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Background and Aims: There was no previous trial comparing aspirin monotherapy with a P2Y12 inhibitor monotherapy following short dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents., Methods: In the STOPDAPT-3, patients with acute coronary syndrome or high bleeding risk (HBR) were randomly assigned to either 1-month dual antiplatelet therapy with aspirin and prasugrel followed by aspirin monotherapy (aspirin group) or 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group). This secondary analysis compared aspirin monotherapy with clopidogrel monotherapy by the 30-day landmark analysis. The co-primary endpoints were the cardiovascular endpoint defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischaemic stroke and the bleeding endpoint defined as Bleeding Academic Research Consortium 3 or 5., Results: Of the 6002 assigned patients, 5833 patients (aspirin group: N = 2920 and clopidogrel group: N = 2913) were included in the 30-day landmark analysis. Median age was 73 (interquartile range 64-80) years, women 23.4%, acute coronary syndrome 74.6%, and high bleeding risk 54.1%. The assigned monotherapy was continued at 1 year in 87.5% and 87.2% in the aspirin and clopidogrel groups, respectively. The incidence rates beyond 30 days and up to 1 year were similar between the aspirin and clopidogrel groups for both cardiovascular endpoint [4.5 and 4.5 per 100 person-year, hazard ratio 1.00 (95% confidence interval .77-1.30), P = .97], and bleeding endpoint [2.0 and 1.9, hazard ratio 1.02 (95% confidence interval .69-1.52), P = .92]., Conclusions: Aspirin monotherapy compared with clopidogrel monotherapy was associated with similar cardiovascular and bleeding outcomes beyond 1 month and up to 1 year after percutaneous coronary intervention with drug-eluting stents (STOPDAPT-3 ClinicalTrials.gov number, NCT04609111)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Guideline-directed medical therapy (GDMT) is essential to prevent future cardiovascular events in chronic coronary syndrome (CCS) patients. However, whether achieving optimal GDMT could improve clinical outcomes in CCS patients with deferred lesions based on fraction flow reserve (FFR) remains thoroughly investigated. We sought to evaluate the association of GDMT adherence with long-term outcomes after FFR-based deferral of revascularization in a real-world registry., Methods and Results: This is a post-hoc analysis of the J-CONFIRM registry (long-term outcomes of Japanese patients with deferral of coronary intervention based on fractional flow reserve in multicentre registry). Optimal GDMT was defined as combining four types of medications: antiplatelet drug, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, beta-blocker, and statin. After stratifying patients by the number of individual GDMT agents at 2 years, landmark analysis was conducted to assess the relationship between GDMT adherence at 2 years and 5-year major adverse cardiac events (MACEs), defined as a composite of all-cause death, target vessel-related myocardial infarction, clinically driven target vessel revascularization. Compared with the suboptimal GDMT group (continuing ≤3 types of medications, n = 974), the optimal GDMT group (n = 139) showed a lower 5-year incidence of MACE (5.2% vs. 12.4%, P = 0.02). The optimal GDMT was associated with a lower risk of MACE (hazard ratio: 0.41; 95% confidence interval: 0.18 to 0.92; P = 0.03)., Conclusion: Patients with optimal GDMT were associated with better outcomes, suggesting the importance of achieving optimal GDMT on long-term prognosis in CCS patients after FFR-guided deferral of revascularization., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The association between guideline adherence and long-term outcomes in patients with acute myocardial infarction in real-world clinical practice remains unclear., Methods: We investigated 3283 consecutive patients with acute myocardial infarction who were selected from a prospective, nation-wide, multicentre registry (J-MINUET) database covering 28 institutions in Japan between July 2012 and March 2014. Among the 2757 eligible patients, we evaluated the use of seven guideline-recommended therapies, including urgent revascularisation, door-to-balloon time of 90 minutes or less, and five discharge medications (P2Y12 inhibitors on aspirin, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins, lipid-lowering drugs). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, cardiac failure and urgent revascularisation for unstable angina up to 3 years., Results: The overall median composite guideline adherence was 85.7%. Patients were divided into the following three groups: complete (100%) adherence group ( n =862); moderate adherence (75% to <100%) group ( n =911); and low adherence (0-75%) group ( n =984). The rate of adverse cardiovascular events was significantly lower in the complete adherence group than in the low and moderate adherence groups (log rank P <0.0001). Multivariate Cox regression analysis showed complete guideline adherence was also significantly associated with lower adverse cardiovascular events compared with low guideline adherence (hazard ratio 0.66; 95% confidence interval 0.52-0.85; P =0.001)., Conclusion: The use of guideline-based therapies for patients with acute myocardial infarction in contemporary clinical practice was associated with significant decreases in adverse long-term clinical outcomes., Trial Registration: UMIN Unique trial Number: UMIN000010037.

Aims: Living alone is reported as an independent risk factor for cardiovascular disease. However, little is known about the association between clinical outcomes and living alone in patients with acute coronary syndrome (ACS). The aim of this study was to determine whether living alone is an independent prognostic risk factor for long-term mortality stratified by age in patients with ACS who were treated with primary percutaneous coronary intervention (PCI)., Methods and Results: We conducted an observational cohort study of ACS patients who underwent PCI between January 1999 and May 2015 at Juntendo University Shizuoka Hospital, Japan. The primary endpoint was all-cause death. Among 2547 ACS patients, 381 (15.0%) patients were living alone at the onset of ACS. The cumulative incidence of all-cause death was comparable between living alone and living together (34.8% vs. 34.4%, log-rank P = 0.63). However, among younger population (aged <65 years), the incidence of all-cause death was significantly higher in the living alone group (log-rank P = 0.01). Multivariate Cox hazard analysis revealed a significant association between living alone and all-cause death, even after adjusting for other risk factors (hazard ratio 2.30, 95% confidence interval 1.38-3.84, P = 0.001)., Conclusion: Although living alone was not significantly associated with long-term clinical outcomes in patients with ACS, it was a predictive risk factor among younger ACS patients. Careful attention should be paid to patients' lifestyle, especially younger patients with ACS., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Objectives: We aimed to compare the dose constraints fulfillment rate of the three-dimensional conformal radiotherapy treatment plan before and after a hydrogel spacer insertion., Methods: The planning computed tomography scans of 39 patients who received stereotactic body radiotherapy for prostate cancer were used. All patients inserted a hydrogel spacer and underwent computed tomography scans before and after spacer insertion. The three-dimensional conformal radiotherapy plans according to NCCN classification, low-, intermediate- and high-risk, were made for each patient. Clinical target volume included prostate and seminal vesicle 2 cm for high risk, prostate and seminal vesicle 1 cm for intermediate risk and prostate only for low risk. Three-dimensional conformal radiotherapy including a seven-field conformal technique with 76 Gy in 38 fractions. Dose constraints for rectum and bladder were V70 Gy ≤ 15%, V65 Gy ≤ 30% and V40 Gy ≤ 60%., Results: Among 39 patients, 35 (90%), 19 (49%) and 13 (33%) and 38 (97%), 38 (97%) and 34 (87%) patients before and after the spacer insertion fulfilled rectum dose constraints for low-, intermediate- and high-risk plans, respectively. A hydrogel spacer significantly reduced rectum dose and improved the rectum dose constraints fulfillment rate in intermediate (P < 0.01) and high (P < 0.01), but no difference was found in low-risk plan (P = 0.25). On multivariate analysis, spacer use was associated with the higher rectum dose constraints fulfillment rate., Conclusions: A hydrogel spacer reduced rectum dose and improved the dose constraints fulfillment rate in three-dimensional conformal radiotherapy plan. Although IMRT is the standard treatment, 3D-CRT using a hydrogel spacer may be a treatment option., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To clarify the efficacy of palliative radiotherapy for the relief of symptoms due to skin invasion in patients with breast cancer., Materials and Methods: We conducted a multi-institutional prospective observational study of patients who received palliative radiotherapy for skin invasion due to a primary lesion or chest wall recurrence. Bleeding/discharge, offensive odor, pain and QOL scores were evaluated before and 1, 3 and 6 months after radiotherapy., Results: Twenty-one patients were assessed. Sixteen patients (76%) received 36 Gy in 12 fractions. The mean (±1 SD) score of bleeding/discharge was 1.90 ± 0.89 before radiotherapy, 1.50 ± 0.74 at 1 month, 0.47 ± 0.58 at 3 months, and 0.82 ± 1.04 at 6 months (P = 0.001). The mean score of offensive odor was 1.21 ± 1.38 before radiotherapy, 0.71 ± 0.92 at 1 month, 0.20 ± 0.41 at 3 months, and 0.27 ± 0.62 at 6 months (P = 0.008). The mean score of pain was 2.90 ± 1.22 before radiotherapy, 3.05 ± 1.36 at 1 month, 3.29 ± 1.10 at 3 months, and 3.31 ± 1.54 at 6 months (P = 0.431). The mean total score of QOL-ACD/QOL-ACD-B was 126.2 ± 24.5 before radiotherapy, 130.3 ± 26.3 at 1 month, 136.2 ± 26.6 at 3 months, and 126.6 ± 32.8 at 6 months (P = 0.178)., Conclusion: Palliative radiotherapy for skin invasion in patients with breast cancer might be effective, especially for the relief of bleeding/discharge and offensive odor.

Background: The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy (WBRT) was previously reported to significantly increase skin water content (WC) and help improve skin dryness and desquamation. The prospective open-label, randomized trial included an exploratory arm to investigate the preventive efficacy of heparinoid moisturizer for acute radiation dermatitis (ARD)., Methods: Between April 2011 and April 2013, patients receiving WBRT were assigned (1:2:2) to receive either: moisturizer for prophylaxis (group P), moisturizer starting 2 weeks after WBRT for treatment (group M), and no moisturizer (group C). This paper presents the results of comparison between the exploratory arm and no moisturizer group. Skin WC was measured prior to WBRT, on the last day of WBRT, and 2 weeks, 4 weeks and 3 months following WBRT. Signs and symptoms were also assessed., Results: Comparing two groups, WC values were significantly higher in group P until 4 weeks following WBRT. At 2 weeks following WBRT, mean WC values in group P and C were 38.5 ± 6.1 arbitrary units (a.u.) and 30.2 ± 7.8 a.u., respectively (P < 0.001). In group C, dryness was more severe at 2 and 4 weeks following WBRT and desquamation more severe until 3 months following WBRT. However, the erythema score showed no difference between the two groups. Regarding symptoms, group C pain scores on the last day of WBRT were significantly higher than in group P (P < 0.030)., Conclusions: The preventive application of heparinoid moisturizer has the potential of reducing skin desquamation and dryness in patients receiving WBRT.

Some patients undergoing breast reconstruction require post-mastectomy radiation therapy, but the metallic ports used in temporary tissue expanders attenuate the X-rays. In this study, we evaluated by the film method, the attenuation of 4 MV and 6 MV X-rays after passing through a metallic port, with the aim of identifying a useful method for determining the appropriate density to use in the radiation treatment planning system (RTPS), taking into account the distance between the metallic port and the targets. Radiochromic film was used to measure depth doses after the X-rays passed through the metallic port. The physical density allotted to the metal port portion was varied on the RTPS within the range 1-16 g/cm3, and the physical density values were calculated that best reproduced the depth-dose distribution extrapolated from the film method. When the metallic port was orientated perpendicularly, the attenuation of the X-rays peaked at ~7% at both 4 MV and 6 MV. In the parallel orientation, the X-rays were attenuated by up to ~40% at 4 MV and by up to ~30% at 6 MV. We estimated the optimum physical density to be 9.8 g/cm3, which yielded the best fit with the actual measurements. We demonstrated the most likely range for the target depth from the CT images of actual patients and, within this range, we identified the optimum physical density at which the measured and calculated values were most consistent with each other.

The purpose of this study was to examine the prognosis for patients with head and neck cancer after reirradiation using Cyberknife stereotactic body irradiation with special focus on mucosal ulceration. We conducted a retrospective multi-institutional review of 107 patients with previously irradiated head and neck cancer. The median follow-up time for all patients was 15 months, and the 2-year overall survival rate was 35%. Significant prognostic factors for overall survival were primary site (nasopharynx versus other sites), presence of ulceration, and PTV volume. Detailed analysis of ulceration showed a lower response rate (28%) in the ulceration (+) group than the ulceration (-) group (63%; P = 0.0045). The 2-year overall survival rates were 8% in the ulceration (+) group and 42.7% (P = 0.0001) in the ulceration (-) group, respectively. We recorded 22 severe toxicities, including 11 patients with carotid blow-out syndrome (CBOS), which was fatal in 9 patients. CBOS occurred in 6 patients with ulceration (6/25; 24%), and 5 patients experienced CBOS without ulceration (5/82; 6%; P=0.027). In conclusion, ulceration is an important prognostic factor, not only for adverse events but also for survival after reirradiation using CyberKnife., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: The effect of heparinoid moisturizer use after acute skin damage for patients receiving whole-breast radiotherapy after lumpectomy is understudied., Methods: A total of 30 patients were randomly assigned to receive heparinoid moisturizer (Group M), and 32 patients comprised the control group (Group C). Patients in Group M were instructed to apply heparinoid moisturizer from 2 weeks following whole-breast radiotherapy, and to continue to use the moisturizer until 3 months after completion of whole-breast radiotherapy. Group C patients were instructed to not apply any topical moisturizer during the study period. The relative ratio of skin water content ratio (RWCR(t) = (It /Nt)/(I0/N0)) between irradiated and non-irradiated field was calculated. Signs and symptoms were also assessed. The primary endpoint was the difference in relative ratio of skin water content ratio between 2 and 4 weeks following whole-breast radiotherapy., Results: In Group C, relative ratio of skin water content ratio dropped to 0.80 ± 0.15 at 2 weeks and maintained the low level at 4 weeks following whole-breast radiotherapy. Similarly, in Group M, relative ratio of skin water content ratio dropped to 0.81 ± 0.19 at 2 weeks (prior to application), however, it returned to baseline level (1.05 ± 0.23) at 4 weeks (2 weeks after application). The arithmetic difference of relative ratio of skin water content ratio in Group M was 0.24 ± 0.23 and was significantly larger than in Group C (0.06 ± 0.15; P < 0.01). Skin dryness and desquamation were less severe in Group M., Conclusions: The application of heparinoid moisturizer for 2 weeks following whole-breast radiotherapy significantly increased water content and helped improve skin dryness and desquamation compared with no use of moisturizer., (© The Author 2015. Published by Oxford University Press.)

The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent PTH administration. The mechanisms by which estrogens suppress but PTH promotes periosteal expansion are not known. In this report, we show that intermittent PTH(1-34) promotes differentiation of periosteal osteoblast precursors as evidenced by the stimulation of the expression or activity of alkaline phosphatase as well as of targets of the bone morphogenetic protein 2 (BMP-2) and Wnt pathways. In contrast, 17beta-estradiol (E2) had no effect by itself. However, it attenuated PTH- or BMP-2-induced differentiation of primary periosteal osteoblast progenitors. Administration of intermittent PTH to ovariectomized mice induced rapid phosphorylation of the BMP-2 target Smad1/5/8 in the periosteum. A replacement dose of E2 had no effect by itself but suppressed PTH-induced phosphorylation of Smad1/5/8. In contrast to its effects to stimulate periosteal osteoblast differentiation, PTH promoted and subsequently suppressed proliferation of periosteal osteoblast progenitors in vitro and in vivo. E2 promoted proliferation and attenuated the antiproliferative effect of PTH. Both hormones protected periosteal osteoblasts from apoptosis induced by various proapoptotic agents. These observations suggest that the different effects of PTH and estrogens on the periosteum result from opposing actions on the recruitment of early periosteal osteoblast progenitors. Intermittent PTH promotes osteoblast differentiation from periosteum-derived mesenchymal progenitors through ERK-, BMP-, and Wnt-dependent signaling pathways. Estrogens promote proliferation of early osteoblast progenitors but inhibit their differentiation by osteogenic agents such as PTH or BMP-2.

Background: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan., Method: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered., Results: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence., Conclusion: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.

Background: Liver metastasis from breast cancer has a poor prognosis. While there are some reports of good response rates of hepatic metastasis from breast cancer by hepatic intra-arterial infusion chemotherapy, no phase I study including pharmacokinetic analysis has been reported. We performed a phase I/II study of intra-arterial infusion chemotherapy using adriamycin and 5-fluorouracil to find the maximum tolerated dose and response rate in patients with advanced or recurrent breast cancer., Methods: A hepatic arterial catheter with an access port was inserted into the proper hepatic artery. Patients received 30 mg/m2 adriamycin on days 1 and 8 and 100 mg/m2 5-fluorouracil at level 1, 200 mg/m2 at level 2,300 mg/m2 at level 3 and 400 mg/m2 at level 4 continuously from day 1 through day 14 every 28 days. At least two cycles were required before evaluation. Twenty-eight patients were entered into this study and 26 patients were evaluable. Seventeen patients had hepatic metastasis only, although nine patients had additional metastasis to other sites., Results: Dose-limiting toxicity of thrombocytopenia and neurotoxicity occurred at level 4. Leukocytopenia (ECOG grade 3-4) was observed in five (19%), thrombocytopenia in three (12%) and anemia in two (8%) patients. There were 11 catheter-related complications which were not dose dependent. Seven out of 13 evaluable patients (54%) responded at level 3. The median duration of response was 5.8 months (range, 1-23+) and median survival was 25.3 months (range, 6.2-54.7+)., Conclusion: Hepatic arterial infusion therapy appears to be safe and effective but catheter-related complications must be overcome before starting a phase III trial.

To evaluate the efficacy and toxicity of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) therapy, a phase II study of EPI, 130 mg/m2, plus CPA, 1000 mg/m2, with G-CSF every 3 weeks was carried out for 51 advanced or recurrent breast cancer patients by the Japan Clinical Oncology Group (JCOG). Fifty out of the 51 patients who were eligible for our criteria were treated with this regimen as first-line chemotherapy for visceral metastases or hormone-independent tumors. In this trial, 203 cycles were administered with an average of four cycles per patients. In 50 patients who were evaluable for response, there were 7 complete (CR) and 25 partial responses (PR) with an overall response rate of 64% (95% confidence interval, 50.1-75.9%). Symptomatic and hematological acute toxicity more than grade 3 occurred frequently; however, no treatment-related death occurred. The incidence of toxicities (> or = grade 3) was as follows: leukopenia 98%, thrombocytopenia 42%, nausea/vomiting 56% and hair loss 12%. In each cycle, daily administration of 2 micrograms/kg G-CSF (granulocyte-colony stimulating factor) was given on days 2-15 subcutaneously. The incidence of cardiotoxicity was low. Arrhythmia (< or = grade 2) was observed in 8% and a slight decrease of ejection fraction index (< or = grade 2) was observed in 2% in this trial. The median follow-up period for patients was 37.2 (24.6-51.5) months and the median survival period was 17.4 months. These data indicate that high-dose EPI + CPA combination chemotherapy was effective and well tolerated for breast cancer patients with visceral metastases or hormone-independent tumors. A randomized trial of high-dose EPI vs conventional chemotherapy is required to ascertain the usefulness of this regimen.

In a nation-wide collaborative study on mass screening for breast cancer, we collected 152 cases of interval breast cancer diagnosed at 35 hospitals or clinics distributed throughout Japan. The definition of interval breast cancer used in the present study is "breast cancer cases which were diagnosed as having 'no malignant findings' in a previous screening for breast cancer but subsequently diagnosed as 'breast cancer' at a hospital or medical clinic within two years of the previous screening." The clinical stages and prognoses of these interval cancer were analyzed and compared with those of other breast cancers detected through mass screening and in outpatient clinics. In the clinical staging of interval breast cancer, Tis (non infiltrating cancer) accounted for only 2.1%, compared to 8.0% in cases detected through mass screening. At stage I 43.4% were interval breast cancers compared to 32.9% breast cancers detected through mass screening and 25.4% diagnosed in outpatient clinics. The stage differences between interval breast cancers and breast cancers detected through mass screening were not statistically significant. Five-year survival rates were 85.6% for interval breast cancers, 91.7% for breast cancers detected through mass screening and 84.7% for breast cancers diagnosed in outpatient clinics. Ten-year survival rates were 75.9, 80.5 and 78.1%, respectively, suggesting the interval breast cancer cases to show a similar prognosis to that of breast cancer cases diagnosed in outpatient clinics. The differences in five- and 10-year survival rates among the three groups were not statistically significant. From the present study we were not able to confirm the general belief of interval cancer being more aggressive in nature and showing a poorer prognosis than cancer detected through periodic screening. The reasons for this are discussed.