw: A clinical investigation.

Medication-related osteonecrosis of the jaw (MRONJ) is an intractable condition caused by drugs such as bisphosphonates and denosumab. This study investigated the changes in the incidence of MRONJ in the previous 10 years and examined the poor prognostic factors during surgery in at-risk patients. We compared 57 and 64 patients diagnosed with MRONJ at our hospital between January 2012 and December 2016 and January 2017 and December 2021, respectively. The disease stage and triggers at the time of initial diagnosis in eligible patients were investigated. Additionally, the adverse prognostic factors were examined in 166 patients at risk of MRONJ who underwent tooth extraction at our department during these 10 years. The results indicated that there was no change in the proportion of patients with osteoporosis and malignancy among those with MRONJ. The number of cases after tooth extraction decreased, and those after dental infections increased on comparing the recent 5 years and the preceding 5 years. The number of MRONJ patients receiving denosumab also increased. Denosumab was a significant post-extraction prognostic factor for delayed healing in the 166 patients at risk of MRONJ. The findings suggest that patients receiving denosumab should be closely monitored when undergoing surgery to prevent MRONJ.

Hypoproteinemia Associated with a Gigantic Odontogenic Tumor: A Report of 2 Cases.

BACKGROUND Hypoproteinemia is caused by a decrease in protein level in the blood. This report describes 2 cases of hypoproteinemia associated with a gigantic odontogenic tumor. CASE REPORT Case 1, a 65-year-old man, visited our hospital with the chief concern of swelling in the right mandible, approximately 100 mm in diameter, and ameloblastoma was diagnosed. Abscess drainage was observed in the fistula of the tumors. Total protein and albumin levels were low before surgery. Hemimandibulectomy was performed under general anesthesia. The final pathological diagnosis based on the specimen was ameloblastic carcinoma. After surgery, the total protein and albumin levels improved and remained stable 6 months after the operation. At 21 months after surgery, there were no signs of recurrence. Case 2, a 60-year-old woman, visited our hospital with a chief concern of swelling in the left mandible, approximately 100 mm in diameter, and ameloblastoma was diagnosed. Abscess drainage was observed in the fistula of the tumors. The patient had a history of hypoproteinemia; preoperative levels of total protein and albumin were low, and edema of the body was observed before surgery. Hemimandibulectomy was performed under general anesthesia. The final pathological diagnosis based on the specimen was ameloblastoma. After surgery, the total protein and albumin levels improved, and remained stable 6 weeks after surgery. There were no signs of recurrence 9 months after surgery. CONCLUSIONS These 2 cases indicate the possibility that hypoproteinemia can be caused by plasma leakage from fistulas associated with gigantic odontogenic tumors.

Diagnostic Accuracy of High-Grade Intraepithelial Papillary Capillary Loops by Narrow Band Imaging for Early Detection of Oral Malignancy: A Cross-Sectional Clinicopathological Imaging Study.

This study aimed to clarify the advantages and disadvantages of conventional visual inspection (CVI), endoscopic white light imaging (WLI), and narrow-band imaging (NBI) and to examine the diagnostic accuracy of intraepithelial papillary capillary loops (IPCL) for the detection of oral squamous cell carcinoma (OSCC). This cross-sectional study included 60 participants with oral mucosal diseases suspected of having oral potentially malignant disorders (OPMDs) or OSCC. The patients underwent CVI, WLI, NBI, and incisional biopsy. Images were evaluated to assess the lesion size, color, texture, and IPCL. Oral lichen planus (OLP) and oral leukoplakia lesions were observed in larger areas with NBI than with WLI; 75.0% were associated with low-grade (Type 0-II) IPCL. Various types of oral leukoplakia were seen; however, all OSCC cases showed high-grade (Type III-IV) IPCL. The diagnostic accuracy of high-grade IPCL for OSCC showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 80.9%, 59.1%, 100%, and 85.0%, respectively. A non-homogeneous lesion with high-grade IPCL strongly suggested malignancy. Overall, our results indicate that WLI and NBI are powerful tools for detecting precancerous and cancerous lesions using IPCL. However, NBI is influenced by mucosal thickness; therefore, image interpretation is important for accurate diagnosis.

Oral and Gut Microbial Dysbiosis and Non-alcoholic Fatty Liver Disease: The Central Role of Porphyromonas gingivalis.

Gut microbiota play many important roles, such as the regulation of immunity and barrier function in the intestine, and are crucial for maintaining homeostasis in living organisms. The disruption in microbiota is called dysbiosis, which has been associated with various chronic inflammatory conditions, food allergies, colorectal cancer, etc. The gut microbiota is also affected by several other factors such as diet, antibiotics and other medications, or bacterial and viral infections. Moreover, there are some reports on the oral-gut-liver axis indicating that the disruption of oral microbiota affects the intestinal biota. Non-alcoholic fatty liver disease (NAFLD) is one of the systemic diseases caused due to the dysregulation of the oral-gut-liver axis. NAFLD is the most common liver disease reported in the developed countries. It includes liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Recently, accumulating evidence supports an association between NAFLD and dysbiosis of oral and gut microbiota. Periodontopathic bacteria, especially Porphyromonas gingivalis, have been correlated with the pathogenesis and development of NAFLD based on the clinical and basic research, and immunology. P. gingivalis was detected in the liver, and lipopolysaccharide from this bacteria has been shown to be involved in the progression of NAFLD, thereby indicating a direct role of P. gingivalis in NAFLD. Moreover, P. gingivalis induces dysbiosis of gut microbiota, which promotes the progression of NAFLD, through disrupting both metabolic and immunologic pathways. Here, we review the roles of microbial dysbiosis in NAFLD. Focusing on P. gingivalis, we evaluate and summarize the most recent advances in our understanding of the relationship between oral-gut microbiome symbiosis and the pathogenesis and progression of non-alcoholic fatty liver disease, as well as discuss novel strategies targeting both P. gingivalis and microbial dysbiosis.

Osteosarcoma of the Mandible in an Elderly Patient.

Osteosarcoma is a malignant tumor in which the cancerous cells produce an osteoid matrix or mineralized bone. Jaw bones are affected in 6% of all osteosarcomas and are the fourth most common site of origin. Surgical treatment of osteosarcoma in elderly patients is rarely reported. Here, we report successful treatment of osteosarcoma arising in the mandible of a 90-year-old man. The patient was referred to our institution for diagnosis and treatment of an oral lesion. Intraoral examination revealed that a hard mass measuring 35 × 27 mm was located on the floor of the oral cavity, attached to the bone, and its growth displaced the tongue posteriorly. Therefore, he experienced difficulty in speech and swallowing. Biopsy of the mandibular mass was suspicious for chondrosarcoma. Preoperative examination did not detect critical risks for general anesthesia or surgery. Based on a clinical diagnosis of a malignant bone tumor of the mandible, segmental mandibular resection with reconstruction using a titanium plate was performed. Surgical site infection occurred on postoperative day 12, which was resolved by drainage, local irrigation, and administration of antibiotics. There was no delirium or cardiovascular or pulmonary complications. Surgery resolved the patient's difficulties in speech and swallowing. There was no evidence of tumor recurrence or metastasis 4 years after surgery. This case showed that it was not necessary to exclude surgical treatment merely because the patient was 90 years old. Indications for surgery should be determined individually to improve the patient's quality of life.

A case of canalicular adenoma with anemia.

An 81-year-old woman presented with bleeding from a soft elastic bulge on the right buccal mucosa. Her medical history included hypertension, chronic renal failure, hysterectomy and a goiter operation. Certain investigations, such as blood tests, which confirmed the minimum hemoglobin level of 5.3 g/dl, computed tomography and magnetic resonance imaging (MRI), were conducted. MRI revealed features confirming the presence of a tumor involving the right buccal mucosa with high signal in T2-enhanced image. Considering the provisional diagnosis and image findings, the tumor mass was excised and histopathological examination of the biopsy specimen confirmed the diagnosis of a canalicular adenoma. Under the diagnosis of various clinical departments, the anemic state of the patient might be chiefly attributed to the bleeding from the tumor. Herein, we report a rare case of a canalicular adenoma in the right buccal mucosa with anemia due to bleeding from the tumor.

Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study.

INTRODUCTION: Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic effects on astrocytes. OBJECTIVES: This follow-up study was designed to confirm the direct effects of BCAA on human astrocytes and clarify their underlying mechanisms using metabolome analysis and evaluation of associated signaling. METHODS: We performed cytotoxicity and cell proliferation tests on astrocytes following BCAA treatment with and without ammonium chloride (NH4Cl) and then compared the results with the effects of BCAA on hepatocytes and neurons. Subsequently, we used metabolomic analysis to investigate intracellular metabolite levels in astrocytes with and without BCAA treatment. RESULTS: The astrocytes showed increased leakage of intracellular lactate dehydrogenase and reduced proliferation rate upon BCAA treatment. Interestingly, our analysis showed a BCAA-induced impairment of intracellular glycolysis/glyconeogenesis as well as amino acid and butyric acid metabolism. Furthermore, BCAA treatment was found to cause decreased levels of Glut-1 and phosphorylated GSK-3ß and mTOR in astrocytes. CONCLUSIONS: Although further investigations of the effect of BCAA on human astrocytes with hyperammonemia are needed, our work demonstrates that BCAA supplementation has direct negative effects on astrocyte survival and intracellular metabolism.

Evidence-based clinical practice guidelines for peptic ulcer disease 2020.

The Japanese Society of Gastroenterology (JSGE) revised the third edition of evidence-based clinical practice guidelines for peptic ulcer disease in 2020 and created an English version. The revised guidelines consist of nine items: epidemiology, hemorrhagic gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcers, non-H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Therapeutic algorithms for the treatment of peptic ulcers differ based on ulcer complications. In patients with NSAID-induced ulcers, NSAIDs are discontinued and anti-ulcer therapy is administered. If NSAIDs cannot be discontinued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recommended as the first-line treatment for H. pylori eradication, and PPIs or VPZ with antibiotics is recommended as a second-line therapy. Patients who do not use NSAIDs and are H. pylori negative are considered to have idiopathic peptic ulcers. Algorithms for the prevention of NSAID- and low-dose aspirin (LDA)-related ulcers are presented in this guideline. These algorithms differ based on the concomitant use of LDA or NSAIDs and ulcer history or hemorrhagic ulcer history. In patients with a history of ulcers receiving NSAID therapy, PPIs with or without celecoxib are recommended and the administration of VPZ is suggested for the prevention of ulcer recurrence. In patients with a history of ulcers receiving LDA therapy, PPIs or VPZ are recommended and the administration of a histamine 2-receptor antagonist is suggested for the prevention of ulcer recurrence.

Detection of microstructural white matter alterations in functional gastrointestinal disorders assessed by diffusion kurtosis imaging.

BACKGROUND AND AIM: We evaluated whether diffusion kurtosis and tensor imaging (DKI/DTI) could reveal microstructural alterations in the brains of patients with functional gastrointestinal disorders (FGIDs), and whether imaging findings were correlated with health-related quality of life (HRQOL). METHODS: Twelve patients with FGIDs fulfilling the Rome IV criteria, and seven healthy controls were examined using a 3 T magnetic resonance (MR) scanner. Tract-based spatial statistics and regions of interest analyses were performed to compare the mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) between patients with FGIDs versus controls. HRQOL was assessed in patients with FGIDs using the eight-item short form of the Medical Outcome Study Questionnaire (SF-8) and the Gastrointestinal Symptom Rating Scale. RESULTS: Patients with FGIDs had extensive, widespread regions of reduced MD in the white matter in comparison with healthy controls, whereas no significant differences were observed in MK and FA. No significant differences in deep gray matter for the MK, FA, and MD values were observed between patients with FGIDs and controls. In patients with FGIDs, the FA values in the globus pallidus had a significant and negative correlation with SF-8 (a mental component summary) (r = -0.797, P = 0.01 uncorrected for multiple comparisons). CONCLUSIONS: DKI/DTI can help identify microstructural white matter alterations in patients with FGIDs. The FA values in the globus pallidus may be useful for a severity assessment of FGIDs.

Radiation Esophagitis in a Patient with Oral Carcinoma and Bone Metastasis.

Radiation esophagitis requiring endoscopic evaluation occurs quite rarely, affecting <1% of patients undergoing radiation treatment. Acute radiation esophagitis develops within 3 weeks of radiation therapy. We describe herein a case of radiation esophagitis in a patient with oral carcinoma with multiple general bone metastases. Cisplatin, fluorouracil, and cetuximab were given for 3 cycles. Radiation therapy (30 Gy) to the thoracic vertebrae and lumbar vertebrae was prescribed to prevent worsening of bone metastases and relieve pain. Neutropenia was also observed due to chemotherapy. After the end of radiation therapy, the patient experienced chest pain, heartburn, and dysphagia. Upper gastrointestinal endoscopy revealed severe radiation esophagitis of endoscopic Fukui Acute Radiation Esophagitis grade 4. Oral food was discontinued and an intravenous proton-pump inhibitor was administered. After 3 weeks, upper gastrointestinal endoscopy showed improvement of radiation esophagitis, with scars. The symptoms of chest pain, heartburn, and dysphagia had also disappeared. This is the first case to be reported of acute radiation esophagitis in a patient with oral carcinoma with bone metastasis who experienced dramatic improvement of endoscopic findings. Neutropenia appears to be associated with more severe acute radiation esophagitis.

Regulatory T cells in Crohn's disease following anti-TNF-α therapy.

BACKGROUND AND AIM: Anti-tumor necrosis factor alpha (TNF-α) therapy is an effective therapy for Crohn's disease (CD). We investigated FoxP3+ and CD127- regulatory T cells (Tregs) before and after administration of anti-TNF-α therapy in CD. METHODS: Eight patients with active CD who had received anti-TNF-α antibodies were enrolled. Treatment responses were followed by physical examination and Crohn's disease activity index (CDAI) scoring before and 2 weeks after the initial administration of anti-TNF-α antibodies. Peripheral blood samples were collected before and 2 weeks after treatment. White blood cell count and serum levels of C-reactive protein (CRP) and albumin were measured. FoxP3+ expression and CD127- Tregs were measured by fluorescence activated cell sorting (FACS) analysis of whole blood samples. RESULTS: Median values of CDAI decreased significantly after treatment. The proportion of FoxP3+ Tregs increased significantly after treatment. There was a significant negative correlation between ΔCD127- Tregs and Δlymphocyte. CONCLUSIONS: Anti-TNF-α therapy would enhance Tregs, which may account for the mechanism underlying the positive effect of the anti-TNF-α treatment in CD patients.

Hypopituitarism manifesting after invasive dental treatment in a patient with carcinoma of the tongue: a case report.

BACKGROUND: The symptoms of hypopituitarism are not usually discussed in the clinical setting of oral surgery. CASE PRESENTATION: We herein report a case of hypopituitarism that became evident after biopsy and extraction of several teeth in a 68-year-old man with tongue cancer. Three days after biopsy, the patient developed nausea and vomiting, and his serum sodium had fallen to 124 mEq/L. His serum cortisol concentration was low. Although the plasma concentration of adrenocorticotropic hormone (ACTH) was within the normal range, ACTH stimulation testing showed a lack of cortisol response. Given these findings, we suspected secondary adrenal insufficiency. To investigate the cause of secondary adrenal insufficiency, MRI of the head was performed, which revealed pituitary gland atrophy. The results of pituitary anterior lobe hormone-stimulation tests were compatible with hypopituitarism. Thirty days after biopsy, partial tongue resection was successfully performed under general anesthesia with perioperative hydrocortisone supplementation. CONCLUSIONS: We must be aware of various signs of hypopituitarism when we perform invasive dental treatment.

Guidelines for standardizing cleansing and disinfection of gastrointestinal endoscopes.

As part of the activities toward standardizing endoscopy procedures, the Japan Gastroenterological Endoscopy Society has prepared guidelines for cleansing and disinfection of gastrointestinal endoscopes. The environment of gastrointestinal endoscopy differs between Japan and advanced Western countries. In advanced Western countries, gastrointestinal endoscopy is performed almost exclusively at specialized facilities, where strict provisions are observed for cleansing and disinfecting endoscopes. In Japan, however, gastrointestinal endoscopy is performed even in small clinics, and the annual number of gastrointestinal endoscopy cases is enormous. In addition, the method for cleansing and disinfecting endoscopes differs among hospitals. Although there is a distinct lack of evidence for how gastrointestinal endoscopes are cleaned and disinfected, it is necessary to standardize the method for doing so to advance the field of endoscopic medicine.

Recipient sepsis caused by Lactococcus garvieae contamination of platelets from a donor with colon cancer.

Lactococcus garvieae is a well-known fish pathogen that has low virulence in humans and is rarely isolated from the blood cultures of endocarditis patients. We describe herein the first reported case of transfusion-transmitted L. garvieae sepsis caused by a contaminated platelet concentrate from a donor who consumed raw octopus before blood donation. Retrospective examination of the laboratory results of the index donor revealed that his haemoglobin levels had been steadily decreasing, which led to the detection of a latent colon cancer. The donors with colon lesions involving a latent cancer may relate an asymptomatic bacteremia.

Plasma-Free Amino Acid Profiles in Crohn's Disease: Relationship With the Crohn Disease Activity Index.

We aimed to clarify the relationship between plasma-free amino acid (PFAA) profiles and the Crohn's disease (CD) activity index (CDAI) in patients with CD. METHODS: We measured fasting PFAA concentrations in 29 patients with CD and their correlation with disease activity. RESULTS: In all patients, significant correlations were noted between CDAI and concentrations of valine, methionine, leucine, histidine, tryptophan, alanine, tyrosine, total amino acids (TAAs), nonessential amino acids (NEAAs), essential amino acids (EAAs), and branched-chain amino acids (BCAAs). In patients with the ileo-colonic type of CD, significant correlations were noted between CDAI and valine, histidine, tryptophan, glutamine, TAA, NEAA, EAA, and BCAA. In ileal type, significant correlations were observed between CDAI and threonine, valine, histidine, serine, and glycine. In colonic type, significant correlations were noted between CDAI and valine, histidine, tryptophan, TAA, NEAA, EAA, and BCAA. CONCLUSIONS: In patients with CD, plasma amino acids appear to be associated with disease activity.

Asymptomatic acute hepatitis E in a female patient with ulcerative colitis.

We present a 60-year-old female patient with asymptomatic acute hepatitis E that was fortuitously detected during the course of ulcerative colitis (UC). She was admitted to hospital on October 30, 2015. Endoscopy and histological examination of the colon showed typical findings of UC. All parameters of liver function tests were normal on this date. Combination therapy with oral prednisolone and mesalazine was started and intravenous administration of infliximab once every 8 weeks was added later. Her symptoms gradually improved after these treatments, and she was discharged on February 7, 2016. In a periodic check-up on July 7, 2016, high levels of serum transaminases were detected in liver function tests. Although drug-induced liver injury was first suspected, anti-hepatitis E virus (HEV) immunoglobulin A was positive. The genotype and subgenotype of this HEV are 3 and 3a, respectively, although the infectious route of the HEV was unclear. Within 2 weeks after the onset of acute liver injury, the HEV viremia disappeared and her liver function tests improved. Examination of serum anti-HEV immunoglobulin A should be added at the time of abnormal liver function tests in patients with UC receiving immunosuppressive and biological drugs.

Evidence-based clinical practice guidelines for peptic ulcer disease 2015.

The Japanese Society of Gastroenterology (JSGE) revised the evidence-based clinical practice guidelines for peptic ulcer disease in 2014 and has created an English version. The revised guidelines consist of seven items: bleeding gastric and duodenal ulcers, Helicobacter pylori (H. pylori) eradication therapy, non-eradication therapy, drug-induced ulcer, non-H. pylori, non-nonsteroidal anti-inflammatory drug (NSAID) ulcer, surgical treatment, and conservative therapy for perforation and stenosis. Ninety clinical questions (CQs) were developed, and a literature search was performed for the CQs using the Medline, Cochrane, and Igaku Chuo Zasshi databases between 1983 and June 2012. The guideline was developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Therapy is initially provided for ulcer complications. Perforation or stenosis is treated with surgery or conservatively. Ulcer bleeding is first treated by endoscopic hemostasis. If it fails, surgery or interventional radiology is chosen. Second, medical therapy is provided. In cases of NSAID-related ulcers, use of NSAIDs is stopped, and anti-ulcer therapy is provided. If NSAID use must continue, the ulcer is treated with a proton pump inhibitor (PPI) or prostaglandin analog. In cases with no NSAID use, H. pylori-positive patients receive eradication and anti-ulcer therapy. If first-line eradication therapy fails, second-line therapy is given. In cases of non-H. pylori, non-NSAID ulcers or H. pylori-positive patients with no indication for eradication therapy, non-eradication therapy is provided. The first choice is PPI therapy, and the second choice is histamine 2-receptor antagonist therapy. After initial therapy, maintenance therapy is provided to prevent ulcer relapse.