Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

A combination of hepatic encephalopathy and body mass index was associated with the point of no return for improving liver functional reserve after sofosbuvir/velpatasvir treatment in patients with hepatitis C virus-related decompensated cirrhosis.

AIMS: The real-world efficacy of sofosbuvir/velpatasvir treatment for patients with hepatitis C virus-related decompensated cirrhosis is unclear. We aimed to identify factors that improve liver functional reserve after treatment. METHODS: This was a multicenter retrospective study of 12-week sofosbuvir/velpatasvir treatment. A total of 48 patients with Child-Pugh (CP) class B or C were enrolled at 11 institutions. We evaluated changes in liver functional reserve at 24 weeks post-treatment. RESULTS: At baseline, 40 and eight patients were CP class B and C, respectively. The overall rate of sustained virologic response 12 weeks post-treatment was 95.8% (46/48). Serum albumin, alanine aminotransferase and α-fetoprotein levels, and the FIB-4 index were significantly improved post-treatment (P < 0.05). Among patients who achieved sustained virologic response 12 weeks post-treatment, those with CP class A increased from 0 to 24 patients (56%) at 24 weeks post-treatment. In multivariate analysis, body mass index (BMI) ≥25 was an independent factor that inhibited CP class improvement (P < 0.05). In decision tree analysis, after treatment, the initial divergent variable for CP class improvement was hepatic encephalopathy, followed by serum sodium level and BMI. CONCLUSION: Sofosbuvir/velpatasvir treatment improved the liver functional reserve in patients with hepatitis C virus-related decompensated cirrhosis at 24 weeks post-treatment. However, BMI ≥25 inhibited improvement in CP class. Additionally, decision tree analysis revealed that a combination of hepatic encephalopathy, serum sodium levels, and BMI were diversity profiles associated with no improvement in liver functional reserve after the treatment.

Ocular candidiasis in a tertiary hospital in Japan: A 10-year single-center retrospective study.

Ocular candidiasis is a major complication of candidemia that is sometimes sight-threatening. Although prompt ophthalmologic consultation and antifungal medication have been emphasized, recent changes in the causative species and drug susceptibilities make the picture unclear. This study aimed to determine whether there are trends among patients with ocular candidiasis and included 80 patients with candidemia who underwent ophthalmological screening at our hospital between 2010 and 2020. Data on the clinical characteristics, comorbidities, biochemical test results, causative Candida species, treatment, outcomes, visual acuity, and antifungal susceptibility were collected and analyzed. Statistical analyses were performed by comparing two groups, namely, the ocular candidiasis (n = 29) and non-ocular candidiasis (n = 51) groups. In the ocular candidiasis group, there were significantly more cases of central venous catheter insertion (82.8%, p = 0.026) and Candida albicans candidemia (72.4%, p < 0.001). Regarding ocular involvement, the majority of patients were asymptomatic. Most cases improved with antifungal therapy, but one case underwent vitrectomy. Between 2016 and 2020, there was a diversification of species, with a decrease in Candida parapsilosis and the emergence of Candida glabrata and Candida tropicalis. Regarding drug susceptibility, the minimum inhibitory concentrations of echinocandin and 5-fluorocytosine against Candida albicans, Candida parapsilosis, and Candida glabrata were slightly increased. In conclusion, in addition to appropriately performing ophthalmologic examinations, it is beneficial to select antifungal agents according to the diversity of species and drug susceptibilities.

Comparative analysis of neurofilament light chain levels in the serum and cerebrospinal fluid in rats subjected to partial sciatic nerve ligation.

Neurofilament light chain (NfL) has recently been used as a biomarker of neurodegeneration. Although cerebrospinal fluid (CSF) NfL levels are hypothesized to affect blood NfL levels, whether blood NfL levels change independently of the CSF during peripheral nerve injury remains unclear. Thus, we evaluated the nervous tissues histopathology and serum and CSF NfL levels in partial sciatic nerve-ligated rats at 6 h and one, three, or seven days after the surgery. Sciatic and tibial nerve fiber damage was observed at 6 h after the surgery, and peaked at three days postoperatively. The serum NfL levels peaked 6 h to one day after ligation, but they tended to return to the normal seven days after ligation. However, the CSF NfL levels were unchanged throughout the study period. In conclusion, the comparative evaluation of serum and CSF NfL levels can provide useful information as biomarkers of nerve tissue damage and its distribution.

Identifying the dataset to define the optimal timing of histopathological examination for central nervous system toxicity in MPTP-induced Parkinson's disease monkey model.

Determining the optimal timing for histopathological examination following exposure to a test article is crucial for assessing neurotoxicity. However, no study has focused on identifying an ideal dataset to define the optimal timing for histopathological examination of central nervous system (CNS) toxicity in monkeys. Therefore, this study aimed to define a predictive endpoint that would guide us in selecting the optimal timing for histopathological examination of CNS toxicity in monkeys. Four cynomolgus monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intravenously at a dosage of 0.6 mg/kg twice at 1-week intervals. Necropsies were performed 1 week after the final dose. The Parkinsonian rating (PR) score and temporal changes in neurofilament light chain and glial fibrillary acidic protein concentrations in the cerebrospinal fluid (CSF) and serum were evaluated and compared with the histopathological findings in the brain. The PR score of all animals administered MPTP increased from days 10 to 11, with some degree of individual variability. Microscopically, all animals showed axonal swelling and vacuolation, with or without microgliosis in the nigrostriatal bundle. However, substantial neurodegenerative findings were observed only in animals with high PR scores at necropsy. A slight increase in CSF biomarker levels at necropsy was also observed in animals with high PR scores. However, their correlation with microscopic findings in these animals was unclear. These data suggest that comprehensive clinical observations, such as PR score alone or combined with other CSF biomarkers, could be further evaluated as potential indicators for triggering anatomic CNS evaluations in monkeys following toxic insults.

The accuracy and clinical impact of the morphological identification of Aspergillus species in the age of cryptic species: A single-centre study.

BACKGROUND: Aspergillus spp. is identified morphologically without antifungal susceptibility tests (ASTs) in most clinical laboratories. The aim of this study was to examine the clinical impact of the morphological identification of Aspergillus spp. to ensure the adequate clinical management of Aspergillus infections. PATIENTS/METHODS: Aspergillus isolates (n = 126) from distinct antifungal treatment-naïve patients with aspergillosis were first identified morphologically, followed by species-level identification via DNA sequencing. An AST for itraconazole (ITC) and voriconazole (VRC) was performed on each Aspergillus isolate. RESULTS: Based on the genetic test results, morphology-based identification was accurate for >95% of the isolates at the species sensu lato level although the test concordance of Aspergillus spp. with low detection rates was low. The rates of cryptic species were found to be 1.2% among the isolates of A. fumigatus complex and 96.8% in the A. niger complex. Cryptic species with lower susceptibilities to antifungal drugs than sensu stricto species among the same Aspergillus section were as follows: The A. lentulus (n = 1) isolates had low susceptibilities to azoles among the A. fumigatus complex species (n = 86), and A. tubingensis isolates (n = 18) exhibited lower susceptibility to azoles among the A. niger complex species (n = 31). CONCLUSION: Diagnostic accuracy was high at the A. fumigatus and A. niger complex level. However, in the presence of cryptic species, a solely morphological identification was insufficient. Particularly, ITC and VRC might be inappropriate for aspergillosis treatment when the A. niger complex is identified morphologically because it is possible that the Aspergillus isolate is A. tubingensis.

Elevated level of microRNA-210 at the initiation of muscular regeneration in acetic acid-induced non-ischemic skeletal muscular injury in mice.

The alteration in microRNA-210 level, a hypoxia-inducible microRNA, is not well known in non-ischemic tissue injury. In this study, we characterized the histopathological time course of acetic acid-induced skeletal muscle injury as a non-ischemic tissue injury model and investigated the expression of microRNA-210, hypoxia-inducible factor 1α, and growth factors using quantitative polymerase chain reaction analysis. After a single intramuscular dose of 3% (v/v) acetic acid to C57BL/6J mice, focal coagulative necrosis of muscle fibers was noted from 3 h after dosing and infiltration of F4/80 and Galectin-3 positive M2 macrophage was noted at 1 d after dosing. Muscular regeneration was initiated from 3 d, when M2 macrophage infiltration was most prominent, till 14 d after dosing. Hif1α and Hgf expression increased from 3 h onwards, and microRNA-210 level increased after 3 d after the treatment. However, no clear elevation in the levels of Igf1 or Vegf was observed. The infiltrative macrophages and regenerative muscle fibers were positive for hypoxia-inducible factor 1α, microRNA-210, and hepatocyte growth factor as assessed by immunohistochemistry or in situ hybridization. In this study, dominant infiltration of M2 macrophages at muscular necrosis and subsequent regeneration after a single intramuscular injection of acetic acid in mice were observed. The increase in hif1α level was observed just after the muscular injury in this non-ischemic tissue injury model, and the elevation in microRNA-210 level was noted at the initiation of tissue regeneration, indicating its effects on tissue protection and repair.

In vivo screening of subcutaneous tolerability for the development of novel excipients.

To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase.

Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate-salt hypertensive uni-nephrectomized KKAy mice.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-ß). Moreover, compound A significantly suppressed TGF-ß-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Zosteriform skin metastasis caused by retrograde lymphatic migration of metastatic squamous cell lung carcinoma.

BACKGROUND: Zosteriform skin metastasis (ZSM) is rare, and its etiology is not well understood. ZSM is possibly derived from the retrograde movement of cancer cells through the lymphatic vessels during disease development. However, it has been difficult to demonstrate it, as no specific findings have been observed. CASE PRESENTATION: A 68-year-old man presented to our department with neck lymphadenopathy. After detailed examinations, squamous cell lung carcinoma (cT2aN3M1c) was diagnosed. Although cisplatin combined with gemcitabine was administered, his cancerous lymphangiopathy was exacerbated, and ZSM was observed on his right chest. Pembrolizumab was initiated as a second-line chemotherapy; however, the patient died 7 months after the initial presentation. In this case, fluorodeoxyglucose-positron emission tomography indicated the presence of skin metastasis and cancerous lymphangiopathy. Similarly, after performing an autopsy, tumor-cell filled lymph ducts were observed in the right subclavian and the cutaneous lymphatic vessel from the right hilar lymph nodes. CONCLUSIONS: To the best of our knowledge, this is the first study to demonstrate that the localization of ZSM in the cutaneous lymphatics was caused by the retrograde movement of cancer cells through the lymphatic vessels, using radiographical and pathological analysis. In addition, fluorodeoxyglucose-positron emission tomography may help predict skin metastasis induced by cancerous lymphangiopathy.

Ion channel mRNA distribution and expression in the sinoatrial node and right atrium of dogs and monkeys.

There are limited data on the gene expression profiles of ion channels in the sinoatrial node (SAN) of dogs and monkeys. In this study, the messenger RNA (mRNA) expression profiles of various ion channels in the SAN of naïve dogs and monkeys were examined using RNAscope® in situ hybridization and compared with those in the surrounding right atrium (RA) of each species. Regional-specific Cav1.3 and HCN4 expression was observed in the SAN of dogs and monkeys. Additionally, HCN1 in dogs was only expressed in the SAN. The expression profiles of Cav3.1 and Cav3.2 in the SAN and RA were completely different between dogs and monkeys. Dog hearts only expressed Cav3.2; however, Cav3.1 was detected only in monkeys, and the expression score in the SAN was slightly higher than that in the RA. Although Kir3.1 and NCX1 in dogs were equally expressed in both the SAN and RA, the expression scores of these genes in the SAN of monkeys were slightly higher than those in the RA. The Kir3.4 expression score in the SAN of dogs and monkeys was also slightly higher than that in the RA. The mRNA expression scores of Kv11.1/ERG and KvLQT1 were equally observed in both the SAN and RA of dogs and monkeys. HCN2 was not detected in dogs and monkeys. In summary, we used RNAscope to demonstrate the SAN-specific gene expression patterns of ion channels, which may be useful in explaining the effect of pacemaking and/or hemodynamic effects in nonclinical studies.

Subendocardial nodular proliferation of myofibroblasts in a laboratory beagle.

A smooth white focus was macroscopically observed in the right ventricular endocardium in a 15-month-old male beagle from a 4-week oral gavage toxicity study. This lesion likely arose from myofibroblasts and was diagnosed as subendocardial nodular proliferation of myofibroblasts. This lesion was observed only in one animal in a low dose group and was an incidental finding. Histopathologically, the well-demarcated nodule comprised abundant collagen containing spindle cells arranged in intermediate to long streams and formed broad interlacing fascicles. The spindle cells had an indistinct cell border with round to elongated hyperchromatic nuclei or nuclei with finely stippled chromatin and indistinct nucleoli. Furthermore, these cells were weakly positive for S100 and positive for α-smooth muscle actin, calponin, and vimentin. Based on the histological features, the proliferating spindle cells resembled phenotypes of smooth muscles or myofibroblasts. However, the proliferating cells lacked well-differentiated smooth muscle cells, cigar-shaped nuclei, and well-developed reticulin fibers outlining individual cells. This study describes the morphological characteristics of an endocardial proliferative lesion in the right ventricle of a beagle.

A case of hepatic leiomyosarcoma with osteosarcomatous differentiation (malignant mesenchymoma) in a dog.

A rare spontaneous hepatic leiomyosarcoma with osteosarcomatous differentiation was observed in a female beagle dog and its morphological and immunohistochemical characteristics were examined. Upon necropsy, an endoceliac mass originating from the liver was detected, which was composed of hematoid fluid-filled cysts and white to grayish solid tissue. There were no macroscopic findings in other organ systems. Histopathologically, the hepatic mass consisted of two different mesenchymal components. One form was spindle cells arranged in interlacing fascicles immunohistochemically positive for smooth muscle actin (SMA) and smoothelin, indicating leiomyosarcomatous differentiation. The other form was composed of short spindle cells positive for S-100 and was producing various amounts of eosinophilic osteoid and trabecula-like matrices positive for osteocalcin, indicating osteosarcomatous differentiation. In addition, invasive growth in the hepatic parenchyma and cell atypia were observed. Based on these findings, the mass was diagnosed as hepatic leiomyosarcoma with osteosarcomatous differentiation (malignant mesenchymoma), which might be derived from undifferentiated mesenchymal cells.

Real-world effects of long-term rifaximin treatment for Japanese patients with hepatic encephalopathy.

AIM: Rifaximin (RFX) improves hepatic encephalopathy (HE). However, information on long-term treatment with RFX is limited. In this study, we aimed to investigate the effect of long-term treatment with RFX on HE and liver function. Moreover, we investigated factors associated with the recurrence of HE under RFX treatment. METHODS: In this retrospective cohort study, we consecutively enrolled 65 patients with HE who initiated RFX treatment (1200 mg/day) in our hospital from January 2017 to June 2018. We evaluated liver function test results, including blood ammonia levels, and the recurrence rate of HE after RFX treatment. RESULTS: The median follow-up duration was 41.6 weeks (range, 1.4-96.7 weeks). The blood ammonia level significantly declined from 157 to 86 µg/dL at 4 weeks after RFX treatment (P < 0.01), and the effect was prolonged. Furthermore, Child-Pugh score decreased in 51% (26/51) of the patients at 12 weeks during RFX treatment. The recurrence rate of HE after RFX treatment was 26.2% (17/65), and presence of ascites at baseline was identified as the only independent risk factor for HE recurrence (hazard ratio 4.71; 95% confidence interval, 1.27-17.5; P = 0.02). The cumulative recurrence rate of HE was significantly lower in patients without ascites than in patients with ascites at baseline (13.8% vs. 50.8%, P = 0.001). CONCLUSIONS: Long-term treatment with RFX was beneficial for HE and liver function in patients with HE. Furthermore, the recurrence rate of HE was low in RFX-treated patients without ascites. Thus, long-term treatment with RFX could be effective for the management of Japanese patients with HE.

Marked accumulation of fluorodeoxyglucose and inflammatory cells expressing glucose transporter-3 in immunoglobulin G4-related autoimmune hepatitis.

Immunoglobulin (Ig)G4-related autoimmune hepatitis (AIH) is a recently proposed subtype that responds well to steroid treatment; however, its pathogenesis remains unclear. We report here a 65-year-old Japanese woman with skin itching and lip swelling. She had liver injury with jaundice, which persisted despite stopping anti-allergic agents. Blood chemistry revealed highly elevated serum IgG and IgG4 (535 mg/dL) levels, and positive anti-nuclear antibody. The diagnosis of AIH was based on liver biopsy. Notably, the IgG4+ /IgG+ cell ratio was 85%. On fluorodeoxyglucose (FDG) positron emission tomography/computed tomography, robust signal intensity was found in the liver, and in enlarged lymph nodes and salivary glands with confirmed IgG4+ cell infiltration. Immunofluorescence analysis of the liver biopsy specimen indicated clear expression of glucose transporter-3 (Glut-3) in IgG4+ inflammatory cells infiltrating into the portal area. This is the first report of simultaneous strong accumulation of FDG and Glut-3 expression in IgG4-related AIH, which might aid in elucidating the pathogenesis of this disease.

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage.

MicroRNAs (miRNA) are short single-stranded RNA sequences that have a role in the post-transcriptional regulation of genes. The identification of tissue specific or enriched miRNAs has great potential as novel safety biomarkers. One longstanding goal is to associate the increase of miRNA in biofluids (e.g., plasma and urine) with tissue-specific damage. Next-generation sequencing (miR-seq) was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen [APAP] or carbon tetrachloride [CCL4 ]). Analyses with traditional serum chemistry and histopathology confirmed that toxicant-induced organ damage was specific. In animals treated with cisplatin, levels of five miRNAs were significantly altered in the kidney, 14 in plasma and six in urine. In APAP-treated animals, five miRNAs were altered in the liver, 74 in plasma and six in urine; for CCL4 the changes were five, 20 and 6, respectively. Cisplatin treatment caused an elevation of miR-378a in the urine, confirming the findings of other similar studies. There were 17 in common miRNAs elevated in the plasma after treatment with either APAP or CCL4 . Four of these (miR-122, -802, -31a and -365) are known to be enriched in the livers of rats. Interestingly, the increase of serum miR-802 in both hepatotoxicant treatments was comparable to that of the well-known liver damage marker miR-122. Taken together, comparative analysis of urine and plasma miRNAs demonstrated their utility as biomarkers of organ injury. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.

Immunohistochemical characterization of urethane-induced lung tumors in CB6F1-Tg rasH2 mice.

The purpose of this study was to define the histopathological characteristics of pulmonary neoplastic lesions, especially focusing on the origin of tumor cells, in urethane-treated Tg rasH2 mice. Bronchiolar-alveolar adenomas/adenocarcinomas were observed in the lungs from all of the urethane-treated animals. Immunohistochemically, these tumors showed an alveolar epithelial type II (AE2) cell phenotype demonstrating positive staining of surfactant protein C (SP-C). Cells expressing Clara cell 10 (CC10), a Clara cell marker, were also observed in a scattered manner in some tumors. Several SP-C and CC10 double-positive cells were observed in these tumors. Most of the urethane-induced pulmonary tumors were considered to have an AE2 cell phenotype, but the presence of SP-C and CC10 double positive cells in the tumors of Tg rasH2 mice suggests that some tumors arose from bronchioalveolar stem cells, which are known to express both SP-C and CC10.

Accumulation of Mott cells in the spleen in a CB6F1-Tg rasH2 mouse.

Mott cells are a variant form of plasma cells in humans and laboratory animals. This report describes the morphological characteristics of Mott cells observed in a 33-week-old female CB6F1-Tg rasH2 mouse. Microscopically, a large number of round cells with abundant eosinophilic globules, which were variable in size, were observed in the spleen and were densely distributed in the red pulp adjacent to the marginal zone. A few similar cells were present in the submandibular lymph node and bone marrow. Neither systemic nor local chronic inflammatory changes were seen in this animal. These cells were positive for mouse immunoglobulins. Ultrastructurally, the dilated rough endoplasmic reticulum had a homogenous substances with an intermediate electron density. On the basis of the above findings, these cells were identified as Mott cells. The present lesion is thought to be a spontaneous lesion, an unusual appearance of Mott cells without any associated pathological conditions.

Assessment of Alloxan-Induced Diabetic Rats as a Periodontal Disease Model Using a Selective Cyclooxygenase (COX)-2 Inhibitor.

Several recent studies have reported that alloxan-treated rats with long-term hyperglycemia can develop naturally occurring periodontal disease (PD). Our previous studies detected dental caries in the same model. Therefore, these two lesions of different etiologies are expected to occur concurrently. In this study, we evaluated the use of diabetic rats as a PD model by employing a selective COX-2 inhibitor reported to be effective against PD. Six-week-old female F344 rats were divided into 3 groups: intact rats (control), alloxan-induced diabetic rats fed a standard diet (AL) and alloxan-induced diabetic rats fed a diet containing 0.01% etodolac (AL+Et). The animals were euthanized at 26 weeks of age, and their oral tissues were examined histopathologically. Gingivitis, marginal periodontitis and alveolar bone resorption were markedly enhanced along with dental caries in the AL group compared with the control group. However, the COX-2 inhibitor had no effect on periodontal inflammation in the AL+Et group. In addition, in the AL group, periodontitis was notably nonexistent around the normal molars, and gingivitis was scarcely worse than that in the control group. In the diabetic rats, the progression of periodontal inflammation was closely correlated with the severity of adjacent dental caries, and marginal periodontitis was frequently continuous with apical periodontitis. In conclusion, an alloxan-induced diabetic rat is not a model of PD but of dental caries. It is probable that in this model, hyperglycemia may enable crown caries to progress to apical periodontitis, while the associated inflammation may rostrally expand to surrounding periodontal tissue.

Significance of Multi-Cancer Genome Profiling Testing for Breast Cancer: A Retrospective Analysis of 3326 Cases from Japan's National Database.

Background: Breast cancer (BC) has the highest morbidity rate and the second-highest mortality rate of all cancers among women. Recently, multi-cancer genome profiling (multi-CGP) tests have become clinically available. In this study, we aimed to clarify the significance of multi-CGP testing of BC by using the large clinical dataset from The Center for Cancer Genomics and Advanced Therapeutics (C-CAT) profiling database in Japan. Materials and Methods: A total of 3744 BC cases were extracted from the C-CAT database, which enrolled 60,250 patients between June 2019 and October 2023. Of the 3744 BC cases, a total of 3326 cases for which the C-CAT included information on ER, PR, and HER2 status were classified into four subtypes, including TNBC, HR+/HER2-, HR+/HER2+, and HR-/HER2+. Comparisons between groups were performed by the χ2 test or Fisher's exact test using EZR. Kaplan-Meier curves were created using the log-rank test. Results: Of all 3326 cases analyzed, 1114 (33.5%) were TNBC cases, HR+/HER2- accounted for 1787 cases (53.7%), HR+/HER2+ for 260 cases (7.8%), and HR-/HER2+ for 165 cases (5.0%). Genetic abnormalities were most frequently detected in TP53 (58.0%), PIK3CA (35.5%), MYC (18.7%), FGF19 (15.5%), and GATA3 (15.1%) across all BCs. The rate of TMB-High was 12.3%, and the rate of MSI-High was 0.3%, in all BC cases. Therapeutic drugs were proposed for patients with mutations in six genes: PIK3CA, ERBB2, PTEN, FGFR1, ESR1, and AKT1. The prognoses of HR+/HER2- cases were significantly (p = 0.044) better in the treated group than in the untreated group. Conclusions: These findings suggest that cancer gene panel testing is useful for HR+/HER2- cases.