Yutaka Matsuyama

Background/Objectives: Neonatal hypoxic–ischemic encephalopathy (HIE) is a major cause of neurodevelopmental diseases. In a previous retrospective study, we revealed that the levels of the soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) are linked to HIE severity. We conducted a prospective investigation to evaluate the association between sLOX-1 levels and HIE severity using the Sarnat staging system, as well as a multicenter study to assess neurodevelopmental sequelae in the short term. Methods: A total of 193 infants were enrolled in the study between April 2018 and March 2021. We divided the infants into groups as follows: infants without HIE were assigned to a normal control group, and those with HIE to mild, moderate, and severe HIE groups. We measured 191 samples, excluding three participants. The distribution of 191 participants was as follows: 88 normal samples of 50 umbilical cord (UC) arteries and 38 venous blood samples (control; CTL), as well as 103 HIE samples of 34 mild, 55 moderate, and 14 severe HIE samples. All the plasma samples were collected until 6 h after birth. Results: The mean sLOX-1 value in the CTL group was 613 pg/mL (IQR: 474–925 pg/mL) and that in the UC group was 497 pg/mL (IQR: 337–693 pg/mL), with no significant difference (p = 0.136). The mean sLOX-1 value in the mild HIE group was 1030 pg/mL (IQR: 658–1547 pg/mL), 1026 pg/mL (IQR: 710–2051 pg/mL) in the moderate HIE group, and 1444 pg/mL (IQR: 766–3927 pg/mL) in the severe HIE group. There were significant differences between the CTL and HIE groups (p = 0.006) and between the CTL and mild HIE groups (p < 0.05), but not between the mild HIE and the moderate and severe HIE groups (p = 0.088). The other blood markers exhibited no correlation with Sarnat severity. Interestingly, blood sLOX-1 levels increased with Sarnat severity. Conclusions: The results of this study indicated that sLOX-1 level was correlated with Sarnat severity. Moreover, early assessment of sLOX-1 level may be useful for deciding whether to induce therapeutic hypothermia and/or other treatments, and sLOX-1 may serve as a short-term outcome biomarker of HIE.

Objective: This randomized phase II/III study evaluated the superiority of neoadjuvant therapy with gemcitabine plus S-1 over upfront surgery for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Background: PDAC is a leading cause of cancer mortality that urgently requires better treatment. Methods: Patients with resectable PDAC (without arterial abutment) were randomly assigned to upfront surgery or neoadjuvant chemotherapy with gemcitabine (1000 mg/m ² days 1 and 8) and S-1 (40–60 mg orally twice daily, days 1–14 every 3 wk for 2 cycles). Phase II and III primary endpoints were resection rate and overall survival, respectively. UMIN Clinical Trials Registry number: UMIN000009634. Results: Patients (n=364) were enrolled and randomly allocated to upfront surgery (UPS; n=182) or neoadjuvant gemcitabine plus S-1 (NAC-GS; n=182). Patient demographics and tumor characteristics were balanced between groups. Median overall survival in the UPS and NAC-GS groups was 26.6 (95% CI: 21.5, 31.5) and 37.0 (95% CI: 28.6, 43.3) months, respectively. The hazard ratio for mortality in the NAC-GS group compared with the UPS group was 0.73 (95% CI: 0.56, 0.95; P =0.018). Median relapse-free survival in the UPS and NAC-GS groups was 11.3 (95% CI: 9.41, 13.5) and 14.3 (95% CI: 11.7, 17.0) months, respectively. The hazard ratio for relapse in the NAC-GS group compared with the UPS group was 0.77 (95% CI: 0.61, 0.98; P =0.030). Conclusions: The Prep-02/JSAP05 trial results showed that neoadjuvant chemotherapy with gemcitabine plus S-1 significantly extends survival compared with upfront surgery in patients with resectable PDAC.

Background: Prostate cancer is one of the most common cancers among men worldwide and the fourth most common cause of death. The number of prostate cancer cases and deaths is increasing every year because of population aging. This study aimed to clarify the risk of developing prostate cancer due to fluctuations in Prostate Specific Antigen (PSA) levels in patients without a history of prostate cancer using large medical information data. Results: This retrospective cohort included 1707 male patients aged 60 years or older who had a PSA level measurement date (2-PSA) within 3 months or more and 2 years from the first PSA level measurement date (1-PSA) in the database between 2008 and 2019. We subtracted 1-PSA from 2-PSA and designated patients with a higher 2-PSA than 1-PSA to the “up” group (n = 967) and patients with a lower 2-PSA than 1-PSA to the “down” group (n = 740). By using Cox proportional hazards model, a significant increase in prostate cancer risk was observed in the up group compared with the down group (adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.21–2.72; adjusted for patient background factors). Subgroup analysis showed that patients with PSA levels < 4 ng/mL had a significantly increased risk of developing prostate cancer if the next PSA level increases by approximately 20% (adjusted HR = 2.94, 95% CI = 1.14–7.58), and patients with PSA levels of 4 ng/mL or higher if the next PSA level is decreased by approximately 20% had a significantly reduced risk of developing prostate cancer (adjusted HR = 0.36, 95% CI = 0.18–0.74), compared to that with no change. Conclusions: This is the first study to clarify the association between PSA variability and risk of developing prostate cancer in patients without a history of prostate cancer. These results suggest that the suppression of elevated PSA levels may lead to the prevention of prostate cancer and that it would be better to perform a biopsy because the risk of developing prostate cancer may increase in the future if the PSA value increases above a certain level.

The demand for methods to ensure safe oral consumption of food and liquids in order to prevent aspiration pneumonia has increased over the last decade. This study investigated the safety of swallowing care selected by adding ultrasound-based observation, evaluated its efficacy, and determined effective content of selected swallowing care. The study employed a pragmatic quasi-experimental research design. Participants were 12 community-dwelling adult patients (age: 44–91 years) who had experienced choking within 1 month prior to the study. After the control phase, in which conventional swallowing care was provided, trained nurses provided ultrasound observation-based swallowing care for a minimum period of 2 weeks. Outcome measurements were compared across three points, namely T1—beginning of the control phase, T2 and T3—before and end of the intervention phase. The mean durations of intervention were 30.8 days in the control phase and 36.5 days in the intervention phase. Pneumonia and suffocation did not occur in the control phase or the intervention phase. The safe intake food level and the food intake level score significantly improved during the intervention phase (p = 0.032 and 0.017, respectively) by adding eating training based on the ultrasound observation. However, there was no significant improvement in the strength of the muscle related to swallowing by the selected basic training. Our results suggest that swallowing care selected based on the ultrasound observation, especially eating training, safely improved safe oral intake among community-dwelling adults with swallowing dysfunction.

In some clinical situations, patients experience repeated events of the same type. Among these, cancer recurrences can result in terminal events such as death. Therefore, here we dynamically predicted the risks of repeated and terminal events given longitudinal histories observed before prediction time using dynamic pseudo-observations (DPOs) in a landmarking model. The proposed DPOs were calculated using Aalen–Johansen estimator for the event processes described in the multi-state model. Furthermore, in the absence of a terminal event, a more convenient approach without matrix operation was described using the ordering of repeated events. Finally, generalized estimating equations were used to calculate probabilities of repeated and terminal events, which were treated as multinomial outcomes. Simulation studies were conducted to assess bias and investigate the efficiency of the proposed DPOs in a finite sample. Little bias was detected in DPOs even under relatively heavy censoring, and the method was applied to data from patients with colorectal liver metastases. The proposed method enabled intuitive interpretations of terminal event settings.

Despite the frequent use of self-controlled methods in pharmacoepidemiological studies, the factors that may bias the estimates from these methods have not been adequately compared in real-world settings. Here, we comparatively examined the impact of a time-varying confounder and its interactions with time-invariant confounders, time trends in exposures and events, restrictions, and misspecification of risk period durations on the estimators from three self-controlled methods. This study analyzed self-controlled case series (SCCS), case-crossover (CCO) design, and sequence symmetry analysis (SSA) using simulated and actual electronic medical records datasets. We evaluated the performance of the three self-controlled methods in simulated cohorts for the following scenarios: 1) time-invariant confounding with interactions between the confounders, 2) time-invariant and time-varying confounding without interactions, 3) time-invariant and time-varying confounding with interactions among the confounders, 4) time trends in exposures and events, 5) restricted follow-up time based on event occurrence, and 6) patient restriction based on event history. The sensitivity of the estimators to misspecified risk period durations was also evaluated. As a case study, we applied these methods to evaluate the risk of macrolides on liver injury using electronic medical records. In the simulation analysis, time-varying confounding produced bias in the SCCS and CCO design estimates, which aggravated in the presence of interactions between the time-invariant and time-varying confounders. The SCCS estimates were biased by time trends in both exposures and events. Erroneously short risk periods introduced bias to the CCO design estimate, whereas erroneously long risk periods introduced bias to the estimates of all three methods. Restricting the follow-up time led to severe bias in the SSA estimates. The SCCS estimates were sensitive to patient restriction. The case study showed that although macrolide use was significantly associated with increased liver injury occurrence in all methods, the value of the estimates varied. The estimations of the three self-controlled methods depended on various underlying assumptions, and the violation of these assumptions may cause non-negligible bias in the resulting estimates. Pharmacoepidemiologists should select the appropriate self-controlled method based on how well the relevant key assumptions are satisfied with respect to the available data.