Clinical Effectiveness of Preoperative 18F-FDG PET/CT in Predicting Pathological Tumor Grade in Patients with Pseudomyxoma Peritonei Originating from Appendix: A Retrospective Cohort Study.

BACKGROUND: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the standard treatment for patients with pseudomyxoma peritonei (PMP). In some malignancies, the standard uptake value of positron emission tomography with 2-deoxy-2-18F-fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) is now accepted as a reliable indicator of neoplastic behavior. This study aimed to evaluate the association between the maximum standardized uptake value (SUVmax) and pathological grade in patients with PMP and to investigate the significance of SUVmax in the preoperative assessment of these patients. PATIENTS AND METHODS: In this retrospective single-center study, consecutively enrolled patients diagnosed with PMP of appendiceal origin underwent preoperative 18F-FDG PET/CT. SUVmax was calculated as the highest SUVmax value in the abdomen excluding the primary site. SUVmax was compared with the pathological grade (low or high grade) of PMP tumors according to the World Health Organization classification and further analyzed with respect to the estimated cutoff point, sensitivity, specificity, and receiver operating characteristic. RESULTS: In total, 160 patients were included. CRS was successfully performed in 93 patients and palliative debulking surgery in 67 patients. The pathological grade was high in 45 patients and low in 115. High-grade patients had a higher median SUVmax on 18F-FDG PET/CT than did low-grade patients (3.83 versus 2.34, p < 0.001). The highest area under the curve was 0.81, with a sensitivity of 77.8%, specificity of 72.3%, and cutoff point of 2.63. CONCLUSION: This study suggests that the SUVmax of preoperative 18F-FDG PET/CT is associated with the pathological grade in patients with PMP.

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

A crossover comparison of patient satisfaction with two teriparatide regimens: primary results of the Japanese Osteoporosis Intervention Trial 06 (JOINT-06).

INTRODUCTION: This study aimed to compare treatment satisfaction with two dosing regimens (two teriparatide [TPTD] self-injection systems) in osteoporosis patients at high risk of fracture. MATERIALS AND METHODS: In this open-label crossover randomized trial comparing self-injected once-daily (1/D)-TPTD with self-injected twice-weekly (2/W)-TPTD, three satisfaction variables were evaluated by questionnaire for 2 years. The primary endpoint was overall satisfaction and secondary endpoints were satisfaction with treatment effectiveness and with utility of the self-injection device. Changes in quality of life (QOL) assessed by EuroQol-5 Dimension, pain assessed by visual analogue scale (VAS), and anthropometric parameters were also analyzed. Safety was evaluated based on the incidence and severity of adverse events (AEs). RESULTS: The 1/D-TPTD and 2/W-TPTD groups consisted of 180 (75.9 ± 7.3 years) and 179 (age: 75.5 ± 6.9 years) patients, respectively. After 26 weeks of treatment, no significant between-group difference in the persistence rate (79.4% vs 72.6% in the 1/D-TPTD and 2/W-TPTD groups, respectively), distributions of overall satisfaction scores, and satisfaction with treatment (p > 0.05) were observed. However, several items of satisfaction with the utility of the injection device were significantly higher in the 2/W-TPTD group (p < 0.05). Statistical improvements from baseline values were observed in QOL and pain VAS in both groups (p < 0.05). No serious AEs were reported. CONCLUSION: The between-group similarity of overall treatment satisfaction and effectiveness scores and between-group difference in satisfaction with the utility of the self-injection device was useful information for real-world treatment of osteoporosis. Both medication regimens were well tolerated.

Influences of intratumoral heterogeneity on assessment of tumor microenvironment in esophageal squamous cell carcinoma.

The intratumoral heterogeneity (ITH) of the tumor microenvironment (TME) has yet to be addressed in esophageal squamous cell carcinoma (ESCC). Here, we studied the ITH of CD8 and PD-L1 status in ESCC, and examined the potential of the tumor surface for representing the TME. In total, 67 surgically resected clinical Stage II ESCC specimens were analyzed. The CD8-cell density, PD-L1 tumor proportion score (TPS), and combined positive score (CPS) were calculated in three (superficial, middle, and deep) areas of each specimen. ITH was quantified by distance-standardized coefficient variations of the three values. The CD8 and PD-L1 status of each area was dichotomized and tumor-surface capabilities for predicting the entire tumor status were estimated. Variables were compared according to the presence of neoadjuvant chemotherapy (NAC). The ITH, especially PD-L1 heterogeneity, differed markedly among specimens. The concordance rates of CD8 and PD-L1 (CPS and TPS) status among the three different areas were 71.6%, 74.6%, and 73.1%, respectively. The sensitivity and the specificity of the tumor surface for predicting the CD8 status of the whole tumor were high, especially in the NAC- group (both 1.0). The tumor surface also showed high capabilities for representing the whole PD-L1 status, while yielding moderate positive predictive values (0.70). The ITH degrees and predictive capabilities did not differ according to NAC. Taken together, the ITH of CD8 and PD-L1 differed among ESCC specimens, while not being markedly affected by NAC. The use of a biopsy specimen from the tumor surface might be feasible for TME evaluation.

Correlation of toxicities and efficacies of pemetrexed with clinical factors and single-nucleotide polymorphisms: a prospective observational study.

BACKGROUND: Pemetrexed is an efficacious multi-targeted antifolate with acceptable toxicity for non-squamous non-small cell lung cancer (non-Sq NSCLC) and malignant pleural mesothelioma. Vitamin B12 and folic acid as premedication can reduce the frequency of severe toxicities of pemetrexed chemotherapy. However, adverse effects are frequent in clinical settings. In this study, we aimed to identify the clinical factors and single-nucleotide polymorphisms (SNPs) associated with the toxicity and efficacy of pemetrexed chemotherapy. METHODS: This observational study was conducted from October 2012 to December 2019; we evaluated the toxicities and efficacies of pemetrexed chemotherapy using multivariate logistic or Cox regression analysis. In total, 106 patients received pemetrexed chemotherapy. SNPs were analyzed for four patients with malignant pleural mesothelioma and 67 with non-Sq NSCLC. RESULTS: The median progression-free survival (PFS) and overall survival of 63 patients with non-Sq NSCLC, excluding four in the adjuvant setting, were 6.8 and 33.3 months, respectively. Per propensity-score-adjusted multivariate Cox analyses, favorable factors for PFS were folic acid level ≥ 9.3 ng/mL before premedication, platinum combination, bevacizumab combination, vitamin B12 level < 1136 pg/mL before chemotherapy, A/A + A/G of BHMT (742 G > A), and A/A + A/C of DHFR (680 C > A). Favorable prognostic factors included good performance status, low smoking index, body mass index ≥ 20.66 kg/m2, folic acid level ≥ 5.55 ng/mL before premedication, higher retinol-binding protein before chemotherapy, and A/G of MTRR (66 A > G). Among the 71 patients who were analyzed for SNPs, the frequencies of hematologic toxicities and non-hematologic toxicities in Grades 3-4 were 38% and 36.6%, respectively. Per propensity-score-adjusted multivariate logistic analyses, risk factors for Grades 3-4 hematologic toxicities were vitamin B12 level < 486 pg/mL before premedication, leucocyte count < 6120 /µL before chemotherapy, folic acid level < 15.8 ng/mL before chemotherapy, status with a reduced dose of chemotherapy, and C/T + T/T of MTHFR (677 C > T). Risk factors for Grades 2-4 non-hematologic toxicities were homocysteine levels ≥ 11.8 nmol/mL before premedication, transthyretin level < 21.5 mg/dL before chemotherapy, C/C + T/T of MTHFR (677 C > T), and A/A + G/G of SLC19A1 [IVS2 (4935) G > A]. CONCLUSION: The information on metabolites and SNPs of the folate and methionine cycle will help predict the toxicities and efficacies of pemetrexed. TRIAL REGISTRATION: This trial was retrospectively registered with the University hospital Medical Information Network (UMIN000009366) on November 20, 2012.

Effect of Bone Resorption Inhibitors on Serum Cholesterol Level and Fracture Risk in Osteoporosis: Randomized Comparative Study Between Minodronic Acid and Raloxifene.

The positive link between osteoporosis and hypercholesterolemia has been documented, and bone resorption inhibitors, such as nitrogen-containing bisphosphonates (N-BP) and selective estrogen receptor modulators (SERMs), are known to reduce serum cholesterol levels. However, the relationship between the baseline cholesterol level and incident fracture rate under the treatment using the bone resorption inhibitors has not been documented. We investigated the relation between vertebral fracture incident and the baseline cholesterol levels and cholesterol-lowering effect of N-BP and SERM in osteoporosis through a prospective randomized open-label study design. Patients with osteoporosis (n = 3986) were allocated into two groups based on the drug used for treatment: minodronic acid (MIN) (n = 1624) as an N-BP and raloxifene (RLX) as an SERM (n = 1623). Serum levels of cholesterol and incidence of vertebral fracture were monitored for 2 years. The vertebral fracture rates between the two groups were compared using the pre-specified stratification factors. The patients receiving MIN with baseline low-density lipoprotein (LDL)-cholesterol level of ≥ 140 mg/dL, high-density lipoprotein cholesterol level < 40 mg/dL, age group of ≥ 75 years, and T score of BMD ≥ -3 SD had significantly lower vertebral fracture rates than those receiving RLX (incidence rate ratios (IRR) 0.45 [95% confidence interval (CI) 0.30 0.75, p = 0.001], 0.25 [95% CI 0.09 0.65, p = 0.005], 0.71 [95% CI 0.56 0.91, p = 0.006], 0.47 [95% CI 0.30 0.75, p = 0.0012], respectively). The cholesterol-lowering effect was stronger in the RLX group than in the MIN group, regardless of prior statin use. These results indicated that MIN treatment was more effective in reducing fracture risk in patients with higher LDL cholesterol levels, although its cholesterol-lowering ability was lesser than the RLX treatment.Trial registration University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR), No. UMIN000005433; date: April 13, 2011.

Predictors of Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients with Non-Dialysis-Dependent Chronic Kidney Disease (RADIANCE-CKD Study).

INTRODUCTION: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance during ESA administration would be very useful in deciding on a treatment plan. METHODS: Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post hoc sub-analysis of a randomized controlled trial. RESULTS: The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI: 0.711-0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status, and hypertensive retinopathy) with the largest χ2 statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634-0.799). To the six existing risk factors, five serum test items that affect anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI: 0.655-0.817), sufficient to predict ESA resistance. CONCLUSIONS: Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.

Comparative effectiveness of tocilizumab vs standard care in patients with severe COVID-19-related pneumonia: a retrospective cohort study utilizing registry data as a synthetic control.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. This study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan. METHODS: This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP), with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study's primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to the SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge. RESULTS: For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% confidence interval [CI]: 0.565-2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596-2.075), 0.628 (95% CI: 0.202-1.953), and 1.019 (95% CI: 0.555-1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582-1.230). CONCLUSIONS: Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistically significant differences in other clinical outcomes, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Efficacy of convalescent plasma therapy for COVID-19 in Japan: An open-label, randomized, controlled trial.

BACKGROUND: Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19). Despite its use for treating several viral infections, we lack comprehensive data on its efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a multicenter, open-label, randomized controlled trial of convalescent plasma therapy with high neutralizing activity against SARS-CoV-2 in high-risk patients within five days after the onset of COVID-19 symptoms. The primary endpoint was the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs from days 0-5. RESULTS: Between February 24, 2021, and November 30, 2021, 25 patients were randomly assigned to either convalescent plasma (n = 14) or standard of care (n = 11) groups. Four patients discontinued their allocated convalescent plasma, and 21 were included in the modified intention-to-treat analysis. The median interval between the symptom onset and plasma administration was 4.5 days (interquartile range, 3-5 days). The primary outcome of the time-weighted average change in the SARS-CoV-2 viral load in nasopharyngeal swabs did not significantly differ between days 0-5 (1.2 log10 copies/mL in the convalescent plasma vs. 1.2 log10 copies/mL in the standard of care (effect estimate, 0.0 [95% confidence interval, -0.8-0.7]; P = 0.94)). No deaths were observed in either group. CONCLUSIONS: The early administration of convalescent plasma with high neutralizing activity did not contribute to a decrease in the viral load within five days compared with the standard of care alone.

Enfortumab vedotin versus platinum rechallenge in post-platinum, post-pembrolizumab advanced urothelial carcinoma: A multicenter propensity score-matched study.

OBJECTIVE: Enfortumab vedotin (EV) was approved for advanced urothelial carcinoma (UC) in 2021 after the EV-301 trial showed its superiority to non-platinum-based chemotherapy as later-line treatment after platinum-based chemotherapy and immune checkpoint inhibitors including pembrolizumab. However, no study has compared EV with rechallenging platinum-based chemotherapy (i.e., "platinum rechallenge") in that setting. METHODS: In total, 283 patients received pembrolizumab for advanced UC after platinum-based chemotherapy between 2018 and 2023. Of them, 41 and 25 patients received EV and platinum rechallenge, respectively, as later-line treatment after pembrolizumab. After excluding two patients with EV without imaging evaluation, we compared oncological outcomes, including progression-free survival (PFS) and overall survival (OS), between the EV (n = 39) and platinum rechallenge groups (n = 25) using propensity score matching (PSM). RESULTS: Analyses on crude data (n = 64) showed no significant differences between the two groups regarding patients' baseline characteristics. PFS (5 months) and OS (11 months) in the EV group were comparable to those (8 and 12 months, respectively) in the platinum rechallenge group. After PSM (n = 36), the baseline characteristics between the two groups became more balanced, and PFS (not reached) and OS (not reached) in the EV group were comparable to those (8 and 11 months, respectively) in the platinum rechallenge group. CONCLUSIONS: EV and platinum rechallenge showed equivalent oncological outcomes, even after PSM, and both treatments should therefore be effective treatment options for post-platinum, post-pembrolizumab advanced UC.

Predictors of rituximab effect on modified Rodnan skin score in systemic sclerosis: a machine-learning analysis of the DesiReS trial.

OBJECTIVES: The double-blind, parallel-group comparison, investigators initiated phase II clinical trial of IDEC-C2B8 (Rituximab) in patients with Systemic sclerosis (DesiReS) trial showed that rituximab is effective in treating skin sclerosis in SSc. However, which patient groups are likely to benefit from rituximab is unknown. METHODS: We performed post-hoc analysis of prospective data from 54 patients who received rituximab or placebo in the DesiReS trial. Twenty-seven baseline factors were used to investigate subpopulations with different magnitudes of rituximab effect on modified Rodnan skin score (mRSS) change at 24 weeks. Based on a machine-learning algorithm called the causal tree, we explored the combination of predictors needed to identify subpopulations that would respond to rituximab and have good treatment outcomes. RESULTS: Three factors were identified as branches of the decision tree: peripheral blood CD19-positive cell counts', 'mRSS', and 'serum surfactant protein D (SP-D) levels'. It was only in the subpopulation of patients with CD19-positive cell counts of <57/µl that rituximab did not show a significant improvement in mRSS vs placebo. In the subpopulation of patients with CD19-positive cell counts of ≥57/µl and mRSS ≥ 17, mRSS was most improved with rituximab [difference -17.06 (95% CI: -24.22, -9.89)]. The second greatest improvement in mRSS with rituximab was in the subpopulation with CD19-positive cell counts of ≥57/µl, mRSS < 17, and serum SP-D levels of ≥151 ng/ml [difference -10.35 (95% CI: -14.77, -5.93)]. CONCLUSION: SSc patients who have high CD19-positive cell counts and high mRSS are expected to have greater improvement in mRSS with rituximab. When the patients with high CD19-positive cell counts show low mRSS, serum SP-D levels may modify the treatment effect. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04274257 and UMIN-CTR; https://center6.umin.ac.jp, UMIN000030139.

Branched chain amino acids in the treatment of polymyositis and dermatomyositis: a phase II/III, multi-centre, randomized controlled trial.

OBJECTIVES: To assess the efficacy and safety of branched chain amino acids (BCAAs) in the treatment of PM/DM prior to official approval of their use in Japan. METHODS: Treatment naïve adults with PM/DM were enrolled in a randomized, double-blind trial to receive either TK-98 (drug name of BCAAs) or placebo in addition to conventional treatment. After 12 weeks, patients with an average manual muscle test (MMT) score <9.5 were enrolled in an open label extension study for a further 12 weeks. The primary endpoint was the change of the MMT score at 12 weeks. The secondary endpoints were the clinical response and the change of functional index (FI). RESULTS: Forty-seven patients were randomized either to the TK-98 (n = 24) or placebo (n = 23) group. The changes of MMT scores at 12 weeks were 0.70 (0.19) [mean (s.e.m.)] and 0.69 (0.18), respectively (P = 0.98). Thirteen patients from the TK-98 group and 12 from the placebo group were enrolled in the extension study. The MMT scores in both groups improved similarly. The increase of the FI scores of the shoulder flexion at 12 weeks was significantly greater in the TK-98 group [27.9 (5.67) vs 12.8 (5.67) for the right shoulder flexion, and 27.0 (5.44) vs 13.4 (5.95) for the left shoulder; P < 0.05]. Frequencies of adverse events up to 12 weeks were similar. CONCLUSION: BCAAs showed no effect on the improvement of the muscle strength evaluated by MMT and the clinical response. However, they were partly effective for improving dynamic repetitive muscle functions. TRIAL REGISTRATION: UMIN-CTR Clinical Trial, https://center6.umin.ac.jp/, UMIN000016233.

Cardiovascular Complications of Hospitalized Patients With Coronavirus Disease 2019 in a Japanese Registry in 2020.

BACKGROUND: Cardiovascular complications of coronavirus disease 2019 (COVID-19) are critical for prognosis but have not been elucidated in Japan.Methods and Results:The COVID-19 Registry Japan, which included data from 19,853 individuals at the end of 2020, was analyzed. The incidences of cardiovascular complications were 0.098% for myocarditis/pericarditis/cardiomyopathy, 0.48% for ventricular tachycardia/fibrillation, 0.17% for myocardial ischemia, 0.062% for endocarditis, 0.59% for deep vein thrombosis, 0.19% for pulmonary embolism, and 0.37% for cerebral infarction/hemorrhage. Excluding endocarditis, all complications were associated with increased in-hospital mortality. CONCLUSIONS: Cardiovascular complications of COVID-19 were infrequent in Japan but were associated with poor prognosis.

Association of change in health-related quality of life and treatment discontinuation in metastatic breast cancer: a post hoc, exploratory analysis of two randomized clinical trials.

PURPOSE: Identifying factors associated with treatment alteration (treatment discontinuation and dose reduction) may help to attain the treatment goals for metastatic breast cancer. The value of changes in the quality of life (QOL) in predicting treatment alteration remained unclear. This study aimed to examine the relationship between changes in the QOL and treatment alteration of first-line chemotherapy for metastatic breast cancer. METHODS: We merged data from two randomized clinical trials in Japan, conducted from 2006 to 2017, that included patients who were diagnosed with human epidermal growth factor receptor 2-negative and endocrine treatment-resistant breast cancer, with metastatic disease at presentation or recurrence after surgery. The European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 was used to assess QOL. The association between change in time-dependent QOL (worsening by 10-point or not) and time to treatment alteration was assessed using the Cox regression models controlling for patient characteristics (age, liver metastasis, hormone status, and treatment regimen) and baseline QOL. RESULTS: Worsening physical functioning, global health status, and dyspnea were significantly associated with treatment discontinuation. Worsening role functioning, global health status, and fatigue were significantly associated with dose reduction. The threshold for defining worsening did not have a significant impact on the relationship. CONCLUSION: Changes in QOL are associated with the probability of treatment alteration among metastatic breast cancer patients. Physical functioning, role functioning, global health status, dyspnea, and fatigue should be prioritized for symptom management in patients with metastatic breast cancer.

Minimal important differences of EORTC QLQ-C30 for metastatic breast cancer patients: Results from a randomized clinical trial.

PURPOSE: To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. METHODS: The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. RESULTS: We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from - 7 to - 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from - 5 to - 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. CONCLUSION: We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30.

Combining nutritional status with TNM stage: a physiological update on gastric cancer staging for improving prognostic accuracy in elderly patients.

BACKGROUND: The tumor-node-metastasis (TNM) staging system does not take the patient's physiological status into consideration, reportedly making it insufficient for predicting survival outcomes in frail cancer patients. We assessed the prognostic values of several nutrition- and inflammation-based markers in combination with pTNM stage in gastric carcinoma (GC) patients. METHODS: In total, 1166 patients undergoing GC surgery were studied. The prognostic capabilities of 3 nutritional and 3 systemic inflammatory parameters were examined. We developed new staging systems by adding these markers, individually, to the pTNM stage. We then compared the prognostic capabilities of our new systems with that of pTNM stage alone. We also assessed the prognostic values of these systems by dividing our patient cohort into elderly (≥ 65 years) and non-elderly groups. RESULTS: Our novel staging systems had greater predictive capabilities for overall survival (OS) than pTNM alone. Most notably, survival discrimination was significantly increased for pTNM when it was combined with albumin-based nutritional indices (geriatric nutritional risk index (GNRI) and prognostic nutritional index (PNI)). Our new staging systems incorporating GNRI or PNI into pTNM had significantly better predictive capability for OS, especially non-GC mortality, than pTNM alone in elderly GC patients. In the non-elderly patients, the predictive capabilities of the new staging systems for OS differed minimally from that of pTNM. CONCLUSIONS: The predictive capability of pTNM stage was particularly enhanced when this parameter was combined with nutritional markers. Our new approach aids in predicting survival outcomes, especially non-GC-related death, in elderly GC patients.

Improved survival in real-world patients with advanced urothelial carcinoma: A multicenter propensity score-matched cohort study comparing a period before the introduction of pembrolizumab (2003-2011) and a more recent period (2016-2020).

OBJECTIVES: Although the treatment strategy for advanced urothelial carcinoma (aUC) has drastically changed since pembrolizumab was introduced in 2017, studies revealing current survival rates in aUC are lacking. This study aimed to assess (1) the improvement in survival among real-world patients with aUC after the introduction of pembrolizumab and (2) the direct survival-prolonging effect of pembrolizumab. METHODS: This multicenter retrospective study included 531 patients with aUC undergoing salvage chemotherapy, including 200 patients treated in the pre-pembrolizumab era (2003-2011; earlier era) and 331 patients treated in a recent 5-year period (2016-2020; recent era). Using propensity score matching (PSM), cancer-specific survival (CSS) and overall survival (OS) were compared between the earlier and recent eras, in addition to between the recent era, both with and without pembrolizumab use, and the earlier era. RESULTS: After PSM, the recent era cohort had significantly longer CSS (21 months) and OS (19 months) than the earlier era cohort (CSS and OS: 12 months). In secondary analyses using PSM, patients treated with pembrolizumab had significantly longer CSS (25 months) and OS (24 months) than those in the earlier era cohort (CSS and OS: 11 months), whereas patients who did not receive pembrolizumab in the recent era had similar outcomes (CSS and OS: 14 months) as the earlier era cohort (CSS and OS: 12 months). CONCLUSIONS: Patients with aUC treated in the recent era exhibited significantly longer survival than those treated before the introduction of pembrolizumab. The improved survival was primarily attributable to the use of pembrolizumab.

Clinical Epidemiology of Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan: Report of the COVID-19 Registry Japan.

BACKGROUND: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. METHODS: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. RESULTS: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. CONCLUSIONS: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.