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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-naive 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.

Summary Objective To observe and analyze the interaction between excessive mechanical stress (MS) and decreased sex hormones on Temporomandibular Joint Osteoarthritis (TMJ-OA), and to discover TMJ-OA disease susceptibility genes by molecular biological analysis to elucidate part of the mechanism of TMJ-OA onset. Design For experimental groups, orchiectomy (ORX) or ovariectomy (OVX) was performed on sexually mature 8-week-old mice. A metal plate was attached to the posterior surface of the maxillary incisors to apply excessive MS on mandibular condyles. Male mice were divided into control, ORX, MS, and ORX + MS groups, while female mice were divided into control, OVX, MS, and OVX + MS groups. Mandibular condyles were evaluated by histology and molecular biology. Results Histomorphometric analysis of the TMJ in ORX + MS and OVX + MS groups revealed the thinnest chondrocyte layers, highest modified Mankin scores, and significant increases in the number of osteoclasts. Gene expression analysis indicated upregulation of Angptl7 and Car1 genes in the mandibular condyles of mice subjected to the combined effects of excessive MS and reduced sex hormones. In vitro analysis suggested that cartilage-like cells overexpressing Angptl7 enhanced calcification, and osteoblast-like cells overexpression Car1 suppressed cell proliferation and calcification. Conclusions A severe TMJ-OA mouse model was successfully developed by applying excessive MS on the mandibular condyle of male and female mice with reduced sex hormones. Disease-susceptibility genes Angptl7 and Car1 were newly discovered in the experimental groups, suggesting their involvement in the onset mechanism of TMJ-OA.

Adoptive immunotherapy has emerged as a powerful approach to cure cancer and chronic infections. Currently, the generation of a massive number of T cells that provide long-lasting immunity is challenged by exhaustion and differentiation-associated senescence, which inevitably arise during in vitro cloning and expansion. To circumvent these problems, several studies have proposed an induced pluripotent stem cell (iPSC)-mediated rejuvenation strategy to revitalize the exhausted/senescent T cell clones. Because iPSC-derived cytotoxic T lymphocytes (iPSC-CTLs) generated via commonly used monolayer systems have unfavorable, innate-like features such as aberrant natural killer (NK) activity and limited replication potential, we modified the redifferentiation culture to generate CD8αβ(+)CD5(+)CCR7(+)CD45RA(+)CD56(−)-adaptive iPSC-CTLs. The modified iPSC-CTLs exhibited early memory phenotype, including high replicative capacity and the ability to give rise to potent effector cells. In expansion culture with an optimized cytokine cocktail, iPSC-CTLs proliferated more than 10(15)-fold in a feeder-free condition. Our redifferentiation and expansion package of early memory iPSC-CTLs could supply memory and effector T cells for both autologous and allogeneic immunotherapies.

Some rare sugars can be potently medicinal, such as l -gulose. In this study, we present a novel alditol oxidase (fAldOx) from the soil fungus Penicillium sp. KU–1, and its application for the effective production of l -gulose. To the best of our knowledge, this is the first report of a successful direct conversion of d -sorbitol to l -gulose. We further purified it to homogeneity with a ∼108-fold purification and an overall yield of 3.26%, and also determined the effectors of fAldOx. The enzyme possessed broad substrate specificity for alditols such as erythritol (kcat/KM, 355 m −1 s−1), thus implying that the effective production of multiple rare sugars for medicinal applications may be possible.

To evaluate the effect of morphine or morphine equivalents on the risk of bile leakage (BL) after hepatectomy. The subjects of this retrospective study were 379 patients who underwent hepatectomy without biliary reconstruction and biliary decompression tube insertion at Gunma University between 2016 and 2020. Clinical BL was defined as International Study Group of Liver Surgery post-hepatectomy bile leakage Grade B or C. Intra- and post-operative analgesia comprised intravenous patient-controlled analgesia (IV-PCA) with fentanyl (n = 58), epidural analgesia with fentanyl (n = 157), epidural analgesia with morphine (n = 151), and epidural analgesia with ropivacaine or levobupivacaine (n = 13). Clinical BL was diagnosed in 14 of the 379 (3.7%) patients. The significant risk factors for clinical BL were hepatocellular carcinoma (HCC), elevated serum total bilirubin, high indocyanine green retention at 15 min, elevated Mac-2-binding protein glycosylated isomer, prolonged duration of surgery, and a large volume of blood loss. There was no significant correlation of clinical BL with intra- and post-operative analgesia and total oral morphine equivalents. Intra- and post-operative IV-PCA and epidural analgesia were not related to clinical BL after hepatectomy. Based on our data, fentanyl and morphine can be administered safely as epidural or intravenous analgesic agents.

Aspergillus fumigatus is the major causative agent of aspergillosis in immunosuppressed hosts and patients with chronic pulmonary diseases. Recently, azole resistance of this fungus has become a problem worldwide; thus, rapid detection of resistant strains is desirable in clinical practice. In this study, we established a matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) combined with multivariate and discriminant analysis to detect azole-resistant A. fumigatus strains. The score plot from a partial least squares discriminant analysis clearly separated resistant and susceptible strains, regardless of the culture period. The discriminant analysis using the support-vector machine algorithm based on a dataset for strains cultured on potato dextrose agar for 3 days showed the best performance, with a correct answer rate of 84.75–99.85%. We found a MS peak (4359.5 m/z) specific to some azole-resistant strains with a 34-bp tandem repeat in the promoter region of cyp51A. These tandem repeat strains are extremely rare in Japan. Instead, most resistant strains in Japan have point mutations in cyp51A. No specific biomarker for strains with point mutations was found, but it was possible to detect these resistant strains using a model for point-mutation strains.

S10.4 Emerging antifungal resistant fungi, September 24, 2022, 10:30 AM - 12:00 PM The most studied azole-resistant mechanism of Aspergillus fumigatus is decreased affinity of the drug for CYP51A, the drug target molecule, due to its amino acid substitutions. Typically, each azole-resistance caused by the designated amino acid substitution of CYP51A has a specific pattern depending on the substitution site. While uncovering non-cyp51A mechanisms responsible for azole resistance should be essential for developing novel methods for prompt diagnosis and effective drug treatment. In our previous study, we reported results that mutation of hmg1, which codes HMG-CoA reductase, the rate-limiting enzyme in ergosterol biosynthesis, would be the mechanism conferring azole-drugs resistance (EID 2018). On the other hand, different azole susceptibility patterns have been reported even among the strains possessing the same mutation in CYP51A. In this way, the overall picture of molecular mechanisms inducing azole resistance remains unclear. We performed a comparative genomic analysis among the strains with the same cyp51A mutation isolated from the same patient but with different azole resistance patterns. To investigate the association between the novel mutation and azole resistance, the mutant allele was replaced with the wild-type allele by the CRISPR-Cas9 system. Antifungal susceptibility tests were performed according to the CLSI-M38. As a result of genome comparison analysis between these two strains using the HiSeq sequencing system (Illumina), another mutation was found in the insulin-induced protein (INSIG) of the multiazole-resistant strain. The INSIG mutation contributes additively to azole resistance in collaboration with the CYP51A mutation but does not alone itself. We have already reported simple and rapid detection methods for A. fumigatus possessing CYP51A mutation using an endonuclease (AAC 2020). Furthermore, using MALDI-TOF-MS, we are developing a discriminant model to detect azole-resistant A. fumigatus.

Introduction: The International Study Group of Liver Surgery (ISGLS) definition of bile leakage is an elevated total bilirubin concentration in the drainage fluid after post-operative day (POD) 3, which has been widely accepted. However, there were no reports about direct bilirubin in drainage fluid to predict bile leakage. Methods: Data from 257 patients who underwent hepatectomy were retrospectively reviewed. The optimal cut-off value was investigated using receiver-operating characteristic curves. The predictive power of drainage fluid total bilirubin (dTB) and drainage fluid direct bilirubin (dDB) to predict bile leakage, which was defined using ISGLS grade B or grade C, were compared. Results: ISGLS grade B bile leakage occurred in 16 patients (6.2%). Area under the curve (AUC) of dDB was always higher than that of dTB on each POD. The AUC of dDB was >0.75 on PODs 2, 3, and 5, and then it increased with the increasing POD. The dDB on POD 5 showed the highest accuracy (0.91) and positive predictive value (PPV) (0.67), which was followed by dTB/serum total bilirubin (sTB) on POD 3 (accuracy, 0.91; PPV, 0.33). Because the PPV of dDB increased as the POD increased, dDB was better than dTB for predicting clinically significant bile leakage. dDB on POD 3 showed the highest negative predictive value (0.97). The positive likelihood of dDB increased and the negative likelihood of dDB decreased on the basis of the POD. Among patients with dTB/sTB ≤3 on POD 3, 19.1% of these patients had bile leakage when dDB was >0.44 on POD 3. Conclusions: Measurement of both dDB and dTB, which are easy to perform, can be used to effectively predict clinically significant bile leakage.

An organized hematoma is a cystic lesion characterized by superficial fibrotic encapsulation. While an organized hematoma is benign, making a differential diagnosis from a malignant lesion is difficult, as both exhibit invasive behavior and cause bone resorption. The objective of this study was to describe a rare case of organized hematoma in the cheek of a 28-year-old male. The swelling in the cheek developed following the extraction of the right mandibular third molar. The extraction site did not show any signs of inflammation and the patient did not have any systemic risk factors. A preoperative magnetic resonance image revealed characteristic findings associated with organized hematoma. Clarithromycin was administered for 2 months before the lesion was surgically removed. The results of this case suggested that antibiotic administration prior to surgical removal was important, as the cause of the organized hematoma was mild inflammation.

Intraductal tubulopapillary neoplasm is a rare pancreatic tumor. The purpose of this study was to clarify the recurrence type and prognosis in recurrent cases after intraductal tubulopapillary neoplasm resection. PubMed was searched for previous reports on surgical resection of intraductal tubulopapillary neoplasm of the pancreas that were published from 2009 to July 2020. The clinical features obtained from these reports were summarized and analyzed. The clinicopathological data of 35 intraductal tubulopapillary neoplasm cases were obtained. Of these, 21 were males, and 14 were females, with an average age of 57.9 years old. Invasive findings were observed in 21 of 35 patients (60%). Recurrence was observed in 11 of the 35 cases (31.4%), including remnant pancreatic recurrence in 6 cases (17.1%) and liver metastasis in 5 cases (14.3%). The tumor size was significantly larger in the liver metastasis group than in the remnant pancreas recurrence group (P = 0.04), and patients with liver metastases tended to have a poorer prognosis than those with remnant pancreas recurrence. The recurrence type of intraductal tubulopapillary neoplasm resection was mainly remnant pancreatic recurrence and liver metastasis recurrence. Total pancreatectomy for remnant pancreatic recurrence may be suitable because of its good prognosis.

CKLF‐like MARVEL transmembrane domain–containing protein 6 (CMTM6) maintains membrane PD‐L1 expression by controlling its endosomal recycling. However, in patients with hepatocellular carcinoma (HCC), the correlation among CMTM6, B7 family ligands, and CD8‐positive cytotoxic T lymphocytes (CTLs), and the molecular function of CMTM6 in HCC have not been established. We performed immunohistochemistry to evaluate the relationships among CMTM6 expression, clinicopathological factors, B7 family ligands expression, and CTL infiltration in HCC samples. Moreover, we established CMTM6‐knockout human HCC cell lines to evaluate the function of human CMTM6 in immune regulation and tumor viability. CMTM6 expression was positively associated with membrane B7 family ligands expression and CTL infiltration in HCC samples. High CMTM6 expression in HCC tissues was associated with the expression of the proliferation marker Ki‐67 and shorter recurrence‐free survival. In vitro analysis showed the downregulation of membrane B7 family ligands and proliferation potency in the CMTM6‐knockout human HCC cell line. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family ligands expression. Thus, CMTM6 might be a biomarker to predict the risk of HCC recurrence and a therapeutic target to suppress tumor growth and increase CTL activity., CMTM6 expression was positively associated with B7 family ligand expression and cytotoxic T lymphocyte (CTL) infiltration in hepatocellular carcinoma (HCC) samples. The CMTM6‐knockout human HCC cell line showed the downregulation of membrane B7 family ligands expression and proliferation potency. High membrane CMTM6 expression was associated with tumor recurrence and proliferation via the regulation of membranous B7 family expression.

A high concentration of dissolved organic matter is intimately related to the chemistry and ecology of water environments linked to peatlands. To understand the variations in the chemical characteristics of peat derived dissolved organic matter, those in drainage water from natural vegetation and an area containing Sitka spruce (Picea sitchensis), surface water (dubh lochans), and stream water associated with a peatland in central Scotland were analyzed after fractionation into two fulvic acids that were desorbed from an XAD-8 column with water (FAs(H

We found that l-gulose, a rare sugar, was produced from d-sorbitol efficiently, using a wheat-bran culture extract of the fungus Penicillium sp. KU-1 isolated from soil. The culture extract showed enzyme activity for the oxidation of d-sorbitol to produce l-gulose; a high production yield of approximately 94% was achieved.

Introduction Infections with Candida glabrata have recently gained worldwide attention owing to its association with long hospitalizations and high mortality rates. This problem is highlighted when the infection is associated with echinocandin resistance, which is used for first-line therapy. Echinocandin resistance is exclusively attributed to functional mutations in FKS genes, and especially in hot spot (HS) regions. Unfortunately, few studies have focused on the rapid identification of FKS mutations associated with echinocandin resistance in C. glabrata. This study was intended to evaluate and validate the use of Surveyor nuclease assay (SN) for detection of FKS gene mutations. Methods SN was evaluated against three segments of FKS1 and FKS2 genes including whole gene, regions including all HSs, and the region including only HS1. Results Our results showed that SN results are basically dependent on the type of gene as well as the segment type. Interestingly, SN can detect mutations in the region containing HS1 in both FKS1 and FKS2 genes. Furthermore, SN can detect mutations in the segment containing all HS regions for FKS1 but not FKS2. SN was unable to detect mutations in the whole FKS1 and FKS2 genes. Conclusions As far as we know, this is the first study to validate SN for rapid identification of FKS gene mutations. This assay could be used as a sample for rapid identification of mutations associated with HS1 region in FKS genes, which have a predominant role for echinocandin resistance induction in C. glabrata.

Vonoprazan (VPZ)-based regimen for Helicobacter pylori (H. pylori) is safe and more efficacious than the proton pump inhibitor-based regimen mainly in adults. This study aimed to evaluate the efficacy and safety of a VPZ-based regimen for H. pylori eradication therapy in adolescents.An H. pylori screening and treatment longitudinal project for third-year junior high school students in Saga Prefecture began in 2016. Students who tested positive for both urine and stool tests received a VPZ-based regimen. On the checklist, students were asked for diarrhea, fever, abdominal pain, nausea, vomiting, urticaria, dysgeusia, or bloody stool occurrence during the therapy.The longitudinal project for H. pylori screening and treatment among third-grade students in Saga Prefecture targeted 41,115 students from 2017 to 2021 and 836 as positive. Of the 645 students, 542 (84.0% in per protocol [PP] analysis and 73.6% in intention-to-treat [ITT] analysis) were successful in primary eradication therapy. The secondary eradication therapy was successful in 79 (96.3% in PP analysis and 76.7% in ITT analysis) of 82 students. In the primary eradication therapy, abdominal pain occurred in 164 (27.9%), diarrhea in 217 (36.9%), nausea or vomiting in 7 (1.2%), and urticaria in 13 (2.2%) students. In the secondary eradication therapy, abdominal pain occurred in 12 (19.4%) and diarrhea in 17 (27.4%) students. The eradication therapy of 5 students was interrupted due to adverse events only by primary eradication therapy.VPZ-based regimen for H. pylori was efficacious and safe for adolescents, as in adults, for both primary and secondary eradication therapies.

BACKGROUND Tumor invasion is the most significant prognostic factor in ampullary cancer and is thus a crucial factor in decision making for treatment. Endoscopic ultrasound can be performed to evaluate tumor invasion, but its diagnostic accuracy varies depending on the endoscopist. This study aimed to assess the usefulness of fluorodeoxyglucose positron emission tomography (FDG-PET) for preoperatively predicting tumor invasion in ampullary cancer. METHODS We retrospectively evaluated 44 patients with ampullary cancer (adenoma, n = 6; adenocarcinoma, n = 38) who underwent surgical resection. The SUVmax of the ampullary tumor site was assessed using FDG-PET, and the correlation among tumor invasion, lymph node metastasis, and other clinicopathological factors was evaluated. RESULTS The SUVmax of the ampullary tumor site gradually increased depending on the extent of tumor invasion (p = 0.0075). Moreover, the SUVmax was significantly different between ≤T1a and ≥T1b, which is an indication for endoscopic papillectomy or surgical resection (p = 0.0015). The SUVmax of the ampullary section was significantly correlated with lymph node metastasis (p = 0.035). CONCLUSION The SUVmax of the ampullary tumor site is correlated with tumor invasion and lymph node metastasis in ampullary cancer. Thus, FDG-PET can be a useful modality for preoperative staging and treatment strategy.

Hirotsugu Takashina,1 Akira Watanabe,2 Koji Komatsu,1 Tadashi Nakano2 1Department of Ophthalmology, Tokyo Rosai Hospital, Tokyo, Japan; 2Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, JapanCorrespondence: Hirotsugu TakashinaDepartment of Ophthalmology, Tokyo Rosai Hospital, 4-13-21 Omori-Minami, Ota-ku, Tokyo, 143-0013, Japan, Tel +81-3-3742-7301 ext 8116Fax +81-3-3744-9310Email two-shina@s7.dion.ne.jpBackground: Subthreshold photocoagulation is one of the treatments for diabetic macular edema. However, the range of adequate laser energy that can be used for subthreshold photocoagulation is very restricted. Therefore, determination of the titration settings for the threshold energy is an essential part of the subthreshold-photocoagulation procedure. This study examined factors influencing the threshold energy used in subthreshold photocoagulation for diabetic macular edema.Methods: For 20 consecutive cases (29 eyes) who had received treatment using Endpoint Management (EpM) between April 2019 and June 2020 for persistent diabetic macular edema after completion of panretinal photocoagulation, multiple regression analysis was used to examine factors influencing threshold energy.Results: Analysis evaluating all the surgical procedures (n=150) determined there was statistical significance for a history of vitrectomy and cataract surgery, central macular thickness, interval from completion of panretinal photocoagulation, superior 6 mm subfield, and nasal 6 mm subfield. Further analysis examined surgical procedures that had been done in patients with a history of vitrectomy and cataract surgery (n=116). This analysis showed that central macular thickness, axial length, interval from completion of panretinal photocoagulation, and HbA1c were all statistically significant factors.Conclusion: Threshold energy for diabetic macular edema was significantly influenced by a history of vitrectomy and cataract surgery, central macular thickness, and interval between the completion of panretinal photocoagulation and initial EpM. Transparency of ocular media and intraocular inflammation were speculated to be associated with these results.Keywords: diabetic macular edema, subthreshold photocoagulation, panretinal photocoagulation, vitrectomy, cataract surgery

Introduction Influenza remains a clinically heavy burden worldwide. The objective of this study was to clarify clinical manifestations of severely ill patients infected with influenza. Methods The clinical data for patients who were severely ill with influenza, and required hospitalization were gathered and analyzed between November 2014 and August 2019 (5 influenza seasons) using an internet-surveillance system. Results A total of 924 patients were enrolled and analyzed. The median age was 78 years (IQR, 67–84), and the patients in the 2015–2016 season were significantly younger than those in other seasons. Pneumonia was the most common disease indicated as a cause for hospitalization, followed by a poor general condition and exacerbation of underlying respiratory diseases. Antiviral drugs were administered in 97.0% of the patients with peramivir being the most-frequently use antiviral. In-hospital death was recorded for 44 patients (4.8%). Multivariate analysis indicated that nursing home resident (OR: 6.554) and obesity (OR: 24.343) were independent predictors of in-hospital mortality. Conclusions Complications of influenza infection remain a heavy burden especially among the elderly. Continuous nationwide surveillance will be required to grasp the actual situation of influenza epidemics. (UMIN000015989).

(Background) Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) by approximately 5 years. However, some patients show resistance to CDK4/6i and have poor prognosis. Thus, predicting resistance in patients is important. Although PAM50 is a strong tool for predicting late recurrence risk in HR+/HER2- BC by analyzing gene expression signatures, it is not always available. The non-luminal disease score (NOLUS), developed as an approximate formula for PAM50, is a pathology-based subtyping assay used to predict non-luminal disease using immunohistochemical analysis (Pascual et al. Front Oncol, 2021). (Materials & Methods) This multicenter, retrospective observational study was approved by the central ethics committee of Gifu University. From December 2017 to December 2021, real-world data of patients with metastatic HR+/HER2- BC who received CDK4/6i therapy were collected from 11 institutes in Japan. Data were obtained for patients who received CDK4/6i, such as palbociclib (PAL) or abemaciclib (ABE), as the first- or second-line endocrine therapy. The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including progression-free survival (PFS) and overall survival (OS). Pathological data, including the expression levels of ER, PgR, HER2, and Ki67, were evaluated according to the ASCO/CAP guidelines by experienced pathologists in each institute using either primary or metastatic tumors. PFS was defined as the period from the 1) starting date of combination therapy to progressive disease (PD); 2) the starting date of combination therapy to PD when CDK4/6i was interrupted due to adverse events or patients’ preference; and 3) the starting date of endocrine monotherapy to PD when CDK4/6i was added. NOLUS was calculated using the formula: NOLUS (0-100) = -0.45*ER% − 0.28*PR% + 0.27*Ki67% + 73, and the patients were divided into two groups, NOLUS(+) [≥ 51.38, non-luminal disease] and NOLUS(−) [< 51.38, luminal disease]. The expression levels of ER, PgR, HER2, and Ki67 in each group were compared using Wilcoxon rank-sum and Fisher’s exact tests. Next, prognosis, including survival rate, PFS, and OS, was evaluated with a 95% confidence interval (CI) using the Kaplan–Meier method with the log-rank test. Statistical significance was set at p < 0.05. (Results) Of the 300 patients, 28 (9.3%) were NOLUS(+) and 272 (90.7%) were NOLUS(−). The expression rates (%) in NOLUS(+) and NOLUS(−) were, respectively, 28.2 ± 19.4 and 89.0 ± 11.3 for ER (p < 0.001); 6.3 ± 15.9 and 44.3 ± 37.9 for PgR (p < 0.001); and 42.5 ± 23.8 and 26.9 ± 19.1 for Ki67 (p < 0.001). The expressions of HER2 (score 0, 1, 2, and ISH-negative, 3) were 42.9%, 28.6%, 28.6%, and 0% for NOLUS(+); and 30.8%, 51.7%, 17.5%, and 0.4% for NOLUS(−) (p = 0.086). There were apparent statistical differences in prognosis between the NOLUS(+) and NOLUS(−) groups. PFSs for 6M and 1y were 71.4% and 30.5% for NOLUS(+), and 85.2% and 66.6% for NOLUS(−) (HR, 3.15; 95%CI: 2.02-4.93; p < 0.001). OS for 6M and 1y were 92.6% and 92.6% for NOLUS(+), and 97.7% and 93.8% for NOLUS(−) (HR, 3.01; 95%CI: 1.48-6.09, p = 0.001). NOLUS(−) patients showed statistically better PFS with first-line therapy than with second-line therapy. However, NOLUS(+) patients showed no prognostic difference between the first and second therapeutic lines, suggesting CDK4/6i inefficacy. (Conclusion) CDK4/6i efficacy and prognosis were significantly different between NOLUS(+) and NOLUS(−) patients. This feasible method can predict patients with CDK4/6i-resistance and help select a better therapeutic approach to overcome resistance. Citation Format: Manabu Futamura, Takahiro Nakayama, Tersuhiro Yoshinami, Chiya Oshiro, Mikiya Ishihara, Midori Morita, Akira Watanabe, Azusa Taniguchi, Masami Tsukabe, Masafumi Shimoda, Kanae Mitta, Yoko Chihara, Hiroyuki Yasojima, Yoshimi Ouchi, Yoshihisa Tokumaru, Takuma Ishihara, Norikazu Masuda. Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative breast cancer in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-05.

Objective In clinical dentistry, tooth extraction is one of the most fundamental techniques learned during mandatory dentist clinical internships. However, there are fewer opportunities for students to perform this procedure on actual patients. Hence, a tooth extraction simulator was developed based on clinical experience to evaluate the appropriate load and magnitude of the three- dimensional forces (x, y, and z axes) applied while using forceps for tooth extraction. Methods Twenty-three subjects were divided into five groups according to experience (i.e., fifth-year dental students, clinical intern dentists, early-career oral surgeons, board-certified members of the Japanese Society of Oral and Maxillofacial Surgeons [JSOMS], and JSOMS specialists and clinical instructors). The simulator was developed with Osada Electric Co. Ltd. using electromagnets and load cells. The magnitude of the three-directional load applied in actual tooth extractions was used as basis for the simulator. Results With increasing clinical experience, a consistent trend in terms of lower variation in loading, stable initial movements, and low directional variability was observed. On determination of the appropriate standards from the measurements of this study, users can not only gauge the amount of force needed to grasp the teeth and tear the periodontal ligament by dislocation but also appreciate the orientation and force required for tooth extractions. Conclusion This study demonstrated the utility of a tooth extraction simulator in evaluating the generated loads and movements during tooth extraction procedures.

Aggressive periodontitis during adolescence has a poor prognosis due to rapid alveolar bone resorption. Few studies have investigated long-term follow-up after surgical orthodontic treatment performed in conjunction with that for invasive periodontitis. Here, we report a case of mandibular prognathism accompanied by generalized aggressive periodontitis and crowding. A 31-year-old woman was referred to our department for treatment of masticatory dysfunction due to reverse overjet. The patient exhibited a class III molar relationship, protrusion of the ANB of －6.0°, and severe maxillary crowding. Initial periodontal examination revealed deep periodontal pockets and extensive inflammation. Mandibular prognathism accompanied by generalized aggressive periodontitis and crowding was diagnosed. Therefore, it was necessary to adopt an interdisciplinary approach involving surgical, orthodontic, and periodontal treatment. Prior to commencement of orthodontic treatment, plaque control, scaling, and root planing of all teeth were performed by a periodontist to suppress inflammation and reduce probing depth. During pre-surgical orthodontic treatment, the maxillary first premolars were extracted to reduce crowding of the maxillary incisors. To correct the mandibular prognathism, the mandible was repositioned by sagittal split ramus osteotomy. Proper occlusion of the incisors and maximum intercuspation were achieved by post-surgical orthodontic treatment. After completion of active orthodontic treatment, acceleration of inflammation was observed together with aggravated resorption of the alveolar bone surrounding the molars. However, reduction of probing depth and inflammation were observed after scaling and root planing. The surgical-orthodontic treatment time was 1 year and 11 months, which was followed by a 2-year retention period. There was no tooth loss due to periodontitis, and an overall satisfactory outcome was achieved.

Differences in vocal tract lengths (VTLs) in individual speakers cause variations in acoustic features of phonemes. In this paper, a simple method to estimate speaker-specific VTLs and to quantitatively evaluate some speaker-normalization effects of the VTLs is proposed. We employed accumulated means of formant trajectories to estimate the VTLs of speakers ranging from children to adults. For the formant estimation, the inverse-filter control (IFC) system was used. In the system, the decision of analysis order, which means number of formants to be estimated, is automated. Moreover, to evaluate the speaker-normalization effect of VTLs, we proposed the data reduction method, which can reasonably find dense areas of ellipses from distributions in the formant space. Using these ellipse areas, we evaluated the three normalization effects of VTLs: normalization by the mean of all VTLs as the standard, by speaker-categorical means of VTLs, and by individual VTLs. The area reduced from the standard area of the original data by 39.5% and 46.6% in the case of the categorical means and individual VTLs, respectively. As a result, our proposed method was used to provide a “normalized vowel map (NVM)” that visualizes universal vowel-distributions as a core image of linguistic information. Finally, we compared the estimated VTLs with those by another method based on magnetic resonance imaging (MRI) data, using the proposed methods.

Hepatic vein embolization (HVE) added to portal vein embolization (PVE) can further increase future remnant liver volume (FRLV) compared with PVE alone. This study was aimed to evaluate feasibility of sequential HVE in a prospective trial and to verify surgical strategy using functional FRLV (fFRLV).Hepatic vein embolization was prospectively indicated for post-PVE patients scheduled for right-sided major hepatectomy if the resection limit of fFRLV using EOB-magnetic resonance imaging was not satisfied. The resection limit was fFRLV: 615 mL/mAll patients underwent HVE with no severe complications. Median fFRLV increased from 396 (range: 251-581) to 634 (range: 422-740) mL/mSequential HVE after PVE is feasible and safe, and HVE induced possibility of further liver growth and its functional improvement. Our surgical strategy using fFRLV may be justified.

The mechanism underlying liver regeneration following partial hepatectomy (PH) is not fully elucidated. We aimed to characterize collagen gene expressing hepatic cells following PH and examine their contribution to liver regeneration.Col-GFP mice, which express GFP under the control of the collagen gene promoter, were used to detect collagen gene expressing cells following PH. The GFP-expressing cells were analyzed via single-cell RNA sequencing (scRNA-seq). Additionally, Col-ER Cre/RFP and Col-ER Cre/DTA mice were utilized to examine the cell fates and functional roles of collagen gene expressing cells in liver regeneration, respectively. The number of collagen gene expressing cells was found to be increased on day 3 and subsequently decreased on day 7 following PH. ScRNA-seq analysis of sorted collagen gene expressing cells showed that the regenerating liver was characterized by three distinct hepatic stellate cell (HSC) clusters, including one representing classic myofibroblasts. The other HSC clusters included an intermediately activated HSC cluster and a proliferating HSC cluster. Of these, the latter cluster was absent in the CClHeterogeneous HSC clusters, one of which was a unique proliferating cluster, were found to appear in the liver following PH. Collagen gene expressing cells, including HSCs, were found to promote liver regeneration.

Granulocyte colony-stimulating factor(G-CSF)is useful for preventing febrile neutropenia induced by chemotherapy. Recently, some cases of aortitis have been reported following administration of G-CSF. Here, we present a case of aortitis induced by pegfilgrastim(peg-G)use during neoadjuvant chemotherapy for treating breast cancer. A 61-year-old woman with breast cancer(cT2N1M0, stage ⅡB, triple negative)started neoadjuvant chemotherapy FEC(100). Eleven days after the third course of peg-G administration, the patient developed a fever and general malaise. Blood test results showed an increase in inflammatory markers and severe anemia. The symptoms were not controlled with antibiotics. Blood and urine culture test results were negative. Computed tomography revealed remarkable wall thickening of the aorta. Therefore, we suspected aortitis induced by peg-G. The symptoms rapidly improved with prednisolone therapy. The possibility of aortitis should be considered for those with fever or raised inflammatory markers following the use of G-CSF. Steroids can be used for the treatment of G-CSF-induced aortitis.