Inhibition of QDPR synergistically modulates intracellular tetrahydrobiopterin profiles in cooperation with methotrexate.

Tetrahydrobiopterin (BH4) is an essential cofactor for dopamine and serotonin synthesis in monoaminergic neurons, phenylalanine metabolism in hepatocytes, and nitric oxide synthesis in endothelial and immune cells. BH4 is consumed as a cofactor or is readily oxidized by autooxidation. Quinonoid dihydropteridine reductase (QDPR) is an enzyme that reduces quinonoid dihydrobiopterin (qBH2) back to BH4, and we have previously demonstrated the significance of QDPR in maintaining BH4 in vivo using Qdpr-KO mice. In addition to the levels of BH4 in the cells, the ratios of oxidized to reduced forms of BH4 are supposed to be important for regulating nitric oxide synthase (NOS) via the so-called uncoupling of NOS. However, previous studies were limited due to the absence of specific and high-affinity inhibitors against QDPR. Here, we performed a high-throughput screening for a QDPR inhibitor and identified Compound 9b with an IC50 of 0.72 µM. To understand the inhibition mechanism, we performed kinetic analyses and molecular dynamics simulations. Treatment with 9b combined with methotrexate (MTX), an inhibitor of another BH4-reducing enzyme, dihydrofolate reductase (DHFR), significantly oxidized intracellular redox states in HepG2, Jurkat, SH-SY5Y, and PC12D cells. Collectively, these findings suggest that 9b may enhance the anticancer and anti-autoimmune effects of MTX.

Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice.

Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy.

How patients with dementia influence caregiver burden using the Dementia Assessment Sheet for Community-based Integrated Care System-21 items (DASC-21) and Zarit Caregiver Burden Interview (ZBI).

BACKGROUND: Dementia is a disease that is frequently associated with significant caregiving burden. The present study was conducted on patients with dementia in order to investigate the causes of caregiver burden using the Dementia Assessment Sheet for Community-based Integrated Care System-21 items (DASC-21) and Zarit Caregiver Burden Interview (ZBI). METHODS: The study subjects consisted of 206 elderly patients (mean age: 80.9 ± 5.9 years) with dementia in an outpatient clinic. Current age, gender, type of dementia, Mini-Mental State Examination, Hasegawa Dementia Scale-Revised, Clinical Dementia Rating (CDR), Geriatric Depression Scale (GDS) and the DASC-21 were investigated. Caregiver burden was assessed by using the ZBI. Behavioural and Psychological Symptom of Dementia (BPSD) were evaluated by using the Neuropsychiatric Inventory (NPI). Simple regression analysis for the ZBI was performed with respective risk factors as independent variables. Thereafter, multiple regression analysis was performed. RESULTS: The mean ZBI score was 28.0 ± 18.1, whereas mean DASC-21 score was 44.4 ± 13.2. Simple regression analysis for the ZBI was performed with respective risk factors as independent variables. The DASC-21 (P < 0.001), CDR (P < 0.001), NPI (P < 0.001), and GDS (P = 0.034) were significantly associated with the ZBI. For each item of the DASC-21, Memory (P < 0.001), Orientation (P < 0.001), Solving issues/Common sense (P < 0.001), Instrumental activities of daily living (IADL) outside the home (P < 0.001), IADL inside the home (P < 0.001), Physical ADL① (P < 0.001) and Physical ADL② (P = 0.014) were also significantly associated with the ZBI. To find the independent association of the ZBI, multiple regression analysis was performed. The results showed that DASC-21 (P < 0.001) and NPI (P < 0.001) had significant correlation. For each item of the DASC-21, Memory (P = 0.014) and Solving issues/Common sense (P < 0.001) were also shown to have significant correlation. CONCLUSIONS: Both BPSD, cognition and IADL have affected caregiver burden. The DASC-21 is useful for determining the causes of caregiver burden of dementia patients.

Impact of immunophenotypic characteristics on genetic subgrouping in childhood acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) study L04-16.

Immunophenotyping was performed in 1044 consecutive childhood acute lymphoblastic leukemia (ALL) patients enrolled in the Tokyo Children's Cancer Study Group L04-16 trial, revealing novel findings associated with genetic abnormalities. In addition to TCF3-PBX1 and MEF2D fusions, the CD10(+) subtype of KMT2A-MLLT3-positive ALL frequently exhibited the cytoplasmic-µ(+) pre-B ALL immunophenotype. Although ETV6-RUNX1 was significantly correlated with myeloid antigen expression, more than half of patients expressed neither CD33 nor CD13, while the CD27(+) /CD44(-) immunophenotype was maintained. Expression of CD117 and CD56 in B-cell precursor-ALL was limited to certain subtypes including ETV6-RUNX1 and KMT2A-MLLT3. Besides BCR-ABL1, CRLF2, hyperdiploidy, and hypodiploidy, CD66c was also expressed in Ph-like kinase fusion-, PAX5 fusion-, and DUX4 fusion-positive ALL, but not in MEF2D fusion-positive ALL, indicating constant selectivity of CD66c expression. In T-ALL, SIL-TAL1-positive patients were likely to exhibit a more mature immunophenotype. Expression of CD21 and CD10 was not rare in T-ALL, while lack of CD28 was an additional feature of early T-cell precursor-ALL. Considering the immunophenotype as a prognostic maker, MEF2D fusion-positive ALL with CD5 expression may be associated with a poorer prognosis in comparison with those lacking CD5 expression. In cases with characteristic marker expression, the presence of certain fusion transcripts could be predicted accurately.

Electrocardiogram abnormalities in residents in cold homes: a cross-sectional analysis of the nationwide Smart Wellness Housing survey in Japan.

BACKGROUND: Excess winter mortality caused by cardiovascular disease is particularly profound in cold houses. Consistent with this, accumulating evidence indicates that low indoor temperatures at home increase blood pressure. However, it remains unclear whether low indoor temperatures affect other cardiovascular biomarkers. In its latest list of priority medical devices for management of cardiovascular diseases, the World Health Organization (WHO) included electrocardiography systems as capital medical devices. We therefore examined the association between indoor temperature and electrocardiogram findings. METHODS: We collected electrocardiogram data from 1480 participants during health checkups. We also measured the indoor temperature in the living room and bedroom for 2 weeks in winter, and divided participants into those living in warm houses (average exposure temperature ≥ 18 °C), slightly cold houses (12-18 °C), and cold houses (< 12 °C) in accordance with guidelines issued by the WHO and United Kingdom. The association between indoor temperature (warm vs. slightly cold vs. cold houses) and electrocardiogram findings was analyzed using multivariate logistic regression models, with adjustment for confounders such as demographics (e.g., age, sex, body mass index, household income), lifestyle (e.g., eating habit, exercise, smoking, alcohol drinking), and region. RESULTS: The average temperature at home was 14.7 °C, and 238, 924, and 318 participants lived in warm, slightly cold, and cold houses, respectively. Electrocardiogram abnormalities were observed in 17.6%, 25.4%, and 30.2% of participants living in warm, slightly cold, and cold houses, respectively (p = 0.003, chi-squared test). Compared to participants living in warm houses, the odds ratio of having electrocardiogram abnormalities was 1.79 (95% confidence interval: 1.14-2.81, p = 0.011) for those living in slightly cold houses and 2.18 (95% confidence interval: 1.27-3.75, p = 0.005) for those living in cold houses. CONCLUSIONS: In addition to blood pressure, living in cold houses may have adverse effects on electrocardiogram. Conversely, keeping the indoor thermal environment within an appropriate range through a combination of living in highly thermal insulated houses and appropriate use of heating devices may contribute to good cardiovascular health. TRIAL REGISTRATION: The trial was retrospectively registered on 27 Dec 2017 to the University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR, https://www.umin.ac.jp/ctr/ , registration identifier number UMIN000030601 ).

Disparities of indoor temperature in winter: A cross-sectional analysis of the Nationwide Smart Wellness Housing Survey in Japan.

The WHO Housing and health guidelines recommend a minimum indoor temperature of 18°C to prevent cold-related diseases. In Japan, indoor temperatures appear lower than in Euro-American countries because of low insulation standards and use of partial intermittent heating. This study investigated the actual status of indoor temperatures in Japan and the common characteristics of residents who live in cold homes. We conducted a nationwide real-world survey on indoor temperature for 2 weeks in winter. Cross-sectional analyses involving 2190 houses showed that average living room, changing room, and bedroom temperatures were 16.8°C, 13.0°C, and 12.8°C, respectively. Comparison of average living room temperature between prefectures revealed a maximum difference of 6.7°C (Hokkaido: 19.8°C, Kagawa: 13.1°C). Compared to the high-income group, the odds ratio for living room temperature falling below 18°C was 1.38 (95% CI: 1.04-1.84) and 2.07 (95% CI: 1.28-3.33) for the middle- and low-income groups. The odds ratio was 1.96 (95% CI: 1.19-3.22) for single-person households, compared to households living with housemates. Furthermore, lower room temperature was correlated with local heating device use and a larger amount of clothes. These results will be useful in the development of prevention strategies for residents who live in cold homes.

Participants in a randomized controlled trial had longer overall survival than non-participants: a prospective cohort study.

PURPOSE: While some studies show improved outcomes in clinical trial participants as compared to non-participants, existence of such a trial effect has not been proved precisely. METHODS: This was a prospective cohort study to compare the prognoses for participants in the randomized controlled trial (SELECT BC) and non-participants. SELECT BC compared S-1 and taxane as first-line treatment for metastatic breast cancer. Non-participants were all patients who met the eligibility criteria of SELECT BC and who had been requested to participate in that trial by attending doctors and declined. The study aimed to compare the prognoses between participants and non-participants. The primary endpoint was median overall survival. RESULTS: The median OS in participants was significantly superior to that in non-participants with a statistically significant difference (36.8 months vs. 25.2 months. HR 1.48, p = 0.022). A similar result was obtained when only patients who received the same chemotherapy (S-1 or taxane) used in SELECT BC after declining participation were assumed as non-participants (36.8 months vs. 22.0 months. HR 2.03, p = 0.006). CONCLUSIONS: This study may suggest the existence of a trial effect, in which, for a given treatment, participation in a clinical trial is associated with a better outcome.

Efficacy of intermittent empagliflozin supplementation on dietary self-management and glycaemic control in patients with poorly controlled type 2 diabetes: A 24-week randomized controlled trial.

AIMS: To explore the effects of intermittent use of empagliflozin, a sodium-glucose co-transporter-2 inhibitor, on dietary self-management and glycaemic control in patients with inadequately controlled type 2 diabetes. MATERIALS AND METHODS: We conducted a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial of 50 patients with type 2 diabetes, treated with no more than three oral antidiabetic drugs (glycated haemoglobin [HbA1c] ≥52 mmol/mol but <86 mmol/mol). The participants were randomized to take 10 mg/d empagliflozin either every day (regular group, n = 25) or on the day on which they considered they had overeaten (intermittent group, n = 25) for 24 weeks. We limited empagliflozin prescription to half of the required period in the intermittent group. The primary endpoint was change in HbA1c at the end of the 24-week treatment period relative to baseline. The secondary outcomes included changes in body weight, daily energy intake and diabetes treatment-related quality of life (QoL). Energy intake was assessed using a diet-specific validated questionnaire rather than actual assessments of food intake. RESULTS: The intake rate of empagliflozin was 96.7 ± 7.2% for the regular group and 45.7 ± 7.0% for the intermittent group. Interestingly, ΔHbA1c was identical in the two groups (-0.64 ± 0.19% and - 0.65 ± 0.17%, respectively). Body weight decreased (-2.72 ± 0.52 and - 1.50 ± 0.45 kg, respectively) and diabetes treatment-related QoL increased significantly from baseline in both groups. Energy intake, however, decreased significantly only in the intermittent group (-221.0 ± 108.3 kcal/d). CONCLUSIONS: Intermittent empagliflozin supplementation is a useful therapeutic option that empowers dietary self-management, improves glycaemic control and is accompanied by body weight loss and an increase in diabetes treatment-related QoL in patients with inadequately controlled type 2 diabetes.

Dementia Cafés as Hubs to Promote Community-Integrated Care for Dementia through Enhancement of the Competence of Citizen Volunteer Staff Using a New Assessment Tool.

INTRODUCTION: Dementia cafés have recently been attracting attention. The increased involvement of citizen volunteers and the competence of dementia café staff could enhance the potential of dementia cafés. The aim of the present study was to examine enhancement of the competence of citizen volunteers using a new assessment tool. METHODS: This cross-sectional analysis included 433 dementia café staff members, including medical and care professionals and citizen volunteers. A 20-item dementia café staff self-assessment (DCSA) instrument was newly developed. After confirmation of the reliability and validity of the instrument, DCSA scores among citizen volunteers were evaluated. RESULTS: DCSA showed very good psychometric properties. The mean (±SD) DCSA score was significantly higher for café staff with a medical and care professional background (n = 267) than for citizen volunteers (n = 166) (2.2±0.5 vs. 1.7±0.7, respectively; p < 0.001). The DCSA scores of citizen volunteers became significantly higher with increasing attendance (minimum: n = 24; 1.3±0.7; intermediate: n = 65; 1.6±0.6; and frequent: n = 77; 1.8±0.7; p < 0.01). CONCLUSION: Assessment of the competence of dementia café staff using the DCSA revealed the potential of citizen volunteers. This tool could also enhance the potential of dementia cafés.

A case of idiopathic normal pressure hydrocephalus in an elder diabetic patient.

The clinical entity idiopathic normal pressure hydrocephalus (iNPH) is characterized by dementia, urinary incontinence, gait ataxia. An 80-year old man with a past history of Type 2 diabetes mellitus admitted to our hospital. Combination of twice Aspart and Aspart premixed30/70 insulin were used. Although, he was unable to inject insulin by himself recently. On physical examination, he walked in a mildly wide based manner. According to his family, urinary incontinence was existed. Laboratory data were as follows: Postrandial blood glucose 243 mg/dl and glycated hemoglobin 8.0% (NGSP). Brain magnetic resonance imaging (MRI) scans showed thinning of the corpus callosum with enlargement of the lateral ventricles on a colonal image. Evan's ratio was 0.29. The revised version of Hasegawa's Dementia scale (HDS-R) was 10. The patient showed no evidence a related antecedent event, such as head trauma, intracerebral hemorrhage and meningitis. Thus, he was diagnosed as having possible Idiopathic normal pressure hydrocephalus (iNPH). The following several psychological tests and walking test were applied. Before and after the tap, he was evaluated using the HDS-R, Mini mental state examination (MMSE), Timed Up and Go test (TUG). Insulin was replaced by glargine, and Sitagliptin was added. On the 31 day, the patient underwent Ventriculo-perioneal shunt. Laboratoly data and memory impairment were also improved. 8 month's later, HbA1c was 7.5%. iNPH occurs in the elderly and is characterized by a clinical triad of gait disturbance, urinary incontinence and dementia. In the present case, thinning of the corpus callosum with enlargement of the lateral ventricles was detected by MRI. 49% of iNPH patients had Diabetes mellitus. However, we were unable to detect a relationship iNPH and Diabetes mellitus. Cognitive impairment may interfere with the insulin therapy. In the present case, failure of insulin self-injection was the first clinical sign to appear. We were able to reduce dose of insulin. We conclude that iNPH is a treatable disorder, especially when treatment is started early in the course of the disease.

[Efficacy of supportive care for albumin-bound paclitaxel(nab-paclitaxel)in 20 patients with metastatic breast cancer].

PURPOSE: The objective of this retrospective study was to evaluate the efficacy of albumin-bound paclitaxel(nab-paclitaxel) treatment and the required supportive care for severe adverse events. METHODS: A total of 20 patients with advanced or recurrent breast cancer received nab-paclitaxel every 3 weeks between February 1, 2011 and December 31, 2012. The treatment course was repeated for 6 cycles thereafter, until evidence of disease progression or unacceptable toxicity was noted. RESULTS: The median number of treatment cycles was 6.0(range 2-6), the median cumulative dose was 1,560(range 440- 1,560)mg/m / / 2, and the median delivered dose intensity was 82.3(range 65.0-86.7)mg/m2week. Primary chemotherapy was associated with higher response rates than second-line or subsequent chemotherapy(42.9% v 23.1%). The response rate was 26.7% for cases with taxane pretreatment. Adverse events included neutropenia in 15 cases(75%), of Grade 4 severity in 4 cases(20%), and febrile neutropenia after 1 cycle in 1 patient(5%). In addition, Grade 3 peripheral neuropathy was observed in 2 cases(10%)during the treatment period. CONCLUSION: Nab-paclitaxel therapy was efficacious as primary chemotherapy and was effective for patients pretreated with taxanes. To prevent severe adverse events, supportive care is important, primarily for febrile neutropenia and neuropathy.

Clinical characteristics of older patients with suspected or diagnosed dementia during hospitalization.

AIM: In Japan, an additional system for patients with suspected or diagnosed dementia during hospitalization for physical illness began in 2016. We examined the clinical characteristics of older patients with suspected or diagnosed dementia during hospitalization. METHODS: The study participants consisted of 569 patients. Current age, sex, comorbidities, causative disease for admission, body mass index (BMI), blood tests, environment before admission, prescription history before admission and rate of delirium were examined. Simple regression analysis for high-frequency diseases was carried out with the respective risk factors as independent variables. Multiple regression analysis was then carried out. RESULTS: Infection had the highest frequency in the causative diseases for admission. A total of 48% of patients had delirium during hospitalization. The delirium group had the highest frequency of being at home. In the infection group, BMI and serum albumin were lower in the non-infection group (BMI 19.0 ± 3.7 vs 20.4 ± 4.1; P < 0.001, albumin 2.1 ± 0.7 vs 3.3 ± 0.6 g/dL; P < 0.001 respectively). White blood cell count and C-reactive protein were higher than in the non-infection group, respectively (white blood cell count 11181.4 ± 6533.3 vs 8765.8 ± 111 424.3/µL; P = 0.007, C-reactive protein 8.6 ± 8.6 vs 3.0 ± 5.2 mg/dL; P < 0.001 respectively). Using independent factors associated with infection, multiple regression analysis was performed. BMI (P = 0.013), serum albumin (P < 0.001) and nursing home care before admission (P < 0.001) had significant correlations. CONCLUSIONS: Assessment of delirium and the environment before admission of older patients with suspected or diagnosed dementia when hospitalized are necessary. Furthermore, evaluation of nutrition might also contribute to reducing deterioration due to physical illness. Geriatr Gerontol Int 2024; 24: 641-645.

Characteristics of Changes in Caregiver Burden during Follow-up at a Memory Clinic: A Retrospective Cohort Study.

Background: Because dementia is a long-term condition, the appropriate involvement of health-care professionals is considered important. However, little is known about the factors associated with changes in family caregiver burden. Objective: To clarify changes in family caregiver burden and associated factors during follow-up at a memory clinic. Methods: A retrospective cohort study was conducted, enrolling 495 pairs of patients with dementia or mild cognitive impairment and their family caregivers. A total of 120 pairs completed the second evaluation. The caregiver burden was assessed using the Zarit Burden Interview (ZBI). Data at the initial visit and after an average follow-up of about 2 years were compared and analyzed. Results: At initial visit, the patients' mean age, Mini-Mental State Examination (MMSE) and ZBI scores were 78.6±5.6 years, 23.3±3.5, and 22.6±16.7, respectively. At follow-up, MMSE scores decreased (21.4±4.5, p < 0.001), but ZBI scores remained similar (22.5±13.6). When the difference in ZBI scores between the two time points was defined as ΔZBI, and the related factors were analyzed by multiple regression analysis, ZBI scores at the initial visit, start of psychotropic drug, and decrease of neuropsychiatric symptoms were identified as significant factors (p < 0.001, p = 0.003, p < 0.001, respectively). A significant negative correlation was found between ZBI scores at the initial visit and ΔZBI (r = -0.588, p < 0.001). Conclusions: These findings suggest the importance of assessing changes in the burden experienced by family caregivers during the disease follow-up.

An experimental verification of fungal overgrowth in temporary houses at the site of the Great East Japan Earthquake.

Fungal contamination in the indoor air of prefabricated temporary houses at the site of the Great East Japan Earthquake revealed extremely high levels compared to those found in conventional residences. We experimentally investigated fungal growth levels on different interior materials to support fungal overgrowth in prefabricated temporary houses. Three species each of allergenic fungi and invasive fungi observed in temporary housing were selected for inoculation tests with various interior materials. The experiments with fungal inoculation were conducted in conformance with standards for industrial products described in the Japanese" JIS Z 2911:2018 Methods of test for fungus resistance" with small modifications. After incubation, visual and stereomicroscopic assessments were performed to determine fungal growth levels. The viability of the fungi varied according to the interior material type. Our findings demonstrate the importance of antifungal measures in indoor environments and the need for additional research on the growth levels of fungal species on various interior materials.

Spatial and temporal indoor temperature differences at home and perceived coldness in winter: A cross-sectional analysis of the nationwide Smart Wellness Housing survey in Japan.

Residents themselves are responsible for controlling their living environment, and their perception of coldness is important to protect their health. Although previous studies examined the association between perceived coldness and indoor temperature, they did not consider the spatial-temporal differences in indoor temperatures. This study, conducted in Japan, measured indoor temperatures in 1,553 houses across several rooms (living room, changing room, and bedroom) and heights (at 1 m above the floor and near the floor) over two weeks and obtained the perceived coldness from 2,793 participants during winter. Results showed substantial temperature differences between rooms (horizontal differences): 3.8 °C between living and changing rooms, and 4.1 °C between living rooms and bedrooms. The average vertical and diel (evening-morning) temperature differences in the living room were 3.1 °C and 3.0 °C, respectively. Regional analysis revealed that the Tohoku region experienced larger horizontal and diel indoor temperature differences, primarily due to its practice of intermittent and partial heating in living rooms only, in contrast to Hokkaido's approach of heating the entire house continuously. Despite Hokkaido's comprehensive heating system, it exhibited the largest vertical temperature difference of 5.1 °C in living rooms, highlighting the insufficiency of heating alone and the necessity for enhanced thermal insulation. The multivariate logistic regression analyses showed that average temperatures and vertical temperature differences were associated with perceived coldness, while horizontal and diel differences did not show a significant association, further emphasizing the importance of improved thermal insulation. Moreover, factors like individual attributes (age and gender), and lifestyle choices (meal quantity, exercise habits, alcohol consumption, and clothing amount) were significantly associated with coldness perception. Notably, older adults were less likely to perceive coldness but more vulnerable to the health impacts of low temperatures, underscoring the necessity of not solely relying on human perception for indoor temperature management to protect cold-related health problems.

Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study.

BACKGROUND: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice. METHODS: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival. RESULTS: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively. CONCLUSION: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice.