MGMT protein expression is a reliable predictive biomarker for temozolomide-containing chemotherapy in osteosarcoma.

The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy.

Predictors of Water Turnover in Older Adults: A Doubly Labeled Water- and Triaxial Accelerometer-Based Study.

BACKGROUND: Water is one of the most essential nutrients for life. The water turnover (WT), total body water (TBW), and total energy expenditure (TEE) can be measured using the doubly labeled water (DLW) method. WT and TBW are lower in older adults than in young adults, and the former are susceptible to dehydration, necessitating to identify predictors of the WT in older adults. OBJECTIVES: The current study aimed to examine the association between WT and physical activity, physical function, and body composition in Japanese adults aged ≥65 y and identify predictors for WT in this population. METHODS: This study enrolled 133 older adults (women, n = 61; men, n = 72) aged 65-88 y. WT, TBW, TEE, fat-free mass (FFM), and percent body fat (%Fat) were determined using the DLW method. The fitness age score (FAS) was obtained from 5 physical fitness tests. Physical activity and the step count were assessed using a previously validated triaxial accelerometer. Multiple regression analyses were performed with WT as the dependent variable. RESULTS: WT was positively associated with weight, physical activity level (PAL), moderate-vigorous physical activity, and TEE, and negatively associated with sedentary behavior. We examined potential predictors for WT using age, sex, height, weight, FFM, %Fat, TEE, PAL, and FAS in older Japanese adults. CONCLUSIONS: Our results confirmed that age, sex, weight, FFM, TEE, and PAL are the potential predictors of WT in older Japanese adults aged ≥65 y.

Efficacy of steroid therapy for improving native liver survival after pediatric acute liver failure with immune activation.

AIM: Recent evidence suggests that acute liver failure (ALF) in some patients may reflect a dysregulated immune response, and that corticosteroids improve survival of the native liver in ALF patients with high serum alanine aminotransferase levels, which are an indication of liver inflammation. However, it is unclear whether steroids are effective for pediatric acute liver failure (PALF). The aim of this retrospective case-control study is to examine whether steroid therapy for PALF accompanied by immune activation improves the survival of native liver and to identify factors that predict responses to steroid treatment. METHODS: Of 38 patients with PALF treated at Kyoto University Hospital from February 2006 to August 2022, 19 receiving steroids who met the specific criteria for identifying the pathophysiology of immune activity in the liver (the "Steroid group"), and seven steroid-free patients who also met the criteria ("Nonsteroid group") were enrolled. Patients in the "Steroid group" were categorized as "responders" or "nonresponders" according to treatment outcome. Clinical and histological data were analyzed. RESULTS: Survival of the native liver in the Steroid group was significantly higher than that in the Nonsteroid group (68% vs. 0%, respectively; p = 0.0052). Nonresponders were significantly younger, with higher Model for End-stage Liver Disease and pediatric end-stage liver disease scores, higher prothrombin time - international normalized ratio, and higher serum ferritin levels than responders. Massive hepatic necrosis was more common in nonresponders. CONCLUSION: Steroid therapy is effective for PALF patients with liver inflammation; however, liver transplantation should be prioritized for young children with ALF accompanied by severe coagulopathy or massive hepatic necrosis.

Determinant of factors associated with water requirement measured using the doubly labelled water method among older Japanese adults.

OBJECTIVE: Water is an essential nutrient for all organisms and is important for maintaining life and health. We aimed to develop a biomarker-calibrated equation for predicting water turnover (WT) and pre-formed water (PW) using the doubly labelled water (DLW) method. DESIGN: Cross-sectional study. SETTING: General older population from the Kyoto-Kameoka Study, Japan. PARTICIPANTS: The 141 participants aged ≥ 65 years were divided into a model developing (n 71) and a validation cohort group (n 70) using a random number generation. WT and PW was measured using the DLW method in May-June of 2012. In developing the cohort, equations for predicting WT and PW were developed by multivariate stepwise regression using all data from the questionnaires in the Kyoto-Kameoka study (including factors such as dietary intake and personal characteristics). WT and PW measured using the DLW method were compared with the estimates from the regression equations developed using the Wilcoxon signed-rank test and correlation analysis in validation cohort. RESULTS: The median WT and PW for 141 participants were 2·81 and 2·28 l/d, respectively. In the multivariate model, WT (R2 = 0·652) and PW (R2 = 0·623) were moderately predicted using variables, such as height, weight and fluid intake from beverages based on questionnaire data. WT (r = 0·527) and PW (r = 0·477) predicted that using this model was positively correlated with the values measured by the DLW method. CONCLUSIONS: Our results showed factors associated with water requirement and indicated a methodological approach of calibrating the self-reported dietary intake data using biomarkers of water consumption.

Predicting invasive disease-free survival in ER-positive, HER2-negative early breast cancer using the PAM50 risk-of-recurrence score: a retrospective analysis using single-center long-term follow-up data of postmenopausal Japanese patients.

BACKGROUND: The prognostic value of the risk-of-recurrence (ROR) score calculated using PAM50 has been validated using clinical trials and patient cohorts. This study aimed to investigate the prognostic value of the PAM50 ROR score in Japanese patients with early breast cancer using long-term follow-up data. METHODS: We enrolled postmenopausal patients with ER-positive, HER2-negative, stage I-II breast cancer who had undergone surgery at the Kyoto University Hospital between 2008 and 2014. The intrinsic subtype and ROR score were calculated using PAM50. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: We enrolled 146 patients, of whom 47 (32%) patients had node-positive disease, and 36 (25%) had received neoadjuvant or adjuvant chemotherapy. The proportions of intrinsic subtypes for luminal A, luminal B, HER2-enriched, and basal-like subtypes were 67%, 27%, 3%, and 2%, respectively. The median follow-up duration was 8.4 (range 6.3-10.0) years, and 21 IDFS events were observed. Based on the ROR score, 37%, 33%, and 30% of the patients were classified as low, intermediate, and high risks, respectively. Patients in the high-risk group had a significantly worse 8-year IDFS rate than those in the low-to-intermediate-risk groups (75.1% vs. 91.6%, p = 0.04). The same trend was observed in patients with and without neoadjuvant or adjuvant chemotherapy. CONCLUSIONS: Using long-term follow-up data, this study showed that the ROR score can predict the prognosis of ER-positive, HER2-negative early breast cancer in Japanese postmenopausal patients. Further investigations are required to confirm the prognostic value of the ROR score in Asian populations.

Anti-C5 monoclonal antibody treatment showing pathological resolution of complement-mediated atypical hemolytic uremic syndrome: a case report.

BACKGROUND: No reports have shown histological changes before and after anti-C5 monoclonal antibody treatment in patients with atypical hemolytic uremic syndrome (aHUS). Here, we report a rare case of complement-mediated aHUS with a complement factor H (CFH) mutation and anti-CFH antibodies who underwent multiple kidney biopsies. CASE PRESENTATION: A 53-year-old woman developed aHUS with CFH gene mutation [c.3572C > T (p. Ser1191 Leu)] and anti-CFH antibodies. Her father had succumbed to acute kidney injury (AKI) in his 30 s. She exhibited AKI, thrombocytopenia, and hemolytic anemia with schistocytes. After improving the platelet count with one session of plasma exchange, a kidney biopsy was performed one month after the onset of symptoms. Blood vessel thrombosis, obvious endothelial swelling, endocapillary hypercellularity, and subendothelial exudative lesions in the glomeruli and arterioles were detected. Anti-C5 monoclonal antibody treatment with eculizumab immediately improved disease activity. A second biopsy 3 months later revealed marked improvement of endothelial injuries with residual membrane double contours and exudative lesions. A third biopsy at 17 months after gradual improvement of kidney function showed a further decrease of double contours along with alterations of the exudative lesions to fibrous intimal thickening. CONCLUSIONS: This is the first report showing the pathophysiology of aHUS in the kidneys and the efficacy of anti-C5 monoclonal antibody treatment by presenting serial kidney pathological features before and after anti-C5 monoclonal antibody treatment. Since her CFH mutation was considered the most important pathological condition, treatment centered on eculizumab was administered, resulting in a good long-term prognosis. In addition, kidney pathological resolution in aHUS occurred over 1 year after anti-C5 monoclonal antibody treatment.

Effects of muscle quantity, muscle quality, and phase angle on whole-body reaction time in 5164 adults aged 20-91 years.

PURPOSE: Muscle quantity, defined as appendicular lean mass (ALM); muscle quality, defined as the ratio of muscle strength to ALM; and bioelectrical impedance analysis (BIA)-derived phase angle (PhA) are determinants of physical performance. We examined whether muscle quality indices were significant predictors of the whole-body reaction time (WBRT) in healthy female and male adults aged 20-91 years. METHODS: Data from 5164 adults (2869 women and 2295 men; mean age ± standard deviation, 60.9 ± 15.6 years) were analyzed. Height and weight were measured, and body mass index was calculated. ALM was estimated using a previously validated 8-electrode multi-frequency BIA. PhA was measured at 50 kHz using a BIA device. Knee extension strength (KES), leg extension power (LEP), and flexibility were examined. The ALM to weight (ALM/weight), KES to ALM (KES/ALM), and LEP to KES (LEP/KES) ratios were calculated. In the WBRT test, participants were asked to stand on a force plate and jump upright as quickly as possible in response to a light stimulus. The WBRT was divided into the response initiation and motion execution phases. RESULTS: ALM/weight, KES/ALM, LEP/KES, PhA, and flexibility were significant independent predictors of WBRT and the time of the motion execution phase (p < 0.001). However, PhA was not a significant predictor of the time of response initiation phase. CONCLUSION: Muscle quantity (ALM/weight), muscle quality (KES/ALM and LEP/KES), PhA, and flexibility are determinants of WBRT test performance, particularly in the motion execution phase.

Morning physical activity may be more beneficial for blood lipids than afternoon physical activity in older adults: a cross-sectional study.

BACKGROUND: The effect of differences in daily physical activity patterns on blood lipids has not been determined. This study examines the effects of the differences in free-living daily physical activity patterns (amount and intensity) on blood lipid levels in older adults. METHODS: This cross-sectional study included 51 older participants (71.8 ± 0.6 years, men = 8, women = 43). A triaxial accelerometer was used to assess physical activity patterns. The time from awakening to bedtime for each participant was used for group classification based on the amount (number of steps) and intensity (moderate-to-vigorous physical activity, MVPA) of physical activity. The morning step group (M Step) was defined as those who took more steps in the morning, and the afternoon step group (A Step) was defined as those who took more steps in the afternoon. The same method was used for MVPA (morning MVPA: M MVPA; afternoon MVPA: A MVPA). Blood samples were collected at the start of the study to determine blood lipid levels. RESULTS: Number of steps taken showed a trend toward lower low-density lipoprotein cholesterol (LDL-C) levels in the M Step group compared with the A Step group. The LDL/high-density lipoprotein (HDL) ratio was significantly lower in the M Step group than the A Step group (p < 0.05). The M MVPA group also had higher HDL-C levels and significantly lower LDL/HDL ratios than the A MVPA group (p < 0.05). CONCLUSIONS: These results suggest that compared with afternoon physical activity, daily morning physical activity (amount and intensity) is more effective in improving blood lipid levels.

An exploratory study for tuft cells in the breast and their relevance in triple-negative breast cancer: the possible relationship of SOX9.

BACKGROUND: Breast cancer is highly heterogeneous, suggesting that small but relevant subsets have been under-recognized. Rare and mainly triple-negative breast cancers (TNBCs) were recently found to exhibit tuft cell-like expression profiles, including POU2F3, the tuft cell master regulator. In addition, immunohistochemistry (IHC) has identified POU2F3-positive cells in the normal human breast, suggesting the presence of tuft cells in this organ. METHODS: Here, we (i) reviewed previously identified POU2F3-positive invasive breast cancers (n = 4) for POU2F3 expression in intraductal cancer components, (ii) investigated a new cohort of invasive breast cancers (n = 1853) by POU2F3-IHC, (iii) explored POU2F3-expressing cells in non-neoplastic breast tissues obtained from women with or without BRCA1 mutations (n = 15), and (iv) reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from normal breast cells. RESULTS: Two TNBCs of the four previously reported invasive POU2F3-positive breast cancers contained POU2F3-positive ductal carcinoma in situ (DCIS). In the new cohort of invasive breast cancers, IHC revealed four POU2F3-positive cases, two of which were triple-negative, one luminal-type, and one triple-positive. In addition, another new POU2F3-positive tumor with a triple-negative phenotype was found in daily practice. All non-neoplastic breast tissues contained POU2F3-positive cells, irrespective of BRCA1 status. The scRNA-seq reanalysis confirmed POU2F3-expressing epithelial cells (3.3% of all epithelial cells) and the 17% that co-expressed the other two tuft cell-related markers (SOX9/AVIL or SOX9/GFI1B), which suggested they were bona fide tuft cells. Of note, SOX9 is also known as the "master regulator" of TNBCs. CONCLUSIONS: POU2F3 expression defines small subsets in various breast cancer subtypes, which can be accompanied by DCIS. The mechanistic relationship between POU2F3 and SOX9 in the breast warrants further analysis to enhance our understanding of normal breast physiology and to clarify the significance of the tuft cell-like phenotype for TNBCs.

Comparison of Bioelectrical Impedance Indices for Skeletal Muscle Mass and Intracellular Water Measurements of Physically Active Young Men and Athletes.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a minimally invasive, safe, easy, and quick technology used to determine body composition. OBJECTIVES: We compared the relationship among impedance indices obtained using single-frequency BIA, multi-frequency BIA, bioelectrical impedance spectroscopy (BIS), and skeletal muscle mass (SMM) of physically active young men and athletes using the creatine (methyl-d3) dilution method. We also compared the SMM and intracellular water (ICW) of athletes and active young men measured using a reference stable isotope dilution and BIS method, respectively. METHODS: We analyzed data from 28 men (mean age, 20 ± 2 y) who exercised regularly. Single-frequency BIA at 5 kHz and 50 kHz (R5 and R50), multi-frequency BIA (R250-5), and BIS (RICW) methods of determining the SMM were compared. The deuterium and sodium bromide dilution methods of obtaining the total body water, ICW, and extracellular water measurements were also used, and the results were compared to those acquired using bioimpedance methods. RESULTS: The correlation coefficients between SMM and L2/R5, L2/R50, L2/R250-5, and L2/RICW were 0.738, 0.762, 0.790, and 0.790, respectively (P < 0.01). The correlation coefficients between ICW and L2/R5, L2/R50, L2/R250-5, and L2/RICW were 0.660, 0.687, 0.758, and 0.730, respectively (P < 0.001). However, the correlation coefficients of L2/R50, L2/R250-5, and L2/RICW for SMM and ICW were not significantly different. CONCLUSIONS: Our findings suggest that single-frequency BIA at L2/R50, multi-frequency BIA, and BIS are valid for assessing the SMM of athletes and active young men. Additionally, we confirmed that the SMM and ICW were correlated with single-frequency BIA, multi-frequency BIA, and BIS. Bioimpedance technologies may be dependable and practical means for assessing SMM and hydration compartment status of active young adult males; however, cross-validation is needed.

Association between doubly labelled water-calibrated energy intake and objectively measured physical activity with mortality risk in older adults.

BACKGROUND: Physical activity or biomarker-calibrated energy intake (EI) alone is associated with mortality in older adults; the interaction relationship between the combined use of both factors and mortality has not been examined. We evaluated the relationship between mortality and calibrated EI and step counts in older adults. METHODS: This prospective study included 4,159 adults aged ≥65 years who participated in the Kyoto-Kameoka study in Japan and wore a triaxial accelerometer between 1 April and 15 November 2013. The calibrated EI was calculated based on a previously developed equation using EI biomarkers. The step count was obtained from the accelerometer ≥ 4 days. Participants were classified into the following four groups: low EI (LEI)/low step counts (LSC) group (EI: <2,400 kcal/day in men and <1,900 kcal/day in women; steps: <5,000 /day), n = 1,352; high EI (HEI)/LSC group (EI: ≥2,400 kcal/day in men and ≥1,900 kcal/day in women; steps: <5,000 /day), n = 1,586; LEI/high step counts (HSC) group (EI: <2,400 kcal/day in men and < 1,900 kcal/day in women; steps: ≥5,000 /day), n = 471; and HEI/HSC group (EI: ≥2,400 kcal/day in men and ≥1,900 kcal/day in women; steps: ≥5,000 /day), n = 750. Mortality-related data were collected until 30 November 2016. We performed a multivariable Cox proportional hazard analysis. RESULTS: The median follow-up period was 3.38 years (14,046 person-years), and 111 mortalities were recorded. After adjusting for confounders, the HEI/HSC group had the lowest all-cause mortality rate compared to other groups (LEI/LSC: reference; HEI/LSC: hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.41-1.23; LEI/HSC: HR: 0.59, 95% CI: 0.29-1.19; and HEI/HSC: HR: 0.10, 95% CI: 0.01-0.76). No significant interaction was observed between the calibrated EI and steps with mortality. The spline model showed that 35-42 kcal/100 steps/day of EI/100 steps was associated with the lowest mortality risk. CONCLUSIONS: HR mortality risk was lowest at 35-42 kcal/100 steps/day, suggesting that very high (≥56 kcal) or low (<28 kcal) EI/100 steps are not inversely associated with mortality. Adherence to optimal EI and adequate physical activity may provide sufficient energy balance to explain the inverse association with mortality among older Japanese adults.

Combined Use of Sleep Quality and Duration Is More Closely Associated With Mortality Risk Among Older Adults: A Population-based Kyoto-Kameoka Prospective Cohort Study.

BACKGROUND: Whether sleep quality and duration assessed from multiple domains, either individually or in combination, are strongly associated with mortality risk in older adults remains unelucidated. We aimed to clarify these relationships. METHODS: We enrolled 7,668 older (age ≥65 years) Japanese adults in the Kyoto-Kameoka prospective cohort study who provided valid responses to the Pittsburgh Sleep Quality Index (PSQI) in a mail-in survey. Sleep quality and duration were classified into six groups using the previously validated PSQI: short sleep duration (SSD: <360 min/day)/sleep disturbance (SD: ≥5.5 PSQI points), n = 701; SSD/non-sleep disturbance (NSD: <5.5 PSQI points), n = 100; optimal sleep duration (OSD: 360-480 min/day)/NSD, n = 1,863; OSD/SD, n = 2,113; long sleep duration (LSD: >480 min/day)/NSD, n = 1,972; LSD/SD, n = 919. Mortality data were collected from February 15, 2012, to November 30, 2016. We evaluated the relationship between all-cause mortality risk and sleep quality and duration (and their combinations) using a multivariable Cox proportional hazards model that included baseline covariates. RESULTS: The median follow-up period was 4.75 years (34,826 person-years), with a total of 616 deaths. After adjusting for confounders, compared with other groups, SSD/SD and LSD/SD had the highest hazard ratio (HR) of mortality (SSD/SD: HR 1.56; 95% confidence interval [CI], 1.10-2.19; SSD/NSD: HR 1.27; 95% CI, 0.47-3.48; OSD/NSD: reference; OSD/SD: HR 1.20; 95% CI, 0.91-1.59; LSD/NSD: HR 1.35; 95% CI, 1.03-1.77; LSD/SD: HR 1.83; 95% CI, 1.37-2.45). However, mortality risk was not associated with the interaction between sleep quality and duration. CONCLUSION: Older adults with sleep disturbances involving SSD and LSD have a strong positive association with mortality risk, suggesting an additive effect between sleep quality and duration.

Histogenetic and disease-relevant phenotypes in thymic epithelial tumors (TETs): The potential significance for future TET classification.

Thymic epithelial tumors (TETs) encompass morphologically various subtypes. Thus, it would be meaningful to explore the expression phenotypes that delineate each TET subtype or overarching multiple subtypes. If these profiles are related to thymic physiology, they will improve our biological understanding of TETs and may contribute to the establishment of a more rational TET classification. Against this background, pathologists have attempted to identify histogenetic features in TETs for a long time. As part of this work, our group has reported several TET expression profiles that are histotype-dependent and related to the nature of thymic epithelial cells (TECs). For example, we found that beta5t, a constituent of thymoproteasome unique to cortical TECs, is expressed mainly in type B thymomas, for which the nomenclature of cortical thymoma was once considered. Another example is the discovery that most thymic carcinomas, especially thymic squamous cell carcinomas, exhibit expression profiles similar to tuft cells, a recently discovered special type of medullary TEC. This review outlines the currently reported histogenetic phenotypes of TETs, including those related to thymoma-associated myasthenia gravis, summarizes their genetic signatures, and provides a perspective for the future direction of TET classification.

Anti-SARS-CoV-2 IgG antibody titer after BNT162b2 mRNA COVID-19 vaccination in Japanese patients who underwent renal replacement therapy, hemodialysis, peritoneal dialysis, and kidney transplantation.

BACKGROUND: Coronavirus disease (COVID-19) vaccination is recommended for patients undergoing renal replacement therapy (RRT), including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT). However, the difference in the immune response between RRT patients and healthy individuals after mRNA vaccines remains uncertain. METHODS: This retrospective observational study evaluated the anti-severe-acute-respiratory-syndrome-coronavirus-2 (anti-SARS-CoV-2) IgG antibody acquisition, titers and their changes, normal response rate (reaching titers of healthy individuals), factors associated with a normal response, and effectiveness of booster vaccination in Japanese RRT patients. RESULTS: Most HD and PD patients acquired anti-SARS-CoV-2 IgG antibodies after the second vaccination; however, their antibody titers and normal response rates (62-75%) were low compared with those of healthy subjects. Approximately 62% of KT recipients acquired antibodies, but the normal response rate was low (23%). Anti-SARS-CoV-2 IgG antibody waning occurred in the control, HD, and PD groups, while negative or very low titers remained in KT recipients. Third booster vaccination was effective in most HD and PD patients. However, the effect was mild in KT recipients - only 58% reached a normal response level. Multivariate logistic regression analyses demonstrated that younger age, higher serum albumin level, and RRT other than KT were significantly associated with a normal response after the second vaccination. CONCLUSIONS: RRT patients, particularly KT recipients, exhibited poor vaccine responses. Booster vaccination would be beneficial for HD and PD patients; however, its effect in KT recipients was mild. Further COVID-19 vaccinations using the latest vaccine or alternative procedures should be considered in RRT patients.

A Case of Biphenotypic Adnexal Carcinoma With Bowenoid and Basaloid Features: Focus on the Expression of SOX9 and Wnt Signaling Pathway Molecules, Including CDX2.

ABSTRACT: An 87-year-old woman presented with a pedunculated nodule of 1.2 × 1.2 × 0.6 cm on her left cheek. Microscopic examination of the lesion revealed bowenoid and rosette-like basaloid components, resembling Bowen disease and neuroendocrine carcinoma, respectively. Immunohistochemically, both components were positive for Wnt signaling pathway molecules-nuclear/cytoplasmic beta-catenin, lymphoid enhancer binding factor 1 (LEF1), and caudal type homeobox 2 (CDX2)-and the adnexal marker SRY-box transcription factor 9 (SOX9). Unlike neuroendocrine tumors and basal cell carcinomas, the basaloid component in the present case was negative for chromogranin A, INSM1, synaptophysin, and p40. Previously reported cases of similar CDX2-positive lesions were diagnosed as squamous cell carcinoma with enteric adenocarcinomatous differentiation and basaloid cutaneous carcinoma with a primitive cytomorphology. However, the lesion in the present case was simultaneously positive for SOX9, indicating adnexal differentiation. In particular, the expression of multiple Wnt signaling pathway molecules indicates follicular differentiation despite the absence of morphological follicular features, such as shadow cells. Moreover, shared immunopositivity for SOX9, CDX2, nuclear/cytoplasmic beta-catenin, and LEF1 by both bowenoid and basaloid components indicated that the bowenoid component did not represent Bowen disease but a part of the adnexal tumor, and that the basaloid component was not a tumor-to-tumor metastasis. After complete excision, no recurrence has been observed for 5 months. The findings of the present case expand the histological spectrum of cutaneous adnexal tumors with follicular immunophenotypic differentiation.

Combined use of the Clinical Frailty Scale and laboratory tests in acutely hospitalized older patients.

AIMS: To evaluate the Clinical Frailty Scale (CFS) and a Frailty Index based on laboratory tests (FI-lab) in terms of what each assesses about frailty and to determine the appropriateness of combined use of these two frailty scales. METHODS: This was a prospective observational cohort study in an acute geriatric ward of a university hospital. The FI-lab is the proportion of laboratory parameters that yield abnormal results from a total of 23. The FI-lab and CFS were assessed at admission. Data on activities of daily living (ADL), cognition, geriatric syndromes, and comorbidities were also collected. Main outcomes were in-hospital mortality and 90-day mortality after admission. RESULTS: In total, 378 inpatients (mean age 85.2 ± 5.8 years, 59.3% female) were enrolled. ADL and cognition correlated strongly with the CFS (Spearman's |r|> 0.60) but weakly with the FI-lab (|r|< 0.30). Both the CFS and FI-lab correlated weakly with geriatric syndromes and comorbidities (|r|< 0.40). The correlation between the CFS and FI-lab was also weak (r = 0.28). The CFS and FI-lab were independently associated with in-hospital mortality and 90-day mortality after admission. The Akaike information criterion was lower for models using both the CFS and FI-lab than for models using either tool alone. CONCLUSIONS: The CFS and FI-lab each reflected only some of the aspects of frailty in acutely hospitalized older patients. The model fit was better when the two frailty scales were used together to assess the mortality risk than when either was used alone.

Surfactant therapy using a bronchofiberscope in respiratory distress syndrome.

BACKGROUND: Avoiding endotracheal intubation and using nasal continuous positive airway pressure as the initial treatment is recommended in infants with respiratory distress syndrome (RDS), and modes of lesser invasive surfactant administration have recently been reported. We report a pilot study assessing the feasibility of surfactant therapy using a bronchofiberscope (STUB) in RDS. METHODS: Surfactant was administered to 31 preterm infants (gestational age range of 28 weeks 0 days to 36 weeks 6 days) diagnosed with RDS, through the working channel of the bronchofiberscope or endotracheal tubes. Patient characteristics, outcomes, adverse events, and comorbidities were assessed in the two groups. RESULTS: Twelve infants received STUB. Two of the 12 infants (17%) needed subsequent intubation and additional surfactant administration. Nineteen infants received surfactant through endotracheal tubes. Four of the 19 infants (21%) required additional surfactants. There was no significant difference in the number of infants that needed additional surfactant (p = 1.00). Gestational age, birthweight, length of hospitalization, adverse events, such as desaturations and bradycardias, and comorbidities were similar between the two groups. Days of invasive ventilation were significantly shorter in the STUB group (p = 0.0002). CONCLUSION: STUB was feasible in this small cohort and reduced the need for intubation to 17%, leading to fewer days of invasive ventilation, without increasing comorbidities and adverse events. To the best of our knowledge, this is the first study to administer surfactants using bronchofiberscopes.

Systematic review and meta-analysis for 2023 clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: The objective of this study is to provide evidence for the revision of clinical practice guidelines for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society databases were searched for articles published between 2015 and 2020 to update the systematic review for existing clinical questions, while PubMed, CENTRAL, EMBASE, and the Japan Medical Abstracts Society were searched for articles published between 2000 and 2020 to conduct a systematic review for newly developed clinical questions. The certainty of evidence was assessed with the GRADE approach. RESULTS: For remission induction, when used in conjunction with cyclophosphamide or rituximab, reduced-dose glucocorticoid lowered the risk of serious adverse events compared to standard-dose glucocorticoid. Avacopan improved sustained remission at 12 months compared to high-dose glucocorticoid. Addition of plasma exchange to remission induction therapy did not reduce the risk of death, end-stage kidney disease, or relapse. For remission maintenance, rituximab reduced the risk of relapse compared to azathioprine. Long-term rituximab or azathioprine reduced the risk of relapse compared to short-term rituximab or azathioprine, respectively. CONCLUSIONS: This systematic review provided evidence required to develop the 2023 clinical practice guideline for the management of ANCA-associated vasculitis.

Tuft cell-like carcinomas: novel cancer subsets present in multiple organs sharing a unique gene expression signature.

BACKGROUND: Tuft cells are chemosensory epithelial cells playing a role in innate immunity. Recent studies revealed cancers with a tuft cell-like gene expression signature in the thorax. We wondered whether this signature might also occur in extrathoracic cancers. METHODS: We examined mRNA expression of tuft cell markers (POU2F3, GFI1B, TRPM5, SOX9, CHAT, and AVIL) in 19 different types of cancers in multiple extrathoracic organs with The Cancer Genome Atlas (TCGA) (N = 6322). Four different extrathoracic cancers in our local archives (N = 909) were analysed by immunohistochemistry. RESULTS: Twenty-two (0.35%) extrathoracic tumours with co-expression of POU2F3 and other tuft cell markers were identified in various TCGA datasets. Twelve of the 22 "tuft cell-like tumours" shared poor differentiation and a gene expression pattern, including KIT, anti-apoptotic BCL2, and ionocyte-associated genes. In our archival cases, eleven (1.21%) tumours co-expressing POU2F3, KIT, and BCL2 on immunohistochemistry, i.e., were presumable tuft cell-like cancers. In three among five TCGA cohorts, the tuft cell-like cancer subsets expressed SLFN11, a promising biomarker of PARP inhibitor susceptibility. CONCLUSIONS: Tuft cell-like carcinomas form distinct subsets in cancers of many organs. It appears warranted to investigate their shared gene expression signature as a predictive biomarker for novel therapeutic strategies.

Influence of ultrasound focus depth on the association between echo intensity and intramuscular adipose tissue.

INTRODUCTION/AIMS: Attenuation of the ultrasound (US) wave is a serious limitation of echo intensity (EI) on B-mode US. The aim of this study was to determine whether the focus depth of US images influences the depth-dependent attenuation of EI and the relationship between EI and intramuscular adipose tissues (IntraMAT). METHODS: The rectus femoris (RF) and vastus intermedius (VI) of the right thigh were studied in 135 adults (92 older, 43 younger). The EI on US images was measured at three focus depth conditions: top of the image, center of the RF, and center of the VI. The depth of the region of interest (ROI) was measured. IntraMAT was calculated using water and fat images based on the two-point Dixon technique with a 3.0-T magnetic resonance imaging scanner. RESULTS: The correlation between EI and IntraMAT was stronger in the focus RF and VI conditions than in the focus top condition and stronger for RF than for VI. The depth of the ROI influenced the IntraMAT-adjusted residual EI more in the focus top condition than in the focus RF and VI conditions, and influenced VI more strongly than it did RF. DISCUSSION: By mitigating EI attenuation, EI with a focus depth adjusted to the ROI reflected IntraMAT more accurately than that without adjustment. However, it may not completely prevent the potential influence of depth-dependent attenuation of EI, especially for deeper muscles such as the VI.