Breach of tolerance versus burden of bile acids: Resolving the conundrum in the immunopathogenesis and natural history of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.

Inhibition of integrin binding to ligand arg-gly-asp motif induces AKT-mediated cellular senescence in hepatic stellate cells.

BACKGROUND & AIMS: Hepatic stellate cells (HSCs) play an essential role in liver fibrogenesis. The induction of cellular senescence has been reported to inhibit HSC activation. Previously, we demonstrated that CWHM12, a small molecule arginine-glycine-aspartic acid (RGD) peptidomimetic compound, inhibits HSC activation. This study investigated whether the inhibitory effects of CWHM12 on HSCs affected cellular senescence. METHODS: The immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on cellular senescence via the disruption of RGD-mediated binding to integrins. RESULTS: CWHM12 induces cell cycle arrest, senescence-associated beta-galactosidase activity, acquisition of senescence-associated secretory phenotype (SASP), and expression of senescence-associated proteins in HSCs. Further experiments revealed that the phosphorylation of AKT and murine double minute 2 (MDM2) was involved in the effects of CWHM12, and the inhibition of AKT phosphorylation reversed these effects of CWHM12 on HSCs. CONCLUSIONS: Pharmacological inhibition of RGD-mediated integrin binding induces senescence in activated HSCs.

Dilated main pancreatic duct can be a negative predictor of pancreatitis related to biliary SEMS insertion across the papilla.

OBJECTIVES: Post-ERCP pancreatitis (PEP) after self-expandable metallic stent (SEMS) insertion across the papilla of Vater is an important adverse event that affects the patient's quality of life (QOL). We examined the predictive factors of PEP after SEMS insertion to treat obstructive jaundice due to malignancy. METHODS: Ninety patients who underwent biliary SEMS insertion for biliary obstruction due to malignancy at Iwata City Hospital between 2010 and 2018 were reviewed. We evaluated the relationship between the incidence of PEP after biliary SEMS insertion and clinical factors. We measured the thickness of the pancreatic parenchyma and diameter of the main pancreatic duct (MPD) at the left side of the corpus vertebrae. RESULTS: Mild and severe PEP were diagnosed in 10 (11.1%) and 1 (1.1%) patients, respectively. Only the thickness of the pancreatic parenchyma and diameter of MPD significantly differed between the PEP and non-PEP groups. The incidence of PEP among patients whose thickness of the pancreatic parenchyma at the left side of the corpus vertebrae was less than 9.5 mm (0%) on computed tomography was lower than that in patients whose thickness was 9.5 mm or greater (34.4%). Similarly, a wider (5 mm or more) diameter of MPD (4.3%) reduced the incidence of PEP compared with a narrower diameter (40.0%). Logistic regression analysis revealed that the probability of PEP decreases 3.91 times for every 1-mm increase in MPD diameter (95% CI 1.23-12.4, p = .02). CONCLUSION: Based on our study, a dilated MPD is a negative predictive factor of pancreatitis related to biliary SEMS insertion.

Texture Analysis Using Preoperative Positron Emission Tomography Images May Predict the Prognosis of Patients With Resectable Oral Squamous Cell Carcinoma.

PURPOSE: Texture analysis is a computer-assisted technique used to measure intratumoral heterogeneity, which is known to have important roles in cancer research. This study aimed to assess the potential prognostic values of textural features extracted from preoperative 18F-fluorodeoxyglucose positron emission tomography images in patients with resectable oral squamous cell carcinoma. PATIENTS AND METHODS: This retrospective cohort study included patients with oral squamous cell carcinoma who underwent resection surgery. We extracted 31 textural indices from preoperative positron emission tomography images. Overall survival (OS) and disease-free survival (DFS) were chosen as the primary outcome variables, and the primary predictor variables were age, sex, primary tumor location, pathological T and N classification, histologic differentiation, resected margin, perineural and lymphovascular invasion, maximum standardized uptake value, and the 14 textural indices selected in the factor analysis. We analyzed OS and DFS using Kaplan-Meier curves, and the differences between survival curves were determined using a log-rank test. The independent prognostic factors were assessed using the Cox-proportional hazards model. RESULTS: We enrolled 81 patients (median age, 67.3 years; range, 32 to 88 years). The median follow-up duration was 50.1 months (range, 6.3 to 133.7 months). The univariable and multivariable analyses revealed that higher entropy values (≥1.91) were associated with worse OS (hazard ratio, 21.49; 95% confidence interval, 1.36 to 340.71; P = .03) and DFS (hazard ratio, 50.69; 95% confidence interval, 5.23 to 491.18; P = .001). CONCLUSIONS: This study showed that entropy is a statistically significant prognostic factor of both OS and DFS. Texture analysis using preoperative positron emission tomography images may contribute to risk stratification.

Remarkable Short-Term Regression of a Posterior Mediastinum Metastasis From Primary Intraosseous Carcinoma Treated With Nivolumab: A Case Report.

Primary intraosseous carcinoma (PIOC; not otherwise specified) is a rare odontogenic malignancy that is believed to arise from the odontogenic epithelium. In addition, some cases arise in odontogenic cysts or other benign precursors. There are no established treatment protocols for PIOC because of its rarity. In particular, no standard therapy has been established for patients with recurrent or metastatic PIOC. This report describes a case in which the use of nivolumab showed a marked treatment response in metastatic PIOC. The patient was a 71-year-old man with PIOC. The patient underwent segmental mandibulectomy with modified radical neck dissection after neoadjuvant chemotherapy, including 2 cycles of paclitaxel, cetuximab, and carboplatin and 1 cycle of docetaxel, cisplatin, and 5-fluorouracil. The lesion rapidly enlarged during neoadjuvant chemotherapy, and surgical specimens showed no histologic therapeutic effects of chemotherapy. Three months after the surgery, contrast-enhanced computed tomograms showed posterior mediastinal lymph node metastasis. Treatment with nivolumab was initiated, and notable clinical improvement was noted after 2 cycles. Although it was a short-term treatment, remarkable effects were observed and no adverse events were noted during and after nivolumab treatment. Nivolumab could be an attractive treatment option for metastatic PIOC that is resistant to traditional chemotherapy and target therapy, including cetuximab. Further investigation of this treatment is warranted.

Idiopathic Isolated Unilateral Hypoglossal Nerve Palsy: A Report of 2 Cases and Review of the Literature.

Hypoglossal nerve palsy (HNP) is a common finding in neurologic diseases when associated with other cranial nerve palsies or further pathology and exhibits characteristic clinical manifestations, including unilateral atrophy of the musculature of the tongue. It occasionally appears as the initial or solitary sign of an intracranial or extracranial space-occupying lesion, head or neck injury, or vascular abnormality of the internal carotid artery. There are few cases of idiopathic isolated unilateral HNP, which should be diagnosed through exclusion. This report describes 2 patients who had different outcomes and presents a literature review of idiopathic isolated unilateral HNP. Case 1 was a 71-year-old man who was referred with a 1-month history of dysphagia and speech impairment. Intraoral examination disclosed marked left-side hemiatrophy of the tongue and deviation toward the left on protrusion. At coronal Tl-weighted magnetic resonance imaging, left-side hemiatrophy of the tongue was clearly visible through deviation of the median septum to the left. The patient was diagnosed with idiopathic isolated unilateral HNP through exclusion and was treated with steroids and mecobalamin, but he did not recover. Case 2 was a 32-year-old man complaining of tongue weakness for 2 days. On examination, left HNP was evident, with deviation of the tongue to the left on protrusion. He was diagnosed with idiopathic isolated unilateral HNP through exclusion and was treated with steroids. After 3 weeks, the patient had completely recovered. To the best of the authors' knowledge, this is the first detailed literature review on idiopathic isolated unilateral HNP. This condition is very rare but should be considered for diagnosis. It warrants a thorough and stepwise approach for etiologic diagnosis.

[A case of obstructive pancreatitis induced by extramedullary pancreatic metastasis in a patient with immunoglobulin D multiple myeloma].

A 51-year-old Brazilian female who had IgD-lambda type multiple myeloma presented with epigastralgia and obstructive jaundice during her follow-up. Contrast-enhanced computed tomography (CT) showed an enhanced mass of 25mm in the pancreatic head, and endoscopic retrograde cholangiopancreatography revealed smooth stenoses in the lower bile duct and main pancreatic duct (MPD) of the head. We diagnosed the patient with extramedullary pancreatic metastasis of multiple myelomas. Plastic stents were endoscopically placed into both the common bile duct and MPD. One week later, she suffered a repeat episode of epigastralgia. A subsequent CT scan showed obstructive pancreatitis due to another mass, 30mm in size, emerging rapidly in the pancreatic body. Pancreatitis improved after we replaced the plastic stent with a longer one so that the distal end reached beyond the stenosis at the MPD of the body. Although both the tumors were treated with radiotherapy and showed temporary reduction, the patient died 1 month later due to progression of the disease. While cases involving obstructive pancreatitis induced by extramedullary pancreatic metastasis of multiple myelomas are very rare, it is crucial that such patients are rapidly diagnosed and treated.

[Schistosomiasis japonica in a patient who emigrated from China: a case report].

A 37-year-old woman exhibited abnormal liver enzyme levels without any symptoms at a medical check-up. She was born and raised in Hubei, China, and had immigrated to Japan in her mid-thirties. Ultrasonography revealed an enlarged caudate lobe of the liver and a wide moniliform portal vein, whereas computed tomography revealed lined calcification on the surface of the liver and on the collateral vein of the portal vein. Although imaging studies provided no critical findings, the crucial information that led to diagnosis was gained through the interview with the patient. Schistosomiasis japonica was known to be prevalent in her hometown, and she reported that her father's past infection was due to Schistosoma japonicum. Serological analysis demonstrated high levels of anti-S. japonicum antibodies, which were reduced using praziquantel administration.

Cervical chyloma after neck dissection: a case report.

Cervical chylomas are rare pseudocystic collections that lack an epithelial lining and arise from the thoracic duct or its tributaries; although they typically develop after neck surgery or trauma, they can arise from unknown causes. Treatment options include not only conservative therapy, such as dietary modification, repeated aspirations, and sclerotherapy, but also include surgical excision. We describe a case of a chyloma in a 64-year-old Japanese woman with squamous cell carcinoma of the gingiva. The chyloma developed following left segmental mandibulectomy with radical neck dissection and reconstruction, using a titanium plate and a pectoralis major myocutaneous flap. One month after surgery, a left supraclavicular swelling was noted, so ultrasound-guided fine-needle aspiration and cytology were performed to exclude a recurrence of neck metastasis. The aspiration yielded a milky fluid without atypical or malignant cells on cytology, confirming the diagnosis of chyloma. Although we performed continuous compressive dressing and started the patient on a low-fat diet, the mass persisted. When the patient died of bone, lung, and liver metastases five months after the second surgery, the mass had not changed in size. Awareness of this complication is important to ensure timely diagnosis and appropriate treatment.

Hepatic Angiosarcoma with Peliosis Hepatis.

A 59-year-old woman presented to our hospital with liver dysfunction. Imaging revealed multiple lesions in the liver. The patient was diagnosed with peliosis hepatis using percutaneous and laparoscopic biopsies. However, her condition worsened with the appearance of new, obvious mass-forming lesions. Therefore, she underwent a second percutaneous biopsy of these lesions and was diagnosed with hepatic angiosarcoma. Her condition progressed rapidly, and she died two weeks after the diagnosis. Diagnosis of hepatic angiosarcoma in the early stages is difficult. It should be noted that hepatic angiosarcoma may be associated with the development of peliosis hepatis.

Simvastatin inhibits hepatic stellate cells activation by regulating the ferroptosis signaling pathway.

BACKGROUND & AIMS: Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs. METHODS: Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression. RESULTS: Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes. CONCLUSIONS: Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway.

Rifaximin Improves Liver Functional Reserve by Regulating Systemic Inflammation.

Rifaximin, a non-absorbable antibiotic, has been demonstrated to be effective against hepatic encephalopathy (HE); however, its efficacy on liver functional reserve remains unknown. Here, we evaluated the efficacy of rifaximin on the liver functional reserve and serological inflammation-based markers in patients with cirrhosis. A retrospective study was conducted on patients who received rifaximin for more than three months at our hospital between November 2016 and October 2021. The recurrence and grade of HE, serological ammonia levels, Child-Pugh score (CPS), and serological inflammation-based markers such as the neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP), and CRP to albumin ratio (CAR) were evaluated. The correlations between serological inflammation-based markers and liver functional reserve were evaluated. HE grades, serum ammonia levels, and inflammation-based markers significantly improved at three months compared with those at baseline. Patients with improved albumin levels showed significantly higher CRP improvement rates at both 3 and 12 months. Patients with an improvement in CAR at 3 months demonstrated a significant improvement in CPS at 12 months. Rifaximin improved the liver functional reserve in patients with cirrhosis. Improvements in inflammation-based markers, particularly CRP and albumin, may be involved in this process.

Efficacy of a deep leaning model created with the transfer learning method in detecting sialoliths of the submandibular gland on panoramic radiography.

OBJECTIVE: This study aimed to compare the performance of 3 deep learning models, including a model constructed with the transfer learning method, in detecting submandibular gland sialoliths on panoramic radiographs. STUDY DESIGN: We used data from 2 institutions (A and B) to create the models for use in institution B. In total, 224 panoramic radiographs with sialoliths were used. Model 1 was created using data from institution A only, model 2 was created using combined data from institutions A and B, and model 3 was created using the transfer learning method by having model 1 transferred and trained in various learning epochs using data from institution B. These models were tested and compared in their detection performance using testing data sets from institution B. RESULTS: Model 2 and model 3 with 300 epochs performed equally well and yielded the highest detection rates (recall: sensitivity of 85%, precision: positive predictive value of 100%, and F measure of 91.9%) for sialoliths on panoramic radiographs. CONCLUSION: The results of this study suggest that use of the transfer learning method with an appropriate number of epochs may be an alternative to sharing patient personal data among institutions.

Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway.

BACKGROUND & AIMS: Liver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs. METHODS: Immortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins. RESULTS: CWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-ß was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK. CONCLUSIONS: These results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.

Performance of deep learning models constructed using panoramic radiographs from two hospitals to diagnose fractures of the mandibular condyle.

OBJECTIVE: The present study aimed to verify the classification performance of deep learning (DL) models for diagnosing fractures of the mandibular condyle on panoramic radiographs using data sets from two hospitals and to compare their internal and external validities. METHODS: Panoramic radiographs of 100 condyles with and without fractures were collected from two hospitals and a fivefold cross-validation method was employed to construct and evaluate the DL models. The internal and external validities of classification performance were evaluated as accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). RESULTS: For internal validity, high classification performance was obtained, with AUC values of >0.85. Conversely, external validity for the data sets from the two hospitals exhibited low performance. Using combined data sets from both hospitals, the DL model exhibited high performance, which was slightly superior or equal to that of the internal validity but without a statistically significant difference. CONCLUSION: The constructed DL model can be clinically employed for diagnosing fractures of the mandibular condyle using panoramic radiographs. However, the domain shift phenomenon should be considered when generalizing DL systems.

Azathioprine-induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report.

This report highlights azathioprine-induced severe myelosuppression in the patient with NUDT15 minor variant. This case report is particularly instructive because several typical symptoms are the clues to this critical adverse drug reaction.

Case report of API2-MALT1 fusion-positive MALT lymphoma arising from bilateral submandibular glands with no evidence of autoimmune syndromes.

Mucosa-associated lymphoid tissue (MALT) lymphoma arising from the salivary glands is usually associated with chronic infection or autoimmune syndromes, such as primary Sjogren syndrome. The occurrence of t(11;18)/API2-MALT1 is rare in salivary MALT lymphoma. Here we describe a case of API2-MALT1 fusion-positive MALT lymphoma of the bilateral submandibular glands with no evidence of autoimmune syndromes. A 70-year-old man complained of a painless swelling in the bilateral submandibular gland. Serology examination results were negative for anti-SSA and anti-SSB. His right submandibular gland was dissected, and he was diagnosed with MALT lymphoma with the API2-MALT1 fusion gene. Positron emission tomography/computed tomography scanning indicated mild fluorine-18-fluorodeoxyglucose uptake in the left submandibular gland and liver. He was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. After 6 years, the patient is alive and disease free. In the present case, the patient with API2-MALT1 fusion-positive MALT lymphoma had a good outcome despite the advanced clinical stage.

The prognostic significance of intratumoral heterogeneity of 18F-FDG uptake in patients with oral cavity squamous cell carcinoma.

PURPOSE: This study aimed to evaluate the prognostic significance of two major indices of intratumoral heterogeneity of 18F-fluorodeoxyglucose uptake by positron emission tomography (PET)/computed tomography (CT), namely heterogeneity index (HI) and heterogeneity factor (HF), in patients with oral squamous cell carcinoma. METHODS: We performed a retrospective analysis of 62 patients who underwent resective surgery. HI, HF, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained from pretreatment PET. HI was obtained by dividing SUVmax by SUVmean for the primary lesion; HF was obtained by taking the derivative (dV/dT) of the volume-threshold function from 30 to 70%. Univariate and multivariate analyses for the overall survival (OS) and disease-free survival (DFS) were performed using PET and clinicopathological parameters. RESULTS: Univariate and multivariate analyses of OS revealed that higher HI levels (threshold for the SUVmean is 30% of the SUVmax) were associated with poorer OS [hazard ratio (HR) = 11.57; 95% confidence interval (CI) = 1.45-92.28; P = 0.021]. Moreover, univariate and multivariate analyses of DFS revealed that higher TLG levels (threshold for the MTV and SUVmean is 4.0 of the SUV) were associated with poorer DFS (HR = 14.48; 95% CI = 1.27-164.78; P = 0.031). CONCLUSIONS: HI and TLG may be statistically significant prognostic factors for OS and DFS, respectively.

Quantitative analysis of chronological changes in the volume of flaps used for reconstruction of oral cavity defects.

Reconstruction of oral defects using flaps following resection of oral cancer has become a standard approach for restoration of oral function. The purpose of this study was to investigate chronological changes in the volume of such flaps used for reconstruction and the factors affecting flap volume. We performed a retrospective analysis of 17 patients who had undergone oral cancer resection and reconstruction with flaps. Measurements were performed using data from computed tomography, and the flaps were selected semi-automatically using a computer-operated region-of-interest system. The data indicated that the change in total flap volume at 1 year after surgery was 30.6%, and that body weight loss was a risk factor for volume reduction. Our results suggested that flaps should be at least 30% larger than the defects they are intended to repair. However, as large flaps have the potential to cause upper airway obstruction, flap volume should be determined on an individual basis according to defect size and location.

A Case of Sialolithiasis in a Minor Salivary Gland of the Buccal Mucosa.

Sialolithiasis is a common disease of the major salivary glands. In contrast, Sialolithiasis of Minor Salivary Glands (SMSG) is very rare. Only 2% of all cases of sialolithiasis develop in minor salivary glands and sublingual glands. Furthermore, the clinical and imaging features of SMSG frequently differ from those encountered in major salivary glands thus, hindering proper clinical diagnosis of SMSG. Histologically, SMSG is characterized by ductal ectasia (sometimes with deep cystic dilatation), acinar atrophy and periductal inflammation. Herein, we describe a patient suffering from SMSG in the left buccal region. Based on the clinicopathological findings of this case and a review of the literature, we propose that this entity should be included in the differential diagnosis of intra-mucosal nodules.