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The mixed model for repeated measures (MMRM) analysis is sometimes used as a primary statistical analysis for a longitudinal randomized clinical trial. When the MMRM analysis is implemented in ordinary statistical software, the standard error of the treatment effect is estimated by assuming orthogonality between the fixed effects and covariance parameters, based on the characteristics of the normal distribution. However, orthogonality does not hold unless the normality assumption of the error distribution holds, and/or the missing data are derived from the missing completely at random structure. Therefore, assuming orthogonality in the MMRM analysis is not preferable. However, without the assumption of orthogonality, the small-sample bias in the standard error of the treatment effect is significant. Nonetheless, there is no method to improve small-sample performance. Furthermore, there is no software that can easily implement inferences on treatment effects without assuming orthogonality. Hence, we propose two small-sample adjustment methods inflating standard errors that are reasonable in ideal situations and achieve empirical conservatism even in general situations. We also provide an R package to implement these inference processes. The simulation results show that one of the proposed small-sample adjustment methods performs particularly well in terms of underestimation bias of standard errors; consequently, the proposed method is recommended. When using the MMRM analysis, our proposed method is recommended if the sample size is not large and between-group heteroscedasticity is expected. [ABSTRACT FROM AUTHOR]

Background: To evaluate the seasonal variability of urinary albumin to creatinine ratio (UACR) and eGFR and these effects on three-year eGFR slope in persons with type 2 diabetes (T2D). Methods: A total of 1135 persons with T2D were analyzed in this single-center, retrospective cohort study in Japan. The standard deviation (SD) of UACR (SD [UACR]) and SD of eGFR (SD [eGFR]) were calculated for each person's 10-point data during the three years, and a multiple linear regression analysis was performed to evaluate associations with eGFR slope. A sensitivity analysis was performed in a group with no medication changes (n = 801). Results: UACR exhibited seasonal variability, being higher in winter and lower in spring, early summer, and autumn especially in the UACR ≥ 30 mg/g subgroup, while eGFR showed no seasonal variability. The eGFR slope was significantly associated with SD (eGFR) (regression coefficient -0.170 [95% CI -0.189–-0.151]) and SD (UACR) (0.000 [-0.001–0.000]). SGLT-2 inhibitors, baseline eGFR, and baseline systolic blood pressure (SBP) were also significantly associated. These associated factors, except baseline SBP, were still significant in the sensitivity analysis. Conclusions: The UACR showed clear seasonal variability. Moreover, SD (UACR) and SD (eGFR) were independently associated with a three-year eGFR slope in persons with T2D. Trial registration: This study was not registered for clinical trial registration because it was a retrospective observational study. [ABSTRACT FROM AUTHOR]

Objectives: Poor cardiorespiratory fitness (CRF) and high body mass index (BMI) increased the risk of developing metabolic Syndrome (MetS) mostly in Caucasians. However, the sex-specific combined association of CRF and BMI on MetS considering health-related behaviors has yet to be thoroughly examined in Japanese. This study aims to investigate the sex-specific independent and combined associations of CRF and BMI with MetS in middle-aged Japanese adults. Methods: 421 participants were included in this cross-sectional study. CRF was estimated using a submaximal cycle ergometer. CRF and BMI were respectively divided into three categories according to tertile distribution. MetS was diagnosed based on five risk factors: waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting glucose. Multivariable logistic regression models were used to estimate independent and combined association of CRF and BMI with MetS. Results: Results showed that 154 (57.5%) and 70 (45.8%) of men and women had MetS, respectively. Compared to men with lower CRF or higher BMI, men with middle and higher CRF or middle and lower BMI were less likely to have MetS. Compared with 'unfit and higher BMI' group, 'unfit and lower BMI', 'fit and higher BMI', and 'fit and lower BMI' groups in men showed statistically significant decreased prevalences of MetS. However, no significant associations were found in women. Conclusions: This study found significant independent and combined associations of CRF and BMI with MetS only in men, but not in women. However, prospective studies are warranted to confirm sex-specific associations of CRF and BMI with MetS. [ABSTRACT FROM AUTHOR]

Simple Summary: Chordoma is a rare cancer that often occurs at the base of the skull. Treating skull base chordoma is challenging because the tumor is difficult to completely remove with surgery and has low radiosensitivity. This study compared two types of radiation modality: particle beam therapy (PT) and photon radiotherapy (RT). We found that PT provides better progression-free survival compared to photon RT. However, PT also has a higher risk of causing brain necrosis. Our findings suggest that PT is more effective for controlling skull base chordoma, but careful planning is needed to minimize side effects. [Objective] The aim of this study was to compare the efficacy of particle beam therapy (PT) with photon radiotherapy (RT) for treatment of skull base chordoma. [Methods] A systematic review was conducted for skull base chordoma treated with PT or photon RT reported from 1990 to 2022. Data were extracted for overall survival (OS) and progression-free survival (PFS), late adverse events, age, gender, gross total resection (GTR) rates, tumor volume, total irradiation dose, and treatment modality. Random-effects meta-regression analysis with the treatment modality as an explanatory variable was performed for each outcome to compare the modalities. [Results] A meta-analysis of 30 selected articles found 3- and 5-year OS rates for PT vs. photon RT or combined photon RT/proton beam therapy (PBT) of 90.8% (95% CI: 87.4–93.3%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6543; 80.0% (95% CI: 75.7–83.6%) vs. 89.5% (95% CI: 83.0–93.6%), p = 0.6787. The 5-year PFS rates for PT vs. photon RT or photon RT/PBT were 67.8% (95% CI: 56.5–76.7%) vs. 40.2% (95% CI: 31.6–48.7%), p = 0.0004. A random-effects model revealed that the treatment modality (PT vs. photon RT or photon RT/PBT) was not a significant factor for 3-year OS (p = 0.42) and 5-year OS (p = 0.11), but was a significant factor for 5-year PFS (p < 0.0001). The rates of brain necrosis were 8–50% after PT and 0–4% after photon RT or photon RT/PBT. [Conclusion] This study shows that PT results in higher PFS compared to photon RT for skull base chordoma, but that there is a tendency for a higher incidence of brain necrosis with PT. Publication and analysis of further studies is needed to validate these findings. [ABSTRACT FROM AUTHOR]

Theoretically, the maximum likelihood estimator has the sandwich-type asymptotic variance-covariance matrix under model misspecification. Its empirical estimator, that is called the robust variance estimator, is consistent. Thus, the estimator is asymptotically valid even under model misspecification. In practice, the robust variance estimator is used for computation of standard errors in longitudinal data analysis. Recently, Golden et al. (2019 Econometrics, 7, 1-27) showed that the maximum likelihood estimator retains a sandwich-type asymptotic variance-covariance matrix in the presence of missing data even when the missing-data mechanism is missing not at random. Although they revealed the asymptotic validity of the robust variance estimator in the simultaneous presence of both model misspecification and missing data, its finite-sample performance did not be investigated. In this article, we evaluated the finite-sample performance via simulation studies and clarify its small-sample problems. In addition, we illustrated the robust variance estimator using longitudinal CD4 count data from a randomized double-blind study. [ABSTRACT FROM AUTHOR]

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6–76 Gy (RBE) in 20–22 fr, 13 received 74.0–76.0 Gy (RBE) in 37–38 fr, and 6 received 60–70.2 Gy (RBE) in 20–30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41–91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0–15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1–49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8–34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1–11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: In this article, we retrospectively evaluate risk factors for local recurrence and radiation necrosis after PBT for 101 cases of skull base chordoma and chondrosarcoma. In multivariate analysis, chordoma and large tumor size were found to be significant factors for local recurrence and higher total dose was a significant factor for radiation necrosis. [Proposal] Here, we retrospectively evaluate risk factors for radiation necrosis and local recurrence after PBT for skull base chordoma or chondrosarcoma. [Patients and Methods] We analyzed 101 patients who received PBT for skull base chordomas and chondrosarcomas from January 1989 to February 2021. Multivariable logistic regression models were applied for local recurrence, temporal lobe radiation necrosis rates, and temporal lobe radiation necrosis. [Results] In multivariate analysis, chordoma and large tumor size were independent significant factors for local recurrence. The 1-, 2-, 3-, 4- and 5-year local recurrence rates were 3.9%, 16.9%, 20.3%, 28.5% and 44.0% for chordoma and 0%, 0%, 0%, 0% and 7.1% for chondrosarcoma, respectively. The local recurrence rates of small tumors (<30 mm) were 4.3%, 14.7%, 17.7%, 17.7% and 25.9%, and those for large tumors were 3.6%, 15.1%, 19.2%, 32.7% and 59.6%, respectively. In multivariate analysis, BED Gy10 and total dose were risk factors for radiation necrosis. [Conclusions] For skull base chordoma and chondrosarcoma, the risk factors of local recurrence were chordoma and large tumor size, and those of radiation necrosis were BED Gy10 and total dose, respectively. DVH analysis is needed to investigate the risk factors for brain necrosis in more detail. [ABSTRACT FROM AUTHOR]