Impact of Tumor Subclassifications for Identifying an Appropriate Surgical Strategy in Patients with Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. The impact of these subclassifications for identifying appropriate surgical strategies remains unclear. PATIENTS AND METHODS: This study included 118 patients with ICC who underwent liver resection. Based on the pathological examination results, the participants were divided into the small duct-type ICC group (n = 64) and large duct-type ICC group (n = 54). The clinicopathological features and postoperative outcomes were compared between the two groups to investigate the impact of subclassification for selecting appropriate surgical strategies. RESULTS: Ten patients in the small duct-type ICC group had synchronous or metachronous hepatocellular carcinoma. The large duct-type ICC group had higher proportions of patients who underwent major hepatectomy, extrahepatic bile duct resection, portal vein resection, and lymph node sampling or dissection than the small duct-type ICC group. The large duct-type ICC group had significantly higher incidences of lymph node metastasis/recurrence and pathological major vessel invasion than the other. The small duct-type ICC group exhibited significantly higher recurrence-free and overall survival rates than the large duct-type ICC group. Further, the large duct-type ICC group had a significantly higher incidence of lymph node metastasis/recurrence than the small duct-type ICC at the perihilar region group. CONCLUSIONS: Suitable surgical strategies may differ between the small and large duct-type ICCs. In patients with large duct-type ICCs, hepatectomy with lymph node dissection and/or biliary reconstruction should be considered, whereas hepatectomy without these advanced procedures can be suggested for patients with small duct-type ICCs.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Definitive chemoradiotherapy with paclitaxel for locally advanced esophageal squamous cell carcinoma in older patients (PARADISE-1): a phase I trial.

BACKGROUND: In older patients, esophageal squamous cell carcinoma (ESCC) is difficult to treat using standard therapies, including surgery and cisplatin-based chemoradiotherapy. Paclitaxel (PTX) has radiosensitizing activity. We conducted a phase I trial of PTX combined with radiotherapy to establish a standard therapy for locally advanced ESCC in older patients. METHODS: Enrollment was conducted at six centers in Japan from April 2016 to September 2019. The participants were aged ≥ 70 years, had locally advanced ESCC, and were intolerant to surgery or unwilling. A fixed 60-Gy radiation dose was administered in 30 fractions. PTX dosing levels started at 30 mg/m2 weekly for 6 weeks. Depending on the number of DLTs, the dose was set to be increased by 10 mg/m2 or switched to biweekly. A geriatric assessment was performed before treatment using the Geriatric-8 screening tool. The primary endpoint was dose-limiting toxicity (DLT). RESULTS: We enrolled 24 patients (6 per group); DLT was observed in one (grade 4 hypokalemia), one (grade 3 aspiration), two (grade 3 radiodermatitis, grade 3 esophageal hemorrhage), and two (grade 3 anorexia, grade 5 pneumonitis) patients in the weekly PTX 30, 40, 50, and 60 mg/m2 groups, respectively. All adverse events, except death in the 60 mg/m2 group, showed reversible improvement, and the safety profile was considered acceptable. The 2-year survival and complete response rates were 40.0% and 54.2%, respectively. There was a significant difference in survival between favorable and unfavorable Geriatric-8 scores. CONCLUSIONS: The recommended PTX dose with concomitant radiation was determined to be 50 mg/m2 weekly. Phase II trials at this dose are underway.

Prevalence and clinical profiles of anti-myelin-associated glycoprotein neuropathy in Japan: A nationwide survey study of 133 patients.

BACKGROUND AND PURPOSE: The aim of this study was to determine the prevalence of anti-myelin-associated glycoprotein (MAG) neuropathy and the current status of such patients in Japan. METHODS: We conducted a nationwide survey in 2021 using established epidemiological methods. Questionnaires were sent to all neurology and pediatric neurology departments throughout Japan to identify patients with anti-MAG neuropathy. An initial questionnaire was used to determine the number of patients, with a second one used to collect detailed clinical information. RESULTS: The estimated number of patients with anti-MAG neuropathy was 353, with a prevalence of 0.28 per 100,000 and an incidence of 0.05 per 100,000. The detailed clinical profiles of 133 patients were available. The median (range) age of onset was 67 (30-87) years, with a prominent peak in the age range 66-70 years, and the male-to-female ratio was 3.6. Most patients had distal sensory-predominant polyneuropathy, and neuropathic pain (50%), or sensory ataxia (42%), while 18% had Waldenström's macroglobulinemia or multiple myeloma. Intravenous immunoglobulin was the most frequently used treatment (65%), but the response rate was <50%, whereas rituximab was given in 32% of patients, and 64% of these showed improvement. At the last visit, 27% of patients could not walk independently. CONCLUSIONS: This study on anti-MAG neuropathy provides updated insights into the epidemiology of this disease, clinical profiles, and treatment approaches in Japan. Rituximab therapy, used for only one-third of the patients, demonstrated efficacy. During the final visit, a quarter of the patients were unable to walk independently. Further studies are warranted to determine the optimal management of this rare and intractable disorder.

Comparison between asymptotic and re-randomisation tests under non-proportional hazards in a randomised controlled trial using the minimisation method.

BACKGROUND: Pocock-Simon's minimisation method has been widely used to balance treatment assignments across prognostic factors in randomised controlled trials (RCTs). Previous studies focusing on the survival outcomes have demonstrated that the conservativeness of asymptotic tests without adjusting for stratification factors, as well as the inflated type I error rate of adjusted asymptotic tests conducted in a small sample of patients, can be relaxed using re-randomisation tests. Although several RCTs using minimisation have suggested the presence of non-proportional hazards (non-PH) effects, the application of re-randomisation tests has been limited to the log-rank test and Cox PH models, which may result in diminished statistical power when confronted with non-PH scenarios. To address this issue, we proposed two re-randomisation tests based on a maximum combination of weighted log-rank tests (MaxCombo test) and the difference in restricted mean survival time (dRMST) up to a fixed time point τ , both of which can be extended to adjust for randomisation stratification factors. METHODS: We compared the performance of asymptotic and re-randomisation tests using the MaxCombo test, dRMST, log-rank test, and Cox PH models, assuming various non-PH situations for RCTs using minimisation, with total sample sizes of 50, 100, and 500 at a 1:1 allocation ratio. We mainly considered null, and alternative scenarios featuring delayed, crossing, and diminishing treatment effects. RESULTS: Across all examined null scenarios, re-randomisation tests maintained the type I error rates at the nominal level. Conversely, unadjusted asymptotic tests indicated excessive conservatism, while adjusted asymptotic tests in both the Cox PH models and dRMST indicated inflated type I error rates for total sample sizes of 50. The stratified MaxCombo-based re-randomisation test consistently exhibited robust power across all examined scenarios. CONCLUSIONS: The re-randomisation test is a useful alternative in non-PH situations for RCTs with minimisation using the stratified MaxCombo test, suggesting its robust power in various scenarios.

Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Decision Tree Analysis Accurately Predicts Discharge Destination After Spinal Cord Injury Rehabilitation.

OBJECTIVES: To predict discharge destination after spinal cord injury (SCI) rehabilitation. STUDY DESIGN: A retrospective, single-center study. We collected the following data from medical charts: age, sex, living arrangement before injury, acute length of stay (LOS), level of injury on admission, American Spinal Injury Association Impairment Scale (AIS) on admission, Upper Extremity Motor Score (UEMS) on admission, Lower Extremity Motor Score on admission (LEMS), Spinal Cord Independence Measure (SCIM) scores on admission and discharge, and discharge destination. A decision tree algorithm was used to establish prediction models in a train-test split manner using features on admission or discharge. SETTING: A spinal center in Tokyo, Japan. PARTICIPANTS: Participants were individuals with SCI admitted to our hospital from March 2016 to October 2021 for the first rehabilitation after the injury. The study included 210 participants divided into 2 groups: training (n=140) and testing (n=70). Random sampling without replacement was used. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Prediction accuracy was evaluated with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating curve (AUC). RESULTS: AIS was significantly different between the groups. The prediction model using total SCIM scores on discharge (D-Classification and Regression Tree [CART]) revealed that a cut-off value of 40 accurately predicted the discharge destination. In contrast, the prediction model using features on admission (A-CART) revealed that subtotal SCIM mobility scores of 5, age of 74 years, and UEMS of 23 were significant predictors. Sensitivity, specificity, PPV, NPV, and AUC of D-CART and A-CART were 0.837, 0.810, 0.911, 0.680, and 0.832 and 0.857, 0.810, 0.913, 0.708, and 0.869, respectively. CONCLUSIONS: D-CART and A-CART showed comparable prediction accuracies. This suggests that, even during the early stages of rehabilitation, it is possible to predict the discharge destination.

Functional Outcome Prediction After Spinal Cord Injury Using Ensemble Machine Learning.

OBJECTIVES: To establish a machine learning model to predict functional outcomes after SCI with Spinal Cord Independence Measure (SCIM) using features present at the time of rehabilitation admission. STUDY DESIGN: A retrospective, single-center study. The following data were collected from the medical charts: age, sex, acute length of stay (LOS), level of injury, American Spinal Injury Association Impairment Scale (AIS), motor scores of each key muscle, Upper Extremity Motor Score (UEMS), Lower Extremity Motor Score (LEMS), SCIM total scores, and subtotal scores on admission and discharge. Based on the multivariate linear regression analysis, age, acute LOS, UEMS, LEMS, and SCIM subtotal scores were selected as features for machine learning algorithms. Random forest, support vector machine, neural network, and gradient boosting were used as the base models and combined using ridge regression as a metamodel. SETTING: A spinal center in Tokyo, Japan. PARTICIPANTS: Participants were individuals with SCI admitted to our hospital from March 2016 to October 2021 for the first rehabilitation after the injury. They were divided into 2 groups: training (n=140) and testing (n=70). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The root-mean-square error (RMSE), R2, and Mean Absolute Error (MAE) were used as accuracy measures. RESULTS: RMSE, R2, and MAE of the meta-model using the testing group were 9.7453, 0.8835, and 7.4743, respectively, outperforming any other single base model. CONCLUSIONS: Our study revealed that functional prognostication could be achieved using machine-learning methods with features present at the time of rehabilitation admission. Goals can be set at the beginning of rehabilitation. Moreover, our model can be used to evaluate advanced medical treatments, such as regenerative medicine.

What Are the Complication Rates and Factors Associated With Total Femur Replacement After Tumor Resection? Findings From the Japanese Musculoskeletal Oncology Group.

BACKGROUND: Patients undergoing massive tumor resection and total femur replacement (TFR) face a substantial risk of hip dislocation and infection, often resulting in multiple implant revisions or hip disarticulation. These complications can impact their independence and prognosis. Additionally, their shorter life expectancy is influenced by challenges in achieving local radical resection and controlling metastases. Identifying suitable candidates for TFR is vital, necessitating investigations into dislocation, infection, implant failure rates, local recurrence, overall survival, and associated factors. QUESTIONS/PURPOSES: (1) What is the postsurgical complication (hip dislocation and infection) rate and factors associated with postsurgical complications in patients who underwent TFR after tumor resection? (2) What is the local recurrence rate, implant failure rate, overall survival rate, and factors associated with local recurrence and implant failure? METHODS: We retrospectively evaluated 42 patients (median [range] age 47 years [10 to 79 years]) who underwent TFR and tumor resection at the time of the same surgical procedure between 1990 and 2020 at 12 registered institutions that specialized in tumor treatment in Japan. A total of 55% (23) of the patients were men, and 79% (33) had bone sarcoma. The median (range) follow-up period was 36.5 months (2 to 327 months). Of the 42 patients, 12% (5) were lost to follow-up before 2 years without meeting a study endpoint (postsurgical complications, revision, or amputation), and another 19% (8) died before 2 years with implants intact, leaving 69% (29) of the original group who had either follow-up of at least 2 years or met a study endpoint before the minimum surveillance duration. Another 10% (4) had a minimum of 2 years of follow-up but had not been seen in the past 5 years. Infection was defined as deep-seated infection involving soft tissues, bones, joints, and the area around the implant. We did not consider superficial infections. Implant failure was defined when a patient underwent reimplantation or amputation. The complication and implant failure rates were assessed by the cumulative incidence function method, considering competing events. The Kaplan-Meier method was used to estimate the overall survival rate. RESULTS: The 1-month, 6-month, 1-year, and 2-year dislocation rates were 5%, 12%, 14%, and 14%, respectively. The 1-month, 6-month, 1-year, and 2-year infection rates were 5%, 7%, 10%, and 15%, respectively. Multivariable analyses for hip dislocation and infection revealed that resection of the abductor muscles and large tumor size were positively associated with hip dislocation. The 6-month, 1-year, and 2-year local recurrence rates were 5%, 15%, and 15%, respectively. The 6-month, 1-year, 2-year, and 5-year implant failure rates were 5% (95% confidence interval 1% to 15%), 7% (95% CI 2% to 18%), 16% (95% CI 6% to 29%), and 16% (95% CI 6% to 29%), respectively. Multivariable analyses of local recurrence and implant failure that led to reimplantation or amputation revealed that a positive surgical margin was positively associated with local recurrence. The 1-year, 2-year, and 5-year overall patient survival rates were 95% (95% CI 87% to 102%), 77% (95% CI 64% to 91%), and 64% (95% CI 48% to 81%), respectively. CONCLUSION: Hip dislocation, infection, and local recurrence were frequently observed in patients who received massive tumor resection and TFR in our study, eventually leading to reimplantation or amputation. Preserving the abductor muscles and resecting the tumor with a wide margin can prevent postoperative dislocation and local recurrence. Future research should focus on patient selection criteria, prevention of hip dislocation, and innovative treatments. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Live two-way video versus face-to-face treatment for depression, anxiety, and obsessive-compulsive disorder: A 24-week randomized controlled trial.

AIM: Live two-way video, easily accessible from home via smartphones and other devices, is becoming a new way of providing psychiatric treatment. However, lack of evidence for real-world clinical setting effectiveness hampers its approval by medical insurance in some countries. Here, we conducted the first large-scale pragmatic, randomized controlled trial to determine the effectiveness of long-term treatment for multiple psychiatric disorders via two-way video using smartphones and other devices, which are currently the primary means of telecommunication. METHODS: This randomized controlled trial compared two-way video versus face-to-face treatment for depressive disorder, anxiety disorder, and obsessive-compulsive disorder in the subacute/maintenance phase during a 24-week period. Adult patients with the above-mentioned disorders were allocated to either a two-way video group (≥50% video sessions) or a face-to-face group (100% in-person sessions) and received standard treatment covered by public medical insurance. The primary outcome was the 36-Item Short-Form Health Survey Mental Component Summary (SF-36 MCS) score. Secondary outcomes included all-cause discontinuation, working alliance, adverse events, and the severity rating scales for each disorder. RESULTS: A total of 199 patients participated in this study. After 24 weeks of treatment, two-way video treatment was found to be noninferior to face-to-face treatment regarding SF-36 MCS score (48.50 vs 46.68, respectively; p < 0.001). There were no significant differences between the groups regarding most secondary end points, including all-cause discontinuation, treatment efficacy, and satisfaction. CONCLUSION: Two-way video treatment using smartphones and other devices, was noninferior to face-to-face treatment in real-world clinical settings. Modern telemedicine, easily accessible from home, can be used as a form of health care.

Interobserver agreement of pathologic classification and grading of tumoral intraductal pre-invasive neoplasms of the bile duct.

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was "substantial" (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was "slight" (κ-value, 0.201), while that of modified types 1 and 2 subclassification was "moderate" (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.

Underweight in young Japanese women over time: a longitudinal retrospective study of the change in body mass index from ages 6 to 20 years.

BACKGROUND: The high prevalence of underweight in young women has become a serious health problem in Japan. When and how young women reach a low body mass index (BMI) has not been clarified. AIM: To clarify the characteristics of BMI standard deviation scores (BMI SDS) trajectory of young Japanese women with underweight. SUBJECTS AND METHODS: A total of 601 Japanese female university students aged 20 years were classified into underweight and healthy weight groups. Their school health check-up data were available from the ages of 6 to 20 years. We evaluated the estimated mean values of BMI SDS at each age and differences in BMI SDS (ΔBMI SDS) from 6 years to each age using a mixed-effects model and compared between the two groups at each age. RESULTS: In the underweight group, the BMI SDS at every age (-1.67 to -0.91) and the ΔBMI SDS after 16 years of age (-0.76 to -0.38) were significantly lower than those in the healthy weight group (-0.41 to -0.13, -0.07 to 0.04), respectively. CONCLUSION: Young Japanese women with underweight have at least two characteristics of BMI SDS trajectory: being constitutionally underweight and shifting their weight status from baseline towards underweight in their late teens.

Intraoperative surgical complications of open surgery for congenital diaphragmatic hernia: a multicenter, observational study in Japan.

PURPOSE: This study aimed to clarify surgical complications associated with open surgery for congenital diaphragmatic hernia (CDH). METHODS: We performed an exploratory data analysis of the clinical characteristics of surgical complications of neonates with CDH who underwent laparotomy or thoracotomy between 2006 and 2021. Data of these patients were obtained from the database of the Japanese CDH Study Group. RESULTS: Among 1,111 neonates with left or right CDH, 852 underwent open surgery (laparotomy or thoracotomy). Of these 852 neonates, 51 had the following surgical complications: organ injury (n = 48; 6% of open surgeries); circulatory failure caused by changes in the organ location (n = 2); and skin burns (n = 1). Injured organs included the spleen (n = 30; 62% of organ injuries), liver (n = 7), lungs (n = 4), intestine (n = 4), adrenal gland (n = 2), and thoracic wall (n = 2). Fourteen of the patients who experienced organ injury required a blood transfusion (2% of open surgeries). The adjusted odds ratio of splenic injury for patients with non-direct closure of the diaphragm was 2.2 (95% confidence interval, 1.1-4.9). CONCLUSION: Of the patients who underwent open surgery for CDH, 2% experienced organ injury that required a blood transfusion. Non-direct closure of the diaphragmatic defect was a risk factor for splenic injury.

Primary hepatobiliary mucoepidermoid carcinoma: a case report and review of literature.

Hepatobiliary mucoepidermoid carcinoma is a rare malignant tumor comprising mucous, intermediate, and epidermoid cells. Herein, we presented a case of primary liver mucoepidermoid carcinoma preoperatively misdiagnosed as conventional intrahepatic cholangiocarcinoma. A 67-year-old male was admitted to our hospital. Preoperative laboratory tests showed increased aspartate transaminase, alanine transaminase, and carbohydrate antigen 19-9. Abdominal Computer Tomography revealed a 4.8 × 4.9 cm liver mass in segment VI. A preliminary diagnosis of intrahepatic cholangiocarcinoma was made, with undergoing partial hepatectomy. However, on histopathology, the tumor comprised a mixture of epidermoid, mucous, and intermediate cells with diffuse infiltrating at the tumor margin. On special stains, mucous and intermedia cells were positive for mucicarmine and Alcian blue, whereas epidermoid cells were positive for Keratin 5/6 and p63. Intermediate cells are also positive for p63. All tumor cells were positive for Keratin 7. The Ki-67 index was 35%. The final diagnosis was primary hepatic mucoepidermoid carcinoma. Although rare, hepatic mucoepidermoid carcinoma should be considered in the intrahepatic cholangiocarcinoma differential diagnosis. We reviewed previous studies and found that hepatobiliary mucoepidermoid carcinoma is more likely to originate from the biliary tract adjacent to the tumor.

Histopathological growth pattern and vessel co-option in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) exhibits different blood imaging features and prognosis depending on histology. To clarity histopathological growth patterns (HGPs) and vascularization processes of iCCA, we collected 145 surgical specimens and histologically classified them into large bile duct (LBD) (20 cases), small bile duct (SBD) (54), cholangiolocarcinoma (CLC) (35), combined SBD-CLC (cSBD-CLC) (26), and ductal plate malformation (DPM) (10) (sub)types. According to the invasive pattern at the interface between tumor and adjacent background liver, HGPs were classified into desmoplastic, pushing, and replacing HGPs. Desmoplastic HGP predominated in LBD type (55.5%), while replacing HGP was common in CLC (82.9%) and cSBD-CLC (84.6%) subtypes. Desmoplastic HGP reflected angiogenesis, while replacing HGP showed vessel co-option in addition to angiogenesis. By evaluating microvessel density (MVD) using vascular markers, ELTD1 identified vessel co-option and angiogenesis, and ELTD1-positive MVD at invasive margin in replacing HGP was significantly higher than those in desmoplastic and pushing HGPs. REDD1, an angiogenesis-related marker, demonstrated preferably higher MVD in the tumor center than in other areas. iCCA (sub)types and HGPs were closely related to vessel co-option and immune-related factors (lymphatic vessels, lymphocytes, and neutrophils). In conclusion, HGPs and vascular mechanisms characterize iCCA (sub)types and vessel co-option linked to the immune microenvironment.

Development and validation of a new asthma questionnaire to help achieve a high level of control in school-age children and adolescents.

BACKGROUND: Maintaining good asthma control minimizes the risk of exacerbations and lung function decline and is a primary goal of asthma management. The Japanese Pediatric Asthma Guidelines (JPGL) employs different classification criteria for control status from other guidelines, stressing a higher level of control. Based on JPGL, we previously developed a caregiver-completed questionnaire for assessing and achieving best asthma control in preschoolers. In this study, we aimed to develop a questionnaire for school-age children and adolescents. METHODS: A working questionnaire comprising 14 items for patients and 34 items for caregivers was administered to 362 asthma patients aged 6-15 years and their caregivers. Separately, physicians filled out a questionnaire to determine JPGL-defined control. Logistic regression analysis was performed to construct a model to predict control levels using data from a randomly selected set of completed questionnaires from two-thirds of the subjects. Validation was performed using the remaining questionnaires. RESULTS: A set of 7 questions, encompassing self-assessed control status at the time of the visit and in the past month, and nocturnal/early morning asthma symptoms for patients and frequency of asthma symptoms, dyspnea, rescue beta-agonist use, and asthma hospitalization for caregivers, were selected and the 7-item model showed a good statistical fit with AIC of 110.5. The model has been named the Best Asthma Control Test for School Children and Adolescents (Best ACT-S). Best ACT-S scores differed significantly in the hypothetical direction among the groups of different JPGL-defined control levels, step-up/down treatment decisions, and presence/non-presence of exacerbations in the previous year. CONCLUSIONS: The Best ACT-S is a valid questionnaire for children/adolescents aiming for best asthma control.

Assessing anti-SARS-CoV-2 cellular immunity in 571 vaccines by using an IFN-γ release assay.

Memory T cell responses have been analyzed only in small cohorts of COVID-19 vaccines. Herein, we aimed to assess anti-SARS-CoV-2 cellular immunity in a large cohort using QuantiFERON assays, which are IFN-γ release assays (IGRAs) based on short-term whole blood culture. The study included 571 individuals receiving the viral spike (S) protein-expressing BNT162b2 mRNA vaccine. QuantiFERON assays revealed antigen-specific IFN-γ production in most individuals 8 weeks after the second dose. Simultaneous flow cytometric assays to detect T cells expressing activation-induced markers (AIMs) performed for 28 randomly selected individuals provided data correlating with the QuantiFERON data. Simultaneous IFN-γ enzyme-linked immunospot and AIM assays for another subset of 31 individuals, based on short-term peripheral blood mononuclear cell culture, also indicated a correlation between IFN-γ production and AIM positivity. These observations indicated the acquisition of T cell memory responses and supported the usability of IGRAs to assess cellular immunity. The QuantiFERON results were weakly correlated with serum IgG titers against the receptor-binding domain of the S protein and were associated with pre-vaccination infection and adverse reactions after the second dose. The present study revealed cellular immunity after COVID-19 vaccination, providing insights into the effects and adverse reactions of vaccination.

Dynamic CT and Gadoxetic Acid-enhanced MRI Characteristics of P53-mutated Hepatocellular Carcinoma.

Background Imaging markers of hepatocellular carcinoma (HCC) on the basis of molecular classification are important for predicting malignancy grade and prognosis. P53-mutated HCC is a major aggressive subtype; however, its imaging characteristics have not been clarified. Purpose To clarify the imaging characteristics of P53-mutated HCC at dynamic CT and gadoxetic acid-enhanced MRI that are correlated with its clinical features, pathologic findings, and prognosis. Materials and Methods In this retrospective single-center study, patients with surgically resected HCC between January 2015 and May 2018 in a university hospital were evaluated. HCC was classified into P53-mutated HCC and non-P53-mutated HCC using immunostaining. Dynamic CT and gadoxetic acid-enhanced MRI findings, clinical features, pathologic findings, and prognosis were compared using Mann-Whitney test, χ2 test, multivariable regression analysis, receiver operating characteristic analysis, Kaplan-Meier method, and log-rank test. Immunohistochemical expression of P53, organic anion transporting polypeptide 1B3 (OATP1B3), and CD34 were evaluated, and the correlations were analyzed using the Pearson correlation test. Results In total, 149 patients (mean age, 67 years ± 9 [SD]; 103 men) with 173 HCCs were evaluated. P53-mutated HCC (n = 28) demonstrated higher serum α-fetoprotein (median, 127.5 ng/mL vs 5.5 ng/mL; P < .001), larger size (40.4 mm ± 29.7 vs 26.4 mm ± 20.5; P = .001), and higher rates of poorly differentiated HCC (22 of 28 [79%] vs 24 of 145 [17%]; P < .001). Dilated vasculature in the arterial phase of dynamic CT (odds ratio, 14; 95% CI: 3, 80; P = .002) and a lower relative enhancement ratio in the hepatobiliary phase (odds ratio, 0.05; 95% CI: 0.01, 0.34; cutoff value, 0.69; P = .002) independently predicted P53-mutated HCC. OATP1B3 expression and P53 expression were inversely correlated (P = .002; R = -0.24). Five-year overall survival was worse for P53-mutated HCC (50.0% vs 72.6%; P = .02). Conclusion Dilated vasculature at the arterial phase of dynamic CT and a lower relative enhancement ratio at the hepatobiliary phase of gadoxetic acid-enhanced MRI were useful markers for P53-mutated hepatocellular carcinoma with poor prognosis. © RSNA, 2022 Online supplemental material is available for this article.

Tofogliflozin long-term effects on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes mellitus lacking a history of cardiovascular disease: a 2-year extension study of the UTOPIA trial.

BACKGROUND: This study aimed to assess the long-term effects of tofogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on atherosclerosis progression and major clinical parameters in patients with type 2 diabetes lacking an apparent history of cardiovascular disease. METHODS: This was a prospective observational 2-year extension study of the "Using TOfogliflozin for Possible better Intervention against Atherosclerosis for type 2 diabetes patients (UTOPIA)" trial, a 2-year randomized intervention study. The primary endpoints represented changes in the carotid intima-media thickness (IMT). Secondary endpoints included brachial-ankle pulse wave velocity (baPWV) and biomarkers for glucose metabolism, lipid metabolism, renal function, and cardiovascular risks. RESULTS: The mean IMT of the common carotid artery (IMT-CCA) significantly decreased in both the tofogliflozin (- 0.067 mm, standard error 0.009, p < 0.001) and conventional treatment groups (- 0.080 mm, SE 0.009, p < 0.001) throughout the follow-up period; however, no significant intergroup differences in the changes (0.013 mm, 95% confidence interval (CI) - 0.012 to 0.037, p = 0.32) were observed in a mixed-effects model for repeated measures. baPWV significantly increased in the conventional treatment group (82.7 ± 210.3 cm/s, p = 0.008) but not in the tofogliflozin group (- 17.5 ± 221.3 cm/s, p = 0.54), resulting in a significant intergroup difference in changes (- 100.2 cm/s, 95% CI - 182.8 to - 17.5, p = 0.018). Compared to the conventional treatment group, tofogliflozin significantly improved the hemoglobin A1c and high-density lipoprotein cholesterol levels, body mass index, abdominal circumference, and systolic blood pressure. The frequencies of total and serious adverse events did not vary significantly between the groups. CONCLUSIONS: Tofogliflozin was not associated with improved inhibition of carotid wall thickening but exerted long-term positive effects on various cardiovascular risk factors and baPWV while showing a good safety profile.

Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components.

AIMS: Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. METHODS AND RESULTS: Subjects included 33 bile duct adenomas and 17 small-sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot-spot regions and immunohistochemical staining. The expression of p16INK4a , EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small-sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). CONCLUSION: Bile duct adenomas and small-sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs.