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The Japan Society of Clinical Oncology (JSCO) published the "JSCO Clinical Practice Guidelines 2017 for Fertility Preservation in Childhood, Adolescent, and Young Adult Cancer Patients" in 2017. This was the first guideline in cancer reproductive medicine in Japan. In the field of cancer reproductive medicine, close cooperation between an oncologist and a physician for reproductive medicine is important from before treatment initiation until long after treatment. The guideline takes into consideration disease specificity and provides opinions from the perspective of oncologists and specialists in reproductive medicine that are in line with the current state of the Japanese medical system. It is intended to serve as a reference for medical staff in both fields regarding the availability of fertility preservation therapy before the start of cancer treatment. Appropriate use of this guideline makes it easier to determine whether fertility preservation therapy is feasible and, ultimately, to improve survivorship in childhood, adolescent, and young adult cancer patients. In this article (Part 2), we describe details by organ/system and also for pediatric cancer., (© 2021. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: Inflammation after stent graft surgery is known as postimplantation syndrome (PIS) and it causes leukocytosis. However, we have experienced leukopenia in the very early postoperative phase of endovascular surgery at our institution. We investigated leukopenia, an under-recognized phenomenon that occurred after transcatheter aortic valve implantation (TAVI), endovascular aortic repair (EVAR), and thoracic endovascular aortic repair (TEVAR)., Methods: Records of patients who underwent TAVI, EVAR, and TEVAR between March 2018 and February 2019 were retrospectively reviewed. Primary outcomes were the decline rate of white blood cell count (DR-WBC) in the immediate postoperative period and its differences among surgical procedures. The secondary endpoint was the relationship between DR-WBC and infectious complications. Furthermore, the incidence of PIS and its differences among the procedures and associations with DR-WBC were evaluated., Results: A total of 108 patients (TAVI 41, EVAR 37, TEVAR 30) were included. DR-WBC immediately after surgery was higher in the TAVI group when compared with other groups (TAVI, 43.1 ± 22.6%; EVAR, 27.6 ± 17.3%; TEVAR, 25.4 ± 27.4%; P < 0.01). DR-WBC was not significantly different regardless of postoperative infection (P = 0.45) or PIS (P = 0.62). The incidence rate of PIS was higher in the EVAR group compared with the TAVI group, and was not associated with DR-WBC., Conclusions: Leukopenia was a common phenomenon immediately after endovascular surgery, especially TAVI. It resolved a day after surgery and was not associated with PIS or infectious complications. Therefore, it seems to be a transient abnormal hematological finding and a self-limiting condition., (© 2021. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: PedsQL Infant Scales (PedsQL-I) are used to assess parent-reported health-related quality of life for children younger than 2 years. We determined the feasibility, reliability, and validity of the Japanese version of the PedsQL-I., Methods: A total of 183 participants (parents) with infants aged 1-30 months were recruited from 8 day care centers and one pediatric clinic. Participants completed the PedsQL-I (infants aged 1-18 months), the PedsQL-I and the PedsQL-Toddler version (infants aged 19-30 months), and the Kessler-6 psychological distress scale (all participants). We determined feasibility, internal consistency, test-retest reliability, concurrent validity, convergent and discriminant validity, known-groups validity with regard to acute and chronic illness, and relative and transitional validity with PedsQL-Toddler for the use in infants aged 25-30 months., Results: All subscales were internally consistent (Cronbach's alpha for 1-12 months: 0.88-0.98 and for 13-24 months: 0.85-0.97); test-retest reliability was acceptable (intra-class correlation coefficients > 0.40); and all scales were concurrently valid with the PedsQL-Toddler version (Pearson's product-moment correlation coefficient for the total score = 0.74). The scales' convergent and discriminant validity were acceptable (scaling success rate > 80%). Validation for known-groups showed that the Physical Health Summary score was sensitive to acute and chronic disease, the Psychosocial Health Summary score was sensitive to neither acute nor chronic disease, and the total score was sensitive to acute disease. Relative validity showed a ratio of 1.74 for the squared t values for the total score., Conclusions: The PedsQL-I is suitable for assessing health-related quality of life in infants aged 1-24 months in prospective studies., (© 2022. The Author(s).)

Aim: Anxiety and its correlates in parents of patients with breast cancer have rarely been studied. We explored anxiety among parents of postoperative patients with breast cancer and its relationship with parents' social support and care needs and patients' anxiety., Methods: A cross-sectional survey using self-report questionnaires and medical records was conducted among patients with breast cancer after surgery and their parents at four designated cancer care hospitals between September 2015 and June 2016. Anxiety was measured using the Hospital Anxiety and Depression Scale (HADS). Parents provided information about social support and care needs. Multilevel analysis was performed on patient-parent paired data controlling for patient-level variation., Results: Participants included 107 patients, 83 mothers, and 51 fathers. The mean HADS anxiety scores reported by mothers and fathers were 7.2 and 6.5, respectively, which were higher than patients' HADS anxiety scores. Fulfillment of important care needs was related to lower anxiety among mothers and fathers (estimate = -1.38, p = .01). Lower family support and higher patient anxiety were associated with higher anxiety in mothers, but not fathers., Conclusions: Parents of patients with breast cancer had high anxiety. Communication, providing cancer-related information, and fulfilling care needs can alleviate anxiety in parents of patients with breast cancer after surgery. Furthermore, increasing family support and decreasing patients' anxiety are essential to alleviating mothers' anxiety., (© 2021 Japan Academy of Nursing Science.)

The aim of the present study was to investigate the effects on the dose distribution and beam delivery time in spot scanning proton beam therapy (PBT) incorporating the spot deletion technique. A spot scanning plan was created for 30 patients with prostate cancer. The plan was then modified via two processes: Spots with lower weighting depositions were deleted (process A) and spots that were distant from the clinical target volume (CTV) were deleted (process B). The dose distribution to the organs at risk (OAR), the expanded CTV (exCTV), which was defined by a uniform expansion of the CTV by a radius of 5 mm, and the beam delivery time were compared among initial and modified plans. The V 50 Gy [relative biological effectiveness (RBE)] to the rectum and bladder, and V 60 Gy(RBE) to the urethral bulb, inhomogeneity index (INH) of the exCTV showed a difference (P=1.1x10 -14 , P=6.4x10 -14 , P=2.7x10 -7 , P=3.2x10 -17 ), although only changes by process B were significant. Modified plan by process B showed the V 50 Gy(RBE) to the rectum and bladder decreased by -2.4±1.6 and -2.3±1.4%, and the V 60 Gy (RBE) to the urethral bulb decreased by -15.9±19.4%. The INH of the exCTV increased by 0.05±0.03%. On the other hand, modification of the initial plan by process A did not affect the dose of the OAR, exCTV or beam delivery time. In spot scanning PBT, modification of the initial radiotherapy plan by systemic deletion of spots distant from the CTV could result in a dose reduction to the OAR., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Fukumitsu et al.)

Fraction flow reserve (FFR) derived from computed tomography (FFR CT ) has been proposed to be an effective gatekeeper for invasive angiographic referral. The purpose of the present study is to examine the real-world diagnostic performance of FFR CT and myocardial perfusion imaging as well as to assess the utility of FFR CT as a gatekeeper for invasive coronary angiography in patients suspected of having obstructive coronary artery disease. Total of 146 consecutive patients underwent both single-photon emission computed tomography (SPECT) and invasive FFR were evaluated. An FFR CT value 1 to 2 cm distal to a stenosis ≤0.80 was defined as positive for ischemia and a summed stress score ≥2 or transient ischemic dilatation ≥1.2 were positive for ischemia with the invasive FFR value of <0.80 serving as the gold standard. The patient-based sensitivity of FFR CT was significantly higher than SPECT (91 vs 52%, p <0.001) and exhibited similar positive predictive value (82 vs 82%, p = 0.91). These trends were observed even in patients with multivessel and left main trunk disease and those with severe coronary calcification. In conclusion, our data suggest that FFR CT has higher diagnostic performance characteristics than SPECT and details the superior FFR CT analysis in detecting patients with hemodynamically significant coronary artery disease. Our results support the clinical utility of FFR CT analysis as a gatekeeper for invasive coronary angiography in clinical practice., Competing Interests: Disclosures All authors have no conflict of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The optimal site for measuring computed tomography (CT)-derived fractional flow reserve (FFR CT ) to detect significant coronary artery disease (CAD) remains unknown. We investigated how diagnostic performance changes with FFR CT measurement site. Methods and Results: The diagnostic performance of FFR CT , measured 1-2 cm distal to the stenosis vs. a far-distal site, in detecting significant CAD with invasive fractional flow reserve ≤0.8 was evaluated in 254 diseased vessels from 146 patients with stable or suspected CAD diagnosed by coronary CT angiography. Receiver operating characteristic curve analysis revealed a significantly larger area under the curve for FFR CT measured 1-2 cm distal to the stenosis than at a far-distal site (0.829 vs. 0.791, respectively; P=0.0305). The rate of reclassification of positive FFR CT was 19% for measurements made 1-2 cm distal to the stenosis, and diagnostic accuracy for FFR CT 0.71-0.80 improved from 36% to 58% (P=0.0052). Vessel-based diagnostic accuracy of FFR CT 1-2 cm distal to the stenosis and at a far-distal site was 75% and 65%, respectively (P<0.0001), with corresponding sensitivity of 87% and 94% (P=0.0039), specificity of 60% and 29% (P<0.0001), a positive predictive value of 73% and 62% (P=0.028), and a negative predictive value of 78% and 79% (P=0.958). Conclusions: Our data suggest measuring FFR CT 1-2 cm distal to the stenosis has better diagnostic performance for detecting physiologically significant CAD., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2021, THE JAPANESE CIRCULATION SOCIETY.)

We attempted to re-evaluate the efficacy of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) with more recent data. A total of 179 patients with LS-SCLC received radical thoracic radiotherapy and chemotherapy at our institution between 1998 and 2018. One hundred twenty-eight patients who achieved complete response (CR), good partial response (PR), and PR without progression for at least for one year after initial therapy were enrolled in this study. These patients were divided into a PCI group (group A, n = 43), and a non-PCI group (group B, n = 85). Survival outcomes were retrospectively evaluated. Because several background factors differed significantly between groups A and B, propensity score (PS) matching was performed as 1:1 match of the two groups. Finally, we analyzed 64 patients (group A/B = 32/32). Median follow-up periods were 53 and 31 months in groups A and B, respectively. There were no significant differences between the groups' backgrounds. Two-year overall survival (OS) rates were 77% in group A and 62% in group B (p = 0.224). Two-year brain metastasis free survival (BMFS) rates were 85% in group A and 57% in group B (p = 0.008). The number of patients who underwent a brain imaging test for confirmation of no brain metastasis (BM) after radical thoracic radiotherapy and chemotherapy (before PCI) was 84 (group A/B = 32/52). A PS matched analysis for cases of pre-PCI brain imaging group, two-year OS rates for group A/B were 73/59% (p = 0.446). Two-year BMFS rates for group A/B were 91/52% (p = 0.021). Retrospectively, PS matched analysis revealed that adding PCI to LS-SCLC patients who achieved good thoracic control significantly improved BMFS, but OS did not improve., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Verapamil-sensitive atrial tachycardia originating from the atrioventricular node vicinity (AVN-AT) can be eliminated with radiofrequency energy (RF) deliveries targeting either the entrance or exit of its reentry circuit. However, the outcome of these different approaches has not been clarified well. Thus, we compared the catheter ablation outcome targeting the entrance of reentry circuit, identified by the entrainment method (Ent-Group; 21 patients) with that targeting the earliest atrial activation site (EAAS) during AT (Exit-Group; 16 patients). There was no significant difference in the tachycardia cycle length (441.4 ± 87.4 vs. 392.8 ± 64.8 ms, p = 0.0704) or distance from the His bundle (HB) site to the EAAS (6.5 ± 2.0 vs. 7.6 ± 1.8 mm, p = 0.0822) between the Ent- and Exit-Groups. However, distance from the successful ablation site to the HB site in the Ent-Group was significantly longer than that in the Exit-Group (13.4 ± 3.1 vs. 7.6 ± 1.8 mm, p < 0.0001), resulting in more frequent transient atrioventricular block episodes in the Exit-Group than Ent-Group (31.3 vs. 0%, p < 0.01). Initial ATs (AT1s) were terminated in all patients in both Groups. However, ATs accompanied by shifting in the EAAS (AT2) were induced more frequently in the Exit-Group than Ent-Group (50.0 vs. 14.3%, p < 0.02) after eliminating AT1. RF deliveries to the EAAS eliminated all AT2s. The number of RF deliveries was greater in the Exit-Group than Ent-Group (6.9 ± 3.3 vs. 3.9 ± 1.6, p < 0.001). In conclusion, RF ablation targeting the entrance sites can avoid AVN injury and is superior in reducing the number of RF deliveries and occurrence of different ATs than targeting the exit sites in the AVN-AT.

The present study simulated the effect of spot-scanning proton beam therapy (PBT) performed using a device equipped with a multi-leaf collimator (MLC) to calculate the dose distribution. Simulation studies using 18 pediatric patients with brain tumors in the posterior fossa were performed. Treatment plans were created for the MLC at different stages: Fully open (initial plan), fully closed to allow an irradiated area extending to 15 mm from the clinical target volume (CTV) (15-mm plan), or closing only the leaves where an organ at risk (OAR) overlapped with a border at 10 or 5 mm from the CTV (10- and 5-mm plans, respectively). The mean dose values for the brainstem, cervical cord, brain and cochlea in all MLC closure plans decreased as the MLC was closed (P=9.9×10 -10 , P=1.3×10 -17 , P=2.1×10 -16 and P=2.0×10 -5 , respectively). The maximum dose (D max ) values of the cervical cord and cochlea in all MLC closure plans were also decreased as the MLC was closed (P=3.0×10 -4 and P=1.1×10 -5 , respectively). The dose to the CTV was almost unchanged. In 10 patients, the D max of the brain in all MLC-closure plans was higher than that of the initial plan, but the maximum increase was only 0.8 gray relative biological effectiveness [Gy(RBE)]. In conclusion, the existing MLC installed in the treatment device can be used to decrease the OAR dose significantly using spot-scanning PBT without a large capital investment. The dose from the scattered particles was small., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Fukumitsu et al.)

We investigate the effect of uniaxial heterostrain on the interacting phase diagram of magic-angle twisted bilayer graphene. Using both self-consistent Hartree-Fock and density-matrix renormalization group calculations, we find that small strain values (ε∼0.1%-0.2%) drive a zero-temperature phase transition between the symmetry-broken "Kramers intervalley-coherent" insulator and a nematic semimetal. The critical strain lies within the range of experimentally observed strain values, and we therefore predict that strain is at least partly responsible for the sample-dependent experimental observations.

Children and adolescents and young adults (AYAs) with cancer are often treated with a multidisciplinary approach. This includes use of radiotherapy, which is important for local control, but may also cause adverse events in the long term, including second cancer. The risks for limited growth and development, endocrine dysfunction, reduced fertility and second cancer in children and AYAs are reduced by proton beam therapy (PBT), which has a dose distribution that decreases irradiation of normal organs while still targeting the tumor. To define the outcomes and characteristics of PBT in cancer treatment in pediatric and AYA patients, this document was developed by the Japanese Society for Radiation Oncology (JASTRO) and the Japanese Society of Pediatric Hematology/Oncology (JSPHO)., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In consideration of the development of treatment options for squamous cell carcinoma (SCC), the Japanese Skin Cancer Society issued the first guidelines of SCC in 2007 and revised them in 2015. Here, we report the English version of the 2020 edition of the Japanese SCC guidelines. The first half of this article is an overview of SCC including actinic keratosis and Bowen's disease, and the second half discusses three clinical questions: (i) treatment of actinic keratosis; (ii) determination of the resection margin of the primary lesion; and (iii) treatment of radically incurable cases, as contemporary problems encountered in treating SCC. In these evaluations, all processes were implemented according to the Grading of Recommendations, Assessment, Development, Evaluation system. Also, items of recommendation concerning each clinical question were determined by a multidisciplinary expert panel consisting of dermatologists, plastic/reconstructive surgeons, radiologists, and oncologists through a comprehensive literature search and systematic reviews., (© 2021 Japanese Dermatological Association.)

Background This study was conducted to evaluate late toxicities in adolescent and young adult (AYA) patients who received photon or proton therapy. Methodology A total of 106 AYA patients who received proton and photon therapy and were followed-up for more than two years were retrospectively evaluated. The median age of patients was 22 years (range, 15-29 years). A total of 47 patients were male and 59 were female. A total of 35 and 71 patients received photon and proton therapy, respectively. All but one patient received radiotherapy with curative intent. The target disease was benign and malignant in 28 and 78 patients, respectively. Results The median follow-up period in all patients was 62 months (range: 24-293 months). Grade 3 or higher toxicity was observed in 20 patients. There was one case of grade 5 toxicity (myelodysplastic syndrome), which was probably due to chemotherapy. No other secondary cancers were observed. Regarding life events, 15 and 88 patients were married and unmarried at the start of radiotherapy, respectively. Of the 88 unmarried patients, five were married after radiotherapy. Occupation and education were evaluated in 71 patients. Of the 71 patients, 33 were students, 21 were employed, and 16 were unemployed. Of the 33 students, eight were employed and 11 were at a higher educational grade after radiotherapy. Of the 21 employed patients, 17 had the same jobs and four had lost their jobs after radiotherapy. For the 16 unemployed patients, all remained unemployed. Conclusions This study is one of the largest studies to focus on life after radiation therapy among AYAs and suggests that cancer treatment has an influence on life events., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Mizumoto et al.)

We conducted a cross-sectional observational study investigating socioeconomic status among Japanese survivors of pediatric hematopoietic stem cell transplantation (HCT) and the impact of chronic graft-versus-host disease (cGVHD) on socioeconomic outcomes, which are topics not well explored in the previous research. We collected data on socioeconomic outcomes from 442 HCT survivors through a questionnaire and obtained demographic and clinical information from their attending physicians and a national database between February 2013 and November 2014. We used logistic regression analysis to examine the relationship between cGVHD and socioeconomic outcomes in allogeneic HCT (allo-HCT) survivors. Most survivors did not experience socioeconomic problems. Nevertheless, allo-HCT survivors with cGVHD aged 8-15 years had poorer economic status (p = 0.013), and allo-HCT survivors with cGVHD aged ≥ 16 years were more likely to have never married (p = 0.034) and less likely to have more than a high school education (p = 0.023), compared with allo-HCT survivors without cGVHD. Thus, cGVHD in Japanese allo-HCT survivors was a risk factor for economic difficulties for those aged 8-15 years, and for never marrying and low educational achievement in those aged ≥ 16 years.

Motivated by conjectures in holography relating the entanglement of purification and reflected entropy to the entanglement wedge cross section, we introduce two related non-negative measures of tripartite entanglement g and h. We prove structure theorems which show that states with nonzero g or h have nontrivial tripartite entanglement. We then establish that in one dimension these tripartite entanglement measures are universal quantities that depend only on the emergent low-energy theory. For a gapped system, we argue that either g≠0 and h=0 or g=h=0, depending on whether the ground state has long-range order. For a critical system, we develop a numerical algorithm for computing g and h from a lattice model. We compute g and h for various CFTs and show that h depends only on the central charge whereas g depends on the whole operator content.

Background: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer., Patients and Methods: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m 2 ; days 1 and 8, vinorelbine 20 mg/m 2 ). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period., Results: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%., Conclusion: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to develop a Japanese version of the Caregiving Interface Work Scale (J-CIWS) for use with employed Japanese family caregivers., Methods: Permission was obtained from the developer of the original CIWS. The CIWS contains 20 items: 10 measuring care interface work (CIW) and 10 measuring work interface care (WIC). Responses are measured on a five-point Likert scale. The J-CIWS was developed through forward- and back-translation and cognitive interviews of employed family caregivers. An internet survey was conducted with 116 employed family caregivers, and 78 participants answered a retest. Questionnaire items included the J-CIWS and demographic factors. Factor analysis was conducted to determine the J-CIWS factor structure. Validity was assessed based on known-groups, convergent and discriminant validity. Internal consistency was examined by calculating Cronbach's α. Test-retest reliability was examined by calculating the Pearson's correlation coefficient., Results: The mean participant age was 50.3 years; 74 (63.8%) were male. The average weekly working and caregiving hours were 41.6 and 12.1 h, respectively. Confirmatory factor analysis supported the original two-factor model. High internal consistency (Cronbach's alpha >0.90) and sufficient test-retest reliability (weighted κ score >0.45) were demonstrated for both subscales. Convergent and discriminant validity were acceptable for the two subscales (CIW and WIC)., Conclusions: This study confirmed the usefulness of the CIWS within a Japanese context. The J-CIWS may be useful for evaluating the extent of the conflict between work and care among employed family caregivers. Geriatr Gerontol Int 2021; 21: 254-261., (© 2020 Japan Geriatrics Society.)

Fractional flow reserve (FFR) has become an increasingly important index for decision making concerning coronary revascularization. It is commonly accepted that significant improvement in FFR following percutaneous coronary intervention (PCI) is associated with better symptomatic relief and a lower event rate. However, in lesions with insufficient FFR improvement, PCI may not improve prognosis. Leading to the observation that the clinical and angiographic characteristics associated with insufficient FFR improvement have not been fully explored. The purpose of this study was to investigate the factors associated with insufficient improvement in FFR. Using our own PCI database, established between January 2014 and December 2018, we identified 220 stable coronary artery lesions, which had been evaluated for both pre- and post-PCI FFR values. All 220 of these lesions were included in this study. The improvement in FFR (ΔFFR) was calculated in each lesion with the lowest quartile of ΔFFR being defined as the lowest ΔFFR group, and the other quartiles being defined as the intermediate-high ΔFFR group. The mean ΔFFR in the lowest and intermediate-high ΔFFR groups was 0.07 ± 0.02 and 0.21 ± 0.11, respectively. In multivariate logistic regression analysis, a short total stent length (10 mm increase: OR 0.67, 95% CI 0.47-0.96, P = 0.030), higher pre-PCI FFR (0.1 increase: OR 4.07, 95% CI 1.83-9.06, P = 0.001), in-stent restenosis (ISR) (OR 8.02, 95% CI 1.26-51.09, P = 0.028), myocardial infarction (MI) in the target vessel (OR 6.87, 95% CI 1.19-39.69, P = 0.031) and non-use of intravascular imaging (OR 0.35, 95% CI 0.12-0.99, P = 0.048) were significantly associated with the lowest ΔFFR group. The use of short stents, higher pre-PCI FFR values, ISR, MI in the target vessel, and non-use of intravascular imaging were significantly associated with insufficient FFR improvement. It was conversely suggested that full coverage and adequate dilatation of the lesions under an intravascular imaging guidance might contribute to an improvement in FFR.

Background: Many childhood cancer survivors (CCSs) experience physical late effects related to their cancer types and treatment modalities. Physical late effects are an important factor in various occupational outcomes among CCSs. However, the relationship between physical late effects and presenteeism has remained unclear. This study aimed to estimate the impacts of physical late effects on presenteeism among employed CCSs., Methods: Childhood cancer survivors replied to a questionnaire regarding presenteeism, and their attending physicians assessed their physical late effects between September 2014 and December 2015. The Work Limitations Questionnaire was used to measure presenteeism. Propensity score analysis and a generalized linear model were used to adjust covariates related to physical late effects and / or presenteeism., Results: Of the 125 questionnaires distributed, 114 were returned. The data from 61 employed CCSs were analyzed. After controlling for covariates by propensity score analysis and generalized linear model, there were no significant differences in presenteeism between employed CCSs with either no or single physical late effects. However, employed CCSs with multiple physical late effects reported higher scores in Output (Estimate = 9.3, P = 0.041), Physical Demands (Estimate = 12.2, P = 0.020), and Productivity Loss scores (Estimate = 2.4, P = 0.045) on the Work Limitations Questionnaire than employed CCSs with no physical late effects., Conclusions: Employed CCSs with multiple physical late effects were at an increased risk for presenteeism. Healthcare and social welfare systems should be established to provide vocational assistance for CCSs after being employed to alleviate presenteeism., (© 2020 Japan Pediatric Society.)

Background: Standard doses of craniospinal irradiation (CSI) are 23.4 Gy for patients with average-risk and 36 Gy for those with high-risk medulloblastoma (MB). We investigated whether intensified chemotherapy including intrathecal chemotherapy with simultaneous irradiation is able to reduce CSI dose to 18 Gy., Methods: Newly diagnosed average-risk patients aged 3-11 years and high-risk patients aged 3-18 years were eligible. Patients with Stage M1-4 disease were classified as high-risk MB and the others, including M0 patients with >1.5 cm 2 postoperative residual tumor, were classified as average-risk MB. Patients received chemotherapy consisting of cyclophosphamide, etoposide, cisplatin, and vincristine. Radiotherapy was started concomitantly with the second course of chemotherapy. Radiation doses were 50 Gy to the primary site and 18 Gy to the craniospinal axis. Average-risk patients received five courses of chemotherapy. High-risk patients received high-dose chemotherapy consisting of thiotepa and melphalan following four courses of chemotherapy. All patients received intrathecal methotrexate., Results: From 2006 to 2014, 48 patients (35 average and 13 high risk) who met the eligibility/exclusion criteria were enrolled. The 3-year progression-free survival (PFS) and 3-year overall survival (OS) were 90.5% (standard error 5.2%) and 93.9% (4.2%), respectively, for average-risk patients, and 100% and 100%, respectively, for high-risk patients. There was no leukoencephalopathy or treatment-related deaths. Two patients experienced secondary cancer., Conclusions: These results suggest that CSI 18 Gy is adequate at least in a proportion of patients with MB treated with intensified chemotherapy including intrathecal methotrexate and simultaneous irradiation, though the results in high-risk patients were only exploratory., (© 2020 Wiley Periodicals LLC.)

Many attempts to reduce radiation fields for intracranial germ cell tumors (iGCTs) remain unsuccessful. To assess the possibility of reduction, we analyzed registry data of 57 patients who mostly underwent local irradiation for iGCTs between 1997 and 2006. The recommended treatment for pure germinomas (PGNs) included 3 courses of cisplatin and etoposide followed by 24 Gy local irradiation. Intensified chemotherapy using a combination of cyclophosphamide and intrathecal methotrexate was recommended for human chorionic gonadotropin-producing germinomas (hCG-GNs) and nongerminomatous germ cell tumors (NGGCTs); both received 50.4 Gy local irradiation. High-dose chemotherapy was only administered for residual NGGCTs after chemoradiotherapy. Craniospinal irradiation was recommended only in metastatic cases. During the median follow-up of 114.8 months, 8 of 9 relapses from 24 PGNs occurred outside irradiation fields, with a 5-year progression-free survival (5-year PFS) of 75%±8.8%. Conversely, no recurrences occurred from 11 hCG-GNs, with a 5-year PFS of 100%. Eleven of 22 patients with NGGCTs received high-dose chemotherapy; the 5-year PFS was 81.3%±8.4%; 2 of 3 relapses occurred in the spinal cord. Thus, local irradiation for PGNs was insufficient without treatment intensification. The introduction of intensified chemotherapy improved outcomes of both patients with hCG-GNs and NGGCTs. However, the contributions of either modality remained unclear.

Background: This study aims at determining the health-related quality of life (HRQOL) of children with acute lymphoblastic leukemia (ALL) after the induction therapy, assessing the agreement between child self-reports and family proxy-reports HRQOL, and determining the factors related to this agreement, especially child age, family attendance, and children's social relationships beyond the family., Methods: We analyzed questionnaire data (2012-2017) from the Japanese Pediatric Leukemia/Lymphoma Study Group's clinical study (ALL-B12). Participants were children with B-cell precursor ALL aged 5-18 and their family members, who mostly took care of the child during hospitalization. Participants answered the Pediatric Quality of Life Inventory™ (PedsQL™) Generic Core Scales (PedsQL-G), and Cancer Module (PedsQL-C) to measure pediatric HRQOL. We calculated the differences between child self-reported and family proxy-reported subscale scores along with intraclass correlation coefficients (ICC). We conducted multiple regression analyses according to all participant pairs and age groups (young children, school age, and adolescents), with ICCs for all PedsQL-G subscales (ICC-G) and all PedsQL-C subscales (ICC-C) as the outcome variables., Results: Five hundred twenty-two pairs of children and their families were analyzed. We observed a moderate level of agreement on most PedsQL subscales between child self-reports and family proxy-reports; however, worry had the weakest agreement for all PedsQL subscales (ICC = .32, 95% confidence interval = .24-.40). The agreement of ICC-C was positively related to family attendance in the hospitalization, only for the young children group (B = .185, p = .003)., Conclusions: We observed some differences between child self-reports and family proxy-reports of HRQOL of children with ALL. Both child self-reports and family proxy-reports captured HRQOL in the induction therapy. We suggest that attending to young children's hospitalization affects the level of agreement between reports on their HRQOL.

The real-time PCR (qPCR) and digital PCR (dPCR) to amplify a single-copy of house-keeping genes (i.e., hsp60, pheS or tuf) are used for the assay of limited microbial species. In general, with a single-copy gene, there are obviously varied DNA sequences for even the same microbial species, which could cause difficulties with design of primers and probes for PCR when targeting various single copy genes. In general, for identification by dPCR (as a representative case: Lactobacillus paracasei), accumulated DNA sequence information of 16S rDNA, which is much more frequently used, should be targeted. In contrast, next-generation sequencing revealed that there are five copies of 16S rDNA in a live L. paracasei MCC1849. Therefore, we aimed to reveal, if heat-killed L. paracasei supplemented in nutritional foods that aid the host immune system have the relevant five copies per chromosomal DNA, and if the relevant copies remain unchanged on the same chromosomal DNA or remain to be different chromosomal DNA fragments. So, we revealed the actual distribution of the potential original five copies of 16S rDNA using our innovative dPCR, in which both 16S rDNA and hsp60 genes were simultaneously elongated. The molecular ratios of 16S rDNA/hsp60 dispersed in the dPCR chip were then estimated. The 16S rDNA/hsp60 molecular ratios of the heat-killed L. paracasei in foods, resultantly ranged from 5.0 to 7.2, being the same or higher than that of the five copies determined by next-generation sequencing. The 16S rDNA copy number/ratio indicated the chromosomal DNA molecular number and the associated cell number. As significance, different nutritional foods could potentially cause the loss of chromosomal DNA of supplemented beneficial microbes to a much greater degree. Our absolute dPCR does not require standard correlative samples for the estimation of final products. The estimation principle of the ratio of 16S rDNA/a house-keeping single-copy gene by our absolute dPCR could lead to a useful and accurate assay for various nutritional foods.

The clinical benefits of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) is still controversial. The purpose of this study is to assess the quantitative therapeutic benefits of successful PCI for CTO from the clinical data acquired by myocardial perfusion imaging (MPI). Consecutive 42 patients, who were successfully revascularized of CTO between August 2013 and March 2018, were examined. A stress MPI was performed before CTO PCI and at follow-up, and the changes in quantitative gated and perfusion single photon emission computed tomography parameters were examined. The follow-up interval was 18 ± 9 (median 14) months, during which 36 patients were maintained patency (patent CTO), while 6 were re-occluded (R/O CTO). The reduction in the % myocardial ischemia and the improvement in the ejection fraction were significantly higher in the patent CTO group than those in the R/O CTO group (67.5 ± 37.0% vs. - 56.4 ± 84.9%, p < 0.0001, 20.7 ± 49.8% vs. - 9.2 ± 20.6%, p = 0.0247, respectively). Interestingly, the improvements we observed were predominantly in the patients with LAD CTO rather than those with RCA or LCx CTO. Successful CTO PCI was able to reduce myocardial ischemia and improve the cardiac function when the patency after CTO PCI was maintained, with the most notable significance in the patients with LAD CTO.

Background: Patient-reported outcomes (PROs) refer to any report of the status of a patient's health condition, health behavior, or experience with healthcare directly from the patient, without interpretation of the patient's response by a clinician or any other external party. While many PROs, such as the Pediatric Quality of Life Inventory (PedsQL), were originally administered in paper-and-pencil format, these are now available as electronic versions (ePROs). Although ePROs might well have used the same structure as their paper versions, we developed an alternate ePedsQL incorporating three software functions: 1) a non-forcing non-response alert, 2) a conditional question branch of the School Functioning Scale that only displays for (pre) school children, and 3) a vertical item-by-item display for small-screen devices. This report evaluated the effect of these functions on item non-response rate, survey completion time, and user experience., Methods: All surveys were conducted via the online/computer mode. We compared the dynamic format containing the three functions with the basic format in a randomized comparative study in 2803 children and 6289 caregivers in Japan., Results: We found that the non-response alert lowered the item non-response rate (0.338% to 0.046%, t = - 4.411, p < 0.001 by generalized linear mixed model analysis). The conditional question branch had mixed effects on survey completion time depending on the respondents' age. Surprisingly, respondents rated the vertical question display for handheld devices less legible than the matrix format. Further, multigroup structural equation modelling revealed that the same configuration for both formats showed an acceptable fit (CFI 0.933, RMSEA 0.060, SRMR 0.038) but the errors of observed variables were larger for the dynamic format than the basic format., Conclusions: We confirmed the robustness of the ePedsQL in different formats. The non-response rate of ePedsQL was very low even in the absence of an alert. The branch and item-by-item display were effective but unnecessary for all populations. Our findings further understanding of how humans respond to special software functions and different digital survey formats and provide new insight on how the three tested functions might be most successfully implemented.

Background: Reducing non-completion of quality-of-life assessment in clinical trials is an important challenge in obtaining accurate data and unbiased interpretation of patients' quality-of-life for each regimen. We evaluated the effect of changing our questionnaire distribution procedure in a multicenter phase II/III trial on the response rate to a quality-of-life questionnaire., Methods: In the trial, we distributed 1767 questionnaires and 1045 were returned. We adopted a regression discontinuing design and estimated the change in response rate between pre-intervention (quality-of-life questionnaires were sent to each center soon after patient registration) and post-intervention (a set of tailored questionnaires was sent just before the first quality-of-life assessment)., Results: The post-intervention response rate was higher (odds ratio = 1.62) than the pre-intervention response rate., Conclusions: A simple logistic intervention reduced the non-completion of QOL assessment in this case, suggesting that a simple change can contribute to improving clinical trial accomplishment.

Objective: Concurrent chemoradiotherapy using cisplatin was thought to be standard treatment for squamous cell carcinoma of cervix, but it had not been effective for adenocarcinoma. Concurrent chemoradiotherapy using irinotecan hydrochloride (CPT-11) had been effective for colorectal cancer, thus, we chose CPT-11 as a candidate for gynecologic adenocarcinoma. To evaluate the maximum tolerated dose (MTD) of weekly CPT-11 with external pelvic radiotherapy, a phase 1/2 study was conducted according to modified Fibonacci method., Methods: Eligible patients were advanced uterine cancer with measurable diseases [performance score (PS): 0-2]. Study period was from August 1st, 2002 to December 31st, 2008. The starting dose level (DL) of CPT-11 was 30 mg/m 2 (DL1) given weekly for 4 weeks. Subsequently, dose escalation was scheduled in 10 mg/m 2 increments to 60 mg/m 2 (DL4). The fixed radiotherapy consisted of whole pelvic 1.8 Gy/d, once a day in weekday for five weeks and it amounted to 45 Gy (25 fractions) in total., Results: Seventeen patients were enrolled. As for toxicities, one (1/17: 5.9%) grade (G) 4 neutropenia lasting 7 days had been seen in DL4. G2 diarrhea was identified in 35.3% (6/17) of the patients, and 11.8% (2/17) G3 diarrhea was observed in DL3 and DL4. Thus, the MTD of CPT-11 was defined as dose of 60 mg/m 2 . The recommended dose was decided as 50 mg/m 2 . The response rate was 88.2% [9 complete response (CR), 3 partial response (PR), 3 stable disease (SD), 2 not evaluable (NE)]. Disease control rate at 1 month after treatment completion was 100% but distant metastases were found in 24% (4/17) in longer outcome., Conclusions: MTD was 60 mg/m 2 and recommended dose was set as 50 mg/m 2 . This concurrent chemoradiation using weekly CPT-11 was feasible at 50 mg/m 2 , and it might be effective even in adenocarcinoma of the uterus., (Copyright © 2020 Chinese Journal of Cancer Research. All rights reserved.)

Fatty acid-binding protein 4 (FABP4) is predominantly expressed in adipocytes and macrophages and regulates metabolic and inflammatory pathways. FABP4 is secreted from adipocytes during lipolysis, and elevated circulating FABP4 levels are associated with obesity, metabolic disease, and cardiac dysfunction. We previously reported that the bacterial respiratory pathogen Chlamydia pneumoniae infects murine adipocytes and exploits host FABP4 to mobilize fat and replicate within adipocytes. However, whether C. pneumoniae induces FABP4 secretion from adipocytes has not been determined. Here, we show that FABP4 is actively secreted by murine adipocytes upon C. pneumoniae infection. Chemical inhibition of lipase activity and genetic deficiency of hormone-sensitive lipase blocked FABP4 secretion from C. pneumoniae -infected adipocytes. Mechanistically, C. pneumoniae infection induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), resulting in elevated levels of mitochondrial reactive oxygen species and cytosolic Ca 2+ Of note, exposure to a mitochondrial reactive oxygen species-specific scavenger, MitoTEMPO, reduced FABP4 release from C. pneumoniae -infected adipocytes. Furthermore, treatment with azoramide, which protects cells against ER stress, decreased FABP4 release from C. pneumoniae -infected adipocytes. Using gene silencing of CHOP (C/EBP homologous protein), a central regulator of ER stress, we further validated the role of C. pneumoniae infection-induced ER stress/UPR in promoting FABP4 secretion. Overall, these results indicate that C. pneumoniae infection robustly induces FABP4 secretion from adipocytes by stimulating ER stress/UPR. Our findings shed additional light on the etiological link between C. pneumoniae infection and metabolic syndrome., (© 2020 Walenna et al.)

Background: Most childhood medulloblastoma (MB) cases are curable using multimodal treatment, including craniospinal irradiation (CSI). However, late effects are a serious problem for survivors. This prospective registry study evaluated Japanese patients to determine whether a reduced radiation dose was feasible., Patients and Methods: Patients with MB were classified as an infant group (<3 years old) and a high-risk (HR) group (≥3 years old with metastasis). The HR group received intrathecal methotrexate (IT-MTX) and high-dose chemotherapy (HDC) using thiotepa and melphalan, as well as concomitant radiotherapy with a recommended CSI dose of 18 Gy and a total local dose of 50 Gy. Radiotherapy was only considered for infants if residual tumors were present after the HDC., Results: Between 1997 and 2006, we identified 28 HR patients (M1: 9, M2/3: 19) and 17 infant patients (M0: 11, M1: 3, M2/3: 3). During the median follow-up of 9.4 years for the entire HR group, the 5-year progression-free survival (PFS) rate was 82.1 ± 7.2% and the 5-year overall survival (OS) rate was 85.7 ± 6.6%. Subanalyses of the patients who received the recommended treatment revealed that the 5-year PFS and OS rates were both 90.5 ± 6.4%. In the infant group, the 5-year PFS rate was 52.9 ± 12.1% and the 5-year OS rate was 51.8 ± 12.4%. There were no serious adverse events associated with the IT-MTX and HDC treatments., Conclusion: Intensified chemotherapy using HDC and IT-MTX might allow for a reduced prophylactic radiation dose in patients with MB with metastases. Further studies are needed to validate these findings., (© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Background: Some studies have demonstrated that concurrent chemo-radiotherapy is an effective salvage treatment for isolated para-aortic lymph node (PALN) recurrence. However, no studies have compared multi-treatment modalities, such as radiation therapy (RT), concurrent chemoradiotherapy (CCRT), surgery, chemotherapy, and best supportive care (BSC), across a sufficient number of patients with PALN recurrence. We thus aimed to evaluate the clinical outcomes of multi-treatment modalities for isolated PALN recurrence in uterine cervical cancer., Methods: Records of 50 patients who were first diagnosed with isolated PALN recurrence after definitive cervical cancer treatment from 2002 to 2016 at our institution were reviewed retrospectively. The initial definitive cervical cancer therapies included RT alone, CCRT, or surgery with or without post-operative RT. The median follow-up time was 33 months. The median age at recurrence diagnosis was 57 years (range, 26-84 years). The median duration between the end of initial treatment and recurrence was 10 months (range, 1-91 months). The median maximum metastatic lesion size was 17 mm (range, 8-60 mm). Twenty-four patients had one or two PALN metastases, while 26 had 3 or more. Eighteen patients were treated for recurrence with RT alone, seven with CCRT, three with surgery, 17 with chemotherapy, and five with BSC. Potential prognostic factors included histopathology, initial FIGO stage, initial treatment, age at recurrence, tumor markers (serum SCC-Ag and CEA) at recurrence, time to recurrence, maximum size of the metastatic lesion, number of metastases, and the recurrence treatment method., Results: The 3-year overall survival (OS) rates of all patients were 47.0%. The 3-year OS rate of patients who underwent CCRT for recurrence was 85.7%; surgery, 66.7%; chemotherapy, 48.8%; RT, 41.3%; and BSC, 0% (p = 0.014). Univariate analysis revealed that only the recurrence treatment method was significantly associated with OS. The 3-year local control rate (LCR) and progression free survival (PFS) rate for CCRT were 100 and 71.4%; for surgery, 100 and 66.7%; for chemotherapy, 33.6 and 13.7%; and for RT, 55.5 and 14.1%, respectively (LCR: p = 0.028, PFS: p = 0.059). The number of metastatic lesions, SCC-Ag levels and recurrence treatment method were significantly associated with LCR. Age at recurrence, SCC-Ag levels, and number of metastatic lesions were significantly associated with PFS., Conclusions: Although our patient cohort size was small, our results suggest that CCRT may be effective in preventing local disease recurrence in the PALN and may improve OS.

The obligate intracellular bacteria chlamydia is major human pathogen that causes millions of trachoma, sexually transmitted infections and pneumonia worldwide. We serendipitously found that both calpain inhibitors z-Val-Phe-CHO and z-Leu-Nle-CHO showed marked inhibitory activity against chlamydial growth in human epithelial HeLa cells, whereas other calpain inhibitors not. These peptidomimetic inhibitors consist of N-benzyloxycarbonyl group and hydrophobic dipeptide derivatives. Both compounds strongly restrict the chlamydial growth even addition at the 12 h post infection. Notably, inhibitors-mediated growth inhibition of chlamydia was independent on host calpain activity. Electron microscopic analysis revealed that z-Val-Phe-CHO inhibited chlamydial growth by arresting bacterial cell division and RB-EB re-transition, but not by changing into persistent state. We searched and found that z-Leu-Leu-CHO and z-Phe-Ala-FMK also inhibited chlamydial growth. Neither biotin-hydrophobic dipeptide nor morpholinoureidyl-hydrophobic dipeptide shows inhibitory effects on chlamydial intracellular growth. Our results suggested the possibility of some chemical derivatives based on z-hydrophobic dipeptide group for future therapeutic usage to the chlamydial infectious disease., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Our observational study aimed to verify the safety of our original titanium fiducial markers in gynecological cancer by using a simple insertion method. We prospectively evaluated the safety in patients with gynecological cancer who had undergone our insertion procedure of the titanium markers. The decision to implant a titanium marker was at the discretion of each radiation oncologist. The fiducial markers were manufactured by severing ligating clips for surgery into 3-6 mm pieces and were sterilized thereafter. We inserted an 18-gauge injection needle containing the marker before the marker was extruded by a 22-gauge Cattelan needle or shape memory alloy wire into the tumor or tissues close to the tumor. Severe complications within 3 months after implantation were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0. Between August 2016 and December 2018, we enrolled 46 patients. Of 46, 44 underwent implantation. The median age was 58.5 years. The most common primary site was the cervix. Two patients experienced detachment of the markers after implantation. No Grade 3 or higher level of complications was observed. Our simple insertion technique for original titanium fiducial markers was well-tolerated., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Reduced-intensity stem cell transplantation (RIST) minimizes the adverse effects of traditional hematopoietic stem cell transplantation, and low-dose total-body irradiation (TBI) is administered over a short period prior to RIST (TBI-RIST). Different institutes adopt different approaches for the administration of TBI-RIST, and since no study had previously investigated this issue, a survey of the TBI schedules in Japan was conducted. In October 2015, the Japanese Radiation Oncology Study Group initiated a national survey of TBI-RIST procedures conducted between 2010 and 2014. Of 186 institutions performing TBI, 90 (48%) responded to the survey, 78 of which performed TBI-RIST. Of 2488 patients who underwent TBI for malignant disease at these institutions, 1412 (56.8%) patients were treated for leukemia, 477 (19.2%) for malignant lymphoma, 453 (18.2) for myelodysplastic syndrome, 44 (1.8%) for multiple myeloma, and 102 (4.1%) for other malignant diseases. Further, 206 (52.0%) of 396 patients (a high proportion of patients) who underwent TBI for benign disease had aplastic anemia. The TBI-RIST equipment and treatment methods were similar to those used for myeloablative regimens. Routinely shielded organs included the lungs (43.6%), eyes (50.0%) and kidneys (10.2%). The ovaries (14.1%), thyroid (6.4%) and testicles (16.7%) were also frequently shielded, possibly reflecting an emphasis on shielding reproductive organs in children. TBI-RIST was performed more frequently than myeloablative conditioning in patients with benign disease. Genital and thyroid shielding were applied more frequently in patients treated with TBI-RIST than in patients treated with myeloablative conditioning. In conclusion, this study indicates the status of TBI-RIST in Japan and can assist future efforts to standardize TBI-RIST treatment methods and to design a future multicenter collaborative research study., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Small cell carcinoma of the bladder is extremely rare, accounting for <1% of all malignant tumours in the urinary tract. Thus, no standard therapy modality for this malignancy has been established. This study aimed to retrospectively analyse the clinical outcomes associated with definitive radiotherapy for small cell carcinoma of the bladder. A questionnaire-based survey of patients with pathologically proven small cell carcinoma of the bladder treated with definitive radiation therapy between 1990 and 2010 was conducted by the Japanese Radiation Oncology Study Group. The clinical records of 12 eligible patients were collected from nine institutions. The median age of the patients was 70.5 years (range: 44-87 years), and the median follow-up period was 27.3 months (range: 3.3-117.8 months). The median prescribed dose was 60 Gy (range: 50.0-61.0 Gy), and a median of 2.0 Gy (range: 1.2-2.0 Gy) was administered per fraction. Systemic chemotherapy combined with radiotherapy was performed in eight cases (66.7%). The 3- and 5-year overall survival rates were 50.0% and 33.3%, respectively. And the 3- and 5-year local control rates were 66.7% and 55.6%, respectively. Chemotherapy significantly improved overall survival and relapse-free survival (P = 0.006 and 0.001, respectively). No serious adverse events occurred in the observation period. All patients who achieved local control maintained functional bladders. In conclusion, radiotherapy is a potential local treatment option and has an important role in maintaining quality of life. Systemic chemotherapy combined with local radiotherapy seems to be effective in improving survival., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: To compare patient preferences and acute adverse events of hypofractionated (HF) and conventionally fractionated (CF) whole-breast irradiation (WBI) after breast-conserving surgery in our institution., Methods: We conducted a patient preference study comparing CF-WBI (50 Gy/25 fractions) and HF-WBI (41.6 Gy/16 fractions) after breast-conserving surgery. Eligible patients selected either type of fractionation following an explanation from the radiation oncologist. In this report, we analyzed the selection rate and acute toxicities., Results: Between June 2009 and December 2013, 348 patients (349 breasts) were identified as eligible for the study. Among them, 259 patients (260 breasts [74.5%]) selected CF-WBI and 89 patients (89 breasts [25.5%]) selected HF-WBI. Factors significantly associated with the selection of HF-WBI were older age (P = 0.028) and no adjuvant chemotherapy (P = 0.041). Regarding acute adverse events, Grade 2 (G2) or higher radiation dermatitis was less frequently observed in HF-WBI than in CF-WBI (13.8% vs. 29.4%; P = 0.004). In addition, G2 or higher breast pain was only observed in the CF-WBI group (6.9%; P = 0.012). There were no significant differences in the presence of fatigue, wound pain or radiation pneumonitis of G2 or higher between the groups., Conclusions: In this study, in which patients themselves selected the irradiation method, more patients tended to select CF-WBI. The frequency of G2 or higher dermatitis and breast pain was significantly lower in the HF-WBI group than in the CF-WBI group. Our results support the evidence for recommending HF-WBI after breast-conserving surgery while presenting aspects of patient preferences., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The selection of radiation therapy dose fractionation schedules for bone metastases is often based on the estimation of life expectancy. Therefore, accurate prognosis prediction is an important issue. It is reported that the Katagiri scoring system can be used to predict the survival of patients with bone metastases. We aimed to assess prognostic factors and validate the Katagiri scoring system in patients who were treated with radiation therapy for bone metastases., Materials/methods: We retrospectively reviewed data of all patients who were treated with radiation therapy for bone metastases between 2004 and 2013. Age, sex, Karnofsky performance status (KPS), Eastern Cooperative Oncology Group performance status (ECOG PS), primary site (lesions and characteristics), visceral metastases, laboratory data, previous chemotherapy, and multiple bone metastases were analyzed for associations with overall survival (OS). Katagiri scores were calculated for each patient and were used to compare OS., Results: Out of the 616 patients included in this analysis, 574 had died and 42 remained alive. The median follow-up time for survivors was 42 months. Univariate analysis revealed that age (P = 0.604) and multiple bone metastases (P = 0.691) were not significantly associated with OS. Multivariate analysis revealed that sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significantly associated with OS. The survival rates at 3, 6, 12, and 24 months, categorized by Katagiri score, were as follows: score 0-3, 94.4, 77.8, and 61.1%, respectively; score 4-6, 67.7, 48.7, and 31.2%, respectively; and score 7-10, 39.1, 22.1, and 9.0%, respectively (P < 0.001)., Conclusion: Sex, ECOG PS, KPS, primary characteristics, visceral metastases, laboratory data, and previous chemotherapy were significant predictors of survival in patients with bone metastases. The Katagiri scoring system was significantly correlated with OS and can help us select the optimal dose-fractionation.

Aim: The present study aimed to examine the associations among behavioral and psychological symptoms of dementia (BPSD) of persons with dementia (PWD), care burden and family-to-work conflict (FWC) of employed family caregivers., Method: A cross-sectional study was carried out with employed adult daughter or son (or in-law) caregivers for PWD from two rural cities in Japan. FWC, care burden and the degree of BPSD were evaluated by the Survey Work-Home Interaction-NijmeGen, Zarit Burden Scale-Short Version and Dementia Behavior Disturbance Scale, respectively. Of the 200 questionnaires distributed, 130 were returned. A total of 53 respondents were not employed, and seven questionnaires had missing data for demographic variables, Survey Work-Home Interaction-NijmeGen, Zarit Burden Scale-Short Version or Dementia Behavior Disturbance Scale. Thus, complete data from 70 respondents were analyzed through structural equation modeling., Results: The mean age of employed family caregivers was 56 years, and 34 (48.5%) were men. The mean age of PWD was 84 years, and there were 68 (68.6%) men. The path model with a good fit was shown (root mean square error of approximation 0.136, comparative fit index 0.960 and goodness of fit index 0.965). The path model showed that BPSD affected FWC, and that the association was partially mediated by care burden., Conclusions: The results show that a decrease in not only care burden, but also BPSD, of PWD is important for employed family caregivers to reduce their FWC and maintain their work-life balance. Geriatr Gerontol Int 2019; 19: 51-55., (© 2018 Japan Geriatrics Society.)

Chlamydia trachomatis is an obligate intracellular bacterium that scavenges host metabolic products for its replication. Mitochondria are the power plants of eukaryotic cells and provide most of the cellular ATP via oxidative phosphorylation. Several intracellular pathogens target mitochondria as part of their obligatory cellular reprogramming. This study was designed to analyse the mitochondrial morphological changes in response to C. trachomatis infection in HeLa cells. Mitochondrial elongation and fragmentation were found at the early stages and late stages of C. trachomatis infection, respectively. C. trachomatis infection-induced mitochondrial elongation was associated with the increase of mitochondrial respiratory activity, ATP production, and intracellular growth of C. trachomatis. Silencing mitochondrial fusion mediator proteins abrogated the C. trachomatis infection-induced elevation in the oxygen consumption rate and attenuated chlamydial proliferation. Mechanistically, C. trachomatis induced the elevation of intracellular cAMP at the early phase of infection, followed by the phosphorylation of fission-inactive serine residue 637 (S637) of Drp1, resulting in mitochondrial elongation. Accordingly, treatment with adenylate cyclase inhibitor diminished mitochondrial elongation and bacterial growth in infected cells. Collectively, these results strongly indicate that C. trachomatis promotes its intracellular growth by targeting mitochondrial dynamics to regulate ATP synthesis via inhibition of the fission mediator Drp1., (© 2018 John Wiley & Sons Ltd.)

Purpose: In this paper, we report cases of two patients with vaginal tumor who underwent interstitial brachytherapy (ISBT), using three-dimensional (3D)-printed personalized templates designed inversely from computed tomography (CT) or magnetic resonance (MR) images., Material and Methods: Patient 1 presenting with vaginal vault recurrence was planned to receive whole pelvis external beam radiotherapy (EBRT) followed by ISBT. The tumor invaded the paracolpium; thus, we planned to administer ISBT to include the tumor and vaginal membrane. A template was designed with holes for plastic needle applicator insertion considering the appropriate direction based on pre-treatment medical images. Patient 2 presenting with vaginal cancer was scheduled to receive EBRT and ISBT because of a paracolpium invasion. Before ISBT, MR imaging was performed with vaginal cylinder inserted in the patient's vagina. By measuring the length of the tumor manually and projecting the tumor orthogonally to a plane parallel to the bottom surface of the cylinder applicator, a template was designed. Computer-aided design software was used for planning both templates. Polycarbonate/acrylonitrile-butadiene-styrene resin was selected as material of the templates., Results: Patient 1 received 4-fraction ISBT one week apart. A mean of 10 applicators were inserted through the holes of the template in an average of 9 minutes (range, 5-15 minutes). All applicators were inserted toward the planned directions. Median minimum dose covering 90% (D 90% ) of the clinical target volume (CTV) was 634 cGy. Patient 2 underwent three-fraction irradiation twice daily at 6-hour interval. All applicators were inserted through the inside of the template. The median D 90% of the CTV was 703 cGy. No grade 3 or higher toxicity were found in both series., Conclusions: 3D-printed templates designed using medical images are useful, especially for ISBT of vaginal tumors. Further verification of clinical indications, design of templates, and manufacturing process are needed., Competing Interests: Authors report no conflict of interest.

Background: The optimal therapeutic strategy for potentially resectable clinical (c-) stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. This phase II multiinstitutional study (West Japan Oncology Group 5308L) was designed to evaluate the feasibility of induction chemotherapy with concurrent thoracic radiotherapy (50 Gy), followed by resection and postoperative consolidation chemotherapy, in IIIA-N2 NSCLC., Methods: Patients with resectable c-stage IIIA-N2 were eligible, and pathologic confirmation of N2 disease was mandatory. Patients received chemotherapy consisting of weekly carboplatin plus paclitaxel with concurrent radiotherapy (50 Gy in 25 fractions). Unless disease progression was documented, patients underwent surgical resection, and thereafter received two courses of consolidation chemotherapy with carboplatin plus paclitaxel. The primary end point was the proportion of patients who achieved complete resection after induction chemoradiotherapy (R0 rate)., Results: From December 2011 to November 2013, 40 eligible patients were enrolled. All patients completed induction chemoradiotherapy with an overall response rate of 58%, and 32 patients achieved complete resection (R0 rate, 80%) mostly with lobectomy (n = 27). Twenty patients (50%) completed the study treatment, including postoperative chemotherapy. After the median follow-up period of 38 months, the progression-free survival, overall survival, and recurrence-free survival rates at 2 years were 63%, 75%, and 62%, respectively. The 30-day and 90-day mortality were 0%., Conclusions: Induction chemotherapy with concurrent radiotherapy (50 Gy), followed by resection, was a feasible and promising treatment option for resectable c-stage IIIA-N2 NSCLC., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies., Methods: JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy., Results: The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 ± 7.0 and 69.5 ± 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification., Conclusions: The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort.

This trial enrolls patients with untreated Hodgkin's lymphoma aged<20 years at diagnosis and examines the effects of omitting radiation therapy if the FDG-positron emission tomography (PET) findings after two completed cycles of combination chemotherapy are negative. It thereby aims to determine whether patients who truly require radiation therapy can be identified by FDG-PET. If so, this modality could be used to omit radiation therapy for all other patients, decreasing the risk of serious long-term complications without affecting survival rates. The outcomes of patients for whom FDG-PET is used to assess early treatment response will also be determined., Competing Interests: No potential conflict of interest relevant to this article was reported.

A myeloablative regimen that includes total-body irradiation (TBI) before hematopoietic stem cell transplantation results in higher patient survival rates than achieved with regimens without TBI. The TBI protocol, however, varies between institutions. In October 2015, the Japanese Radiation Oncology Study Group initiated a national survey of myeloablative TBI (covering 2010-2014). Among the 186 Japanese institutions performing TBI, 90 (48%) responded. The 82 institutions that had performed myeloablative TBI during this period treated 2698 patients with malignant disease [leukemia (2082 patients, 77.2%), malignant lymphoma (378, 14%)] and 37 with non-malignant disease [severe aplastic anemia (20, 54%), inborn errors of metabolism (5, 14%)]. A linear accelerator was used at all institutions. The institutions were divided into 41 large and 41 small institutions based on the median number of patients. The long source-surface distance technique was the method of choice in the 34 institutions (82.9%) and the moving-couch technique in the 7 (17.1%) in the large institutions. The schedules most routinely used by the participating institutions consisted of 12 Gy/6 fractions/3 days (26 institutions, 63.5%) in the large institutions. The dose rate varied from 5 to 26 cGy/min. The lungs and lenses were routinely shielded in 23 large institutions (56.1%), and only the lungs in 9 large institutions (21.9%). At lung-shielding institutions, the most frequent maximum acceptable total dose for the lungs was 8 Gy (19 institutions, 27.5%). Our results reveal considerable differences in the TBI methods used by Japanese institutions and thus the challenges in designing multicenter randomized trials based on TBI.

Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Highly monodisperse amorphous manganese oxide (MnO x ) nanospheres with diameter of ca. 300nm have been obtained from ammonia aqueous solution of KMnO 4 at room temperature. The amorphous MnO x nanospheres successfully converted to monodisperse K-OMS-2 (cryptomelane) and K-OMS-2/Mn 2 O 3 nanoraspberries through calcination process at 600 and 800°C, respectively. Analyzing the structure of such amorphous MnO x has been a challenge because fewer reports are available to examine amorphous structure. Thus, shape, crystallinity, and structure of the amorphous and crystalline MnO x nanostructures were characterized in detail by X-ray diffraction (XRD), thermogravimetry/differential thermal analysis (TG/DTA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, X-ray Photoelectron Spectroscopy (XPS), and energy dispersive spectroscopy (EDS). We discussed a plausible formation mechanism of amorphous MnO x nanospheres based on the investigations. The obtained MnO x nanostructures have been demonstrated to possess oxidative degradation ability of Rhodamine B (RhB) under acidic aqueous condition without any additives such as chemical oxidizing agents and UV and/or visible light irradiation. RhB degradation rate of amorphous MnO x nanospheres was about one hundred times faster than that of K-OMS-2 nanoraspberries., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fatty acid-binding protein 4 (FABP4), a cytosolic lipid chaperone predominantly expressed in adipocytes and macrophages, modulates lipid fluxes, trafficking, signaling, and metabolism. Recent studies have demonstrated that FABP4 regulates metabolic and inflammatory pathways, and in mouse models its inhibition can improve type 2 diabetes mellitus and atherosclerosis. However, the role of FABP4 in bacterial infection, metabolic crosstalk between host and pathogen, and bacterial pathogenesis have not been studied. As an obligate intracellular pathogen, Chlamydia pneumoniae needs to obtain nutrients such as ATP and lipids from host cells. Here, we show that C. pneumoniae successfully infects and proliferates in murine adipocytes by inducing hormone sensitive lipase (HSL)-mediated lipolysis. Chemical inhibition or genetic manipulation of HSL significantly abrogated the intracellular growth of C. pneumoniae in adipocytes. Liberated free fatty acids were utilized to generate ATP via β-oxidation, which C. pneumoniae usurped for its replication. Strikingly, chemical inhibition or genetic silencing of FABP4 significantly abrogated C. pneumoniae infection-induced lipolysis and mobilization of liberated FFAs, resulting in reduced bacterial growth in adipocytes. Collectively, these results demonstrate that C. pneumoniae exploits host FABP4 to facilitate fat mobilization and intracellular replication in adipocytes. This work uncovers a novel strategy used by intracellular pathogens for acquiring energy via hijacking of the host lipid metabolism pathway., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We previously reported in randomized controlled trials that maoto, a traditional herbal medicine, showed clinical and virological efficacy for seasonal influenza. In this study, a culturing system for influenza was used to test the effect of maoto. A549 cells in the culture were infected with influenza virus A (PR8) and followed after treatment with maoto; the virus titers in the culture supernatant, intracellular viral proteins, and viral RNA were determined. When infected cells were cultured with maoto for 24 hr, the virus titer and protein were significantly reduced compared with medium only. Other subtypes, A/H3N2, H1N1pdm, and B, were also inhibited by maoto. Proliferation of viral RNA in a 6 hr culture was inhibited by maoto in the early phase, especially in the first 30 min. Focusing on the entry step of the influenza virus, we found that endosomal pH, regulated by vacuolar-type H + ATPase (V-ATPase) located in the membrane, was increased when treated with maoto. We also found that uncoating of influenza viruses was also inhibited by maoto, resulting in the increase of the number of virus particles in endosomes. These results strongly suggest that the inhibition of endosomal acidification by maoto results in blocking influenza virus entry to cytoplasm, probably through the inhibition of V-ATPase. The present study provides evidence that supports the clinical use of maoto for the treatment of influenza.